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Physiology LINDA S. COSTANZO, PhD Professor of Physiology and Biophysics Virginia Commonwealth University School of Medicine Richmond, VirginiaWww.Medicalstudyzone.com SEVENTH EDITION
1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 PHYSIOLOGY SEVENTH EDITION ISBN: 978-0-323-47881-6 Copyright © 2018 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2021, 2010, 2006, 2002, and 1998. Library of Congress Cataloging-in-Publication Data Names: Costanzo, Linda S., 1947- author. Title: Physiology / Linda S. Costanzo. Other titles: Physiology (Elsevier) Description: Sixth edition. | Philadelphia, PA : Elsevier, [2018] | Includes index. Identifiers: LCCN 2017002153 | ISBN 9780323478816 (pbk.) Subjects: | MESH: Physiological Phenomena | Physiology Classification: LCC QP31.2 | NLM QT 104 | DDC 612–dc23 LC record available at https://lccn.loc.gov/2017002153 Executive Content Strategist: Elyse O’Grady Senior Content Development Specialist: Jennifer Ehlers Publishing Services Manager: Catherine Jackson Senior Project Manager: Daniel Fitzgerald Designer: Renee Duenow Cover image: Laguna Design/Nerve Cell, abstract artwork/Getty Images Printed in China. Last digit is the print number: 9 8 7 6 5 4 3 2 1Www.Medicalstudyzone.com
To Heinz Valtin and Arthur C. Guyton, who have written so well for students of physiology Richard, Dan, Rebecca, Sheila, Elise, and Max, who make everything worthwhileWww.Medicalstudyzone.com
vii Preface Physiology is the foundation of medical practice. A firm grasp of its principles is essential for the medical student and the practicing physician. This book is intended for students of medicine and related disciplines who are engaged in the study of physiology. It can be used either as a companion to lectures and syllabi in discipline-based curricula or as a primary source in integrated or problem-based curricula. For advanced students, the book can serve as a reference in pathophysiology courses and in clinical clerkships. In the sixth edition of this book, as in the previous editions, the important concepts in physiology are covered at the organ system and cellular levels. Chapters 1 and 2 present the underlying principles of cellular physiology and the autonomic nervous system. Chapters 3 through 10 present the major organ systems: neurophysiology and cardiovascular, respiratory, renal, acid-base, gastrointestinal, endocrine, and reproduc- tive physiology. The relationships between organ systems are emphasized to underscore the integrative mechanisms for homeostasis. This edition includes the following features designed to facilitate the study of physiology: ♦ Text that is easy to read and concise: Clear headings orient the student to the orga- nization and hierarchy of the material. Complex physiologic information is presented systematically, logically, and in a stepwise manner. When a process occurs in a specific sequence, the steps are numbered in the text and often correlate with numbers shown in a companion figure. Bullets are used to separate and highlight the features of a process. Rhetorical questions are posed throughout the text to anticipate the questions that students may be asking; by first contemplating and then answering these questions, students learn to explain difficult concepts and rationalize unexpected or paradoxical findings. Chapter summaries provide a brief overview. ♦ Tables and illustrations that can be used in concert with the text or, because they are designed to stand alone, as a review: The tables summarize, organize, and make comparisons. Examples are (1) a table that compares the gastrointestinal hormones with respect to hormone family, site of and stimuli for secretion, and hormone actions; (2) a table that compares the pathophysiologic features of disorders of Ca2+ homeostasis; and (3) a table that compares the features of the action potential in different cardiac tissues. The illustrations are clearly labeled, often with main headings, and include simple diagrams, complex diagrams with numbered steps, and flow charts. ♦ Equations and sample problems that are integrated into the text: All terms and units in equations are defined, and each equation is restated in words to place it in a physiologic context. Sample problems are followed by complete numerical solutions and explanations that guide students through the proper steps in reasoning; by fol- lowing the steps provided, students acquire the skills and confidence to solve similar or related problems. ♦ Clinical physiology presented in boxes: Each box features a fictitious patient with a classic disorder. The clinical findings and proposed treatment are explained in terms of underlying physiologic principles. An integrative approach to the patient is used to emphasize the relationships between organ systems. For example, the case of type I diabetes mellitus involves a disorder not only of the endocrine system but also of the renal, acid-base, respiratory, and cardiovascular systems.Www.Medicalstudyzone.com
viii • Preface ♦ Practice questions in “Challenge Yourself” sections at the end of each chapter: Practice questions, which are designed for short answers (a word, a phrase, or a numerical solution), challenge the student to apply principles and concepts in problem solving rather than to recall isolated facts. The questions are posed in varying formats and are given in random order. They will be most helpful when used as a tool after studying each chapter and without referring to the text. In that way, the student can confirm his or her understanding of the material and can determine areas of weakness. Answers are provided at the end of the book. ♦ Teaching videos on selected topics: Because stu- dents may benefit from oral explanation of complex principles, brief teaching videos on selected topics are included to complement the written text. ♦ Abbreviations and normal values presented in appendices: As students refer to and use these common abbreviations and values throughout the book, they will find that their use becomes second nature. This book embodies three beliefs that I hold about teaching: (1) even complex information can be trans- mitted clearly if the presentation is systematic, logical, and stepwise; (2) the presentation can be just as effec- tive in print as in person; and (3) beginning medical students wish for nonreference teaching materials that are accurate and didactically strong but without the details that primarily concern experts. In essence, a book can “teach” if the teacher’s voice is present, if the material is carefully selected to include essential infor- mation, and if great care is given to logic and sequence. This text offers a down-to-earth and professional pre- sentation written to students and for students. I hope that the readers of this book enjoy their study of physiology. Those who learn its principles well will be rewarded throughout their professional careers! Linda S. CostanzoWww.Medicalstudyzone.com
ix Acknowledgments I gratefully acknowledge the contributions of Elyse O’Grady, Jennifer Ehlers, and Dan Fitzgerald at Elsevier in preparing the sixth edition of Physiology. The artist, Matthew Chansky, revised existing figures and created new figures—all of which beautifully complement the text. Colleagues at Virginia Commonwealth University have faithfully answered my ques- tions, especially Drs. Clive Baumgarten, Diomedes Logothetis, Roland Pittman, and Raphael Witorsch. Sincere thanks also go to the medical students worldwide who have generously written to me about their experiences with earlier editions of the book. My husband, Richard; our children, Dan and Rebecca; our daughter-in-law, Sheila; and our grandchildren, Elise and Max, have provided enthusiastic support and unquali- fied love, which give the book its spirit.Www.Medicalstudyzone.com
1 CHAPTER 1 Cellular Physiology Volume and Composition of Body Fluids, 1 Characteristics of Cell Membranes, 4 Transport Across Cell Membranes, 5 Diffusion Potentials and Equilibrium Potentials, 14 Resting Membrane Potential, 18 Action Potentials, 19 Synaptic and Neuromuscular Transmission, 26 Skeletal Muscle, 34 Smooth Muscle, 40 Summary, 43 Challenge Yourself, 44 Understanding the functions of the organ systems requires profound knowledge of basic cellular mecha- nisms. Although each organ system differs in its overall function, all are undergirded by a common set of physi- ologic principles. The following basic principles of physiology are introduced in this chapter: body fluids, with particular emphasis on the differences in composition of intracel- lular fluid and extracellular fluid; creation of these concentration differences by transport processes in cell membranes; the origin of the electrical potential differ- ence across cell membranes, particularly in excitable cells such as nerve and muscle; generation of action potentials and their propagation in excitable cells; transmission of information between cells across syn- apses and the role of neurotransmitters; and the mechanisms that couple the action potentials to con- traction in muscle cells. These principles of cellular physiology constitute a set of recurring and interlocking themes. Once these principles are understood, they can be applied and integrated into the function of each organ system. VOLUME AND COMPOSITION OF BODY FLUIDS Distribution of Water in the Body Fluid Compartments In the human body, water constitutes a high proportion of body weight. The total amount of fluid or water is called total body water, which accounts for 50% to 70% of body weight. For example, a 70-kilogram (kg) man whose total body water is 65% of his body weight has 45.5 kg or 45.5 liters (L) of water (1 kg water ≈ 1 L water). In general, total body water correlates inversely with body fat. Thus total body water is a higher percentage of body weight when body fat is low and a lower percentage when body fat is high. Because females have a higher percentage of adipose tissue than males, they tend to have less body water. The distribution of water among body fluid compart- ments is described briefly in this chapter and in greater detail in Chapter 6. Total body water is distributed between two major body fluid compartments: intracel- lular fluid (ICF) and extracellular fluid (ECF) (Fig. 1.1). The ICF is contained within the cells and is two-thirds of total body water; the ECF is outside the cells and is one-third of total body water. ICF and ECF are separated by the cell membranes. ECF is further divided into two compartments: plasma and interstitial fluid. Plasma is the fluid circulating in the blood vessels and is the smaller of the two ECFWww.Medicalstudyzone.com
2 • Physiology equivalent of chloride (Cl−). Likewise, one mole of calcium chloride (CaCl2) in solution dissociates into two equivalents of calcium (Ca2+) and two equivalents of chloride (Cl−); accordingly, a Ca2+ concentration of 1 mmol/L corresponds to 2 mEq/L. One osmole is the number of particles into which a solute dissociates in solution. Osmolarity is the con- centration of particles in solution expressed as osmoles per liter. If a solute does not dissociate in solution (e.g., glucose), then its osmolarity is equal to its molarity. If a solute dissociates into more than one particle in solution (e.g., NaCl), then its osmolarity equals the molarity multiplied by the number of particles in solu- tion. For example, a solution containing 1 mmol/L NaCl is 2 mOsm/L because NaCl dissociates into two particles. pH is a logarithmic term that is used to express hydrogen (H+) concentration. Because the H+ concen- tration of body fluids is very low (e.g., 40 × 10−9 Eq/L in arterial blood), it is more conveniently expressed as a logarithmic term, pH. The negative sign means that pH decreases as the concentration of H+ increases, and pH increases as the concentration of H+ decreases. Thus pH H= − + log [ ]10 subcompartments. Interstitial fluid is the fluid that actually bathes the cells and is the larger of the two subcompartments. Plasma and interstitial fluid are separated by the capillary wall. Interstitial fluid is an ultrafiltrate of plasma, formed by filtration processes across the capillary wall. Because the capillary wall is virtually impermeable to large molecules such as plasma proteins, interstitial fluid contains little, if any, protein. The method for estimating the volume of the body fluid compartments is presented in Chapter 6. Composition of Body Fluid Compartments The composition of the body fluids is not uniform. ICF and ECF have vastly different concentrations of various solutes. There are also certain predictable differences in solute concentrations between plasma and interstitial fluid that occur as a result of the exclusion of protein from interstitial fluid. Units for Measuring Solute Concentrations Typically, amounts of solute are expressed in moles, equivalents, or osmoles. Likewise, concentrations of solutes are expressed in moles per liter (mol/L), equivalents per liter (Eq/L), or osmoles per liter (Osm/L). In biologic solutions, concentrations of solutes are usually quite low and are expressed in millimoles per liter (mmol/L), milliequivalents per liter (mEq/L), or milliosmoles per liter (mOsm/L). One mole is 6 × 1023 molecules of a substance. One millimole is 1/1000 or 10−3 moles. A glucose concentra- tion of 1 mmol/L has 1 × 10−3 moles of glucose in 1 L of solution. An equivalent is used to describe the amount of charged (ionized) solute and is the number of moles of the solute multiplied by its valence. For example, one mole of potassium chloride (KCl) in solution dis- sociates into one equivalent of potassium (K+) and one TOTAL BODY WATER Intracellular fluid Extracellular fluid Cell membrane Capillary wall Interstitial fluid Plasma Fig. 1.1 Body fluid compartments. SAMPLE PROBLEM. Two men, Subject A and Subject B, have disorders that cause excessive acid production in the body. The laboratory reports the acidity of Subject A’s blood in terms of [H+] and the acidity of Subject B’s blood in terms of pH. Subject A has an arterial [H+] of 65 × 10−9 Eq/L, and Subject B has an arterial pH of 7.3. Which subject has the higher concentration of H+ in his blood? SOLUTION. To compare the acidity of the blood of each subject, convert the [H+] for Subject A to pH as follows: pH H Eq/L Eq/L = − = − × = − × + − − log [ ] log ( ) log ( . ) log 10 10 9 10 8 1 65 10 6 5 10 00 10 8 10 8 6 5 0 81 10 8 0 6 5 10 0 81 8 0 7 19 . . log . log . . ( . ) . = = − × = + − = − = − − pH −− − =( . ) .7 19 7 19 Thus Subject A has a blood pH of 7.19 computed from the [H+], and Subject B has a reported blood pH of 7.3. Subject A has a lower blood pH, reflecting a higher [H+] and a more acidic condition. Electroneutrality of Body Fluid Compartments Each body fluid compartment must obey the principle of macroscopic electroneutrality; that is, eachWww.Medicalstudyzone.com
1—Cellular Physiology • 3 Creation of Concentration Differences Across Cell Membranes The differences in solute concentration across cell membranes are created and maintained by energy- consuming transport mechanisms in the cell membranes. The best known of these transport mechanisms is the Na+-K+ ATPase (Na+-K+ pump), which transports Na+ from ICF to ECF and simultaneously transports K+ from ECF to ICF. Both Na+ and K+ are transported against their respective electrochemical gradients; therefore an energy source, adenosine triphosphate (ATP), is required. The Na+-K+ ATPase is responsible for creating the large concentration gradients for Na+ and K+ that exist across cell membranes (i.e., the low intracellular Na+ concentration and the high intracel- lular K+ concentration). Similarly, the intracellular Ca2+ concentration is maintained at a level much lower than the extracellular Ca2+ concentration. This concentration difference is established, in part, by a cell membrane Ca2+ ATPase that pumps Ca2+ against its electrochemical gradient. Like the Na+-K+ ATPase, the Ca2+ ATPase uses ATP as a direct energy source. In addition to the transporters that use ATP directly, other transporters establish concentration differences across the cell membrane by utilizing the transmem- brane Na+ concentration gradient (established by the Na+-K+ ATPase) as an energy source. These transporters create concentration gradients for glucose, amino acids, Ca2+, and H+ without the direct utilization of ATP. Clearly, cell membranes have the machinery to establish large concentration gradients. However, if cell membranes were freely permeable to all solutes, these gradients would quickly dissipate. Thus it is critically important that cell membranes are not freely permeable to all substances but, rather, have selec- tive permeabilities that maintain the concentration gradients established by energy-consuming transport processes. Directly or indirectly, the differences in composition between ICF and ECF underlie every important physi- ologic function, as the following examples illustrate: (1) The resting membrane potential of nerve and muscle critically depends on the difference in concentration of K+ across the cell membrane; (2) The upstroke of the action potential of these same excitable cells depends on the differences in Na+ concentration across the cell membrane; (3) Excitation-contraction coupling in muscle cells depends on the differences in Ca2+ concen- tration across the cell membrane and the membrane of the sarcoplasmic reticulum (SR); and (4) Absorption of essential nutrients depends on the transmembrane Na+ concentration gradient (e.g., glucose absorption in the small intestine or glucose reabsorption in the renal proximal tubule). compartment must have the same concentration, in mEq/L, of positive charges (cations) as of negative charges (anions). There can be no more cations than anions, or vice versa. Even when there is a potential difference across the cell membrane, charge balance still is maintained in the bulk (macroscopic) solutions. (Because potential differences are created by the sepa- ration of just a few charges adjacent to the membrane, this small separation of charges is not enough to measurably change bulk concentrations.) Composition of Intracellular Fluid and Extracellular Fluid The compositions of ICF and ECF are strikingly differ- ent, as shown in Table 1.1. The major cation in ECF is sodium (Na+), and the balancing anions are chloride (Cl−) and bicarbonate (HCO3−). The major cations in ICF are potassium (K+) and magnesium (Mg2+), and the balancing anions are proteins and organic phosphates. Other notable differences in composition involve Ca2+ and pH. Typically, ICF has a very low concentration of ionized Ca2+ (≈10−7 mol/L), whereas the Ca2+ concentra- tion in ECF is higher by approximately four orders of magnitude. ICF is more acidic (has a lower pH) than ECF. Thus substances found in high concentration in ECF are found in low concentration in ICF, and vice versa. Remarkably, given all of the concentration differ- ences for individual solutes, the total solute concentra- tion (osmolarity) is the same in ICF and ECF. This equality is achieved because water flows freely across cell membranes. Any transient differences in osmolar- ity that occur between ICF and ECF are quickly dissi- pated by water movement into or out of cells to reestablish the equality. TABLE 1.1 Approximate Compositions of Extracellular and Intracellular Fluids Substance and Units Extracellular Fluid Intracellular Fluida Na+ (mEq/L) 140 14 K+ (mEq/L) 4 120 Ca2+, ionized (mEq/L) 2.5b 1 × 10−4 Cl− (mEq/L) 105 10 HCO3− (mEq/L) 24 10 pHc 7.4 7.1 Osmolarity (mOsm/L) 290 290 aThe major anions of intracellular fluid are proteins and organic phosphates. bThe corresponding total [Ca2+] in extracellular fluid is 5 mEq/L or 10 mg/dL. cpH is −log10 of the [H+]; pH 7.4 corresponds to [H+] of 40 × 10−9 Eq/L.Www.Medicalstudyzone.com
4 • Physiology Phospholipid Component of Cell Membranes Phospholipids consist of a phosphorylated glycerol backbone (“head”) and two fatty acid “tails” (Fig. 1.2). The glycerol backbone is hydrophilic (water soluble), and the fatty acid tails are hydrophobic (water insolu- ble). Thus phospholipid molecules have both hydro- philic and hydrophobic properties and are called amphipathic. At an oil-water interface (see Fig. 1.2A), molecules of phospholipids form a monolayer and orient themselves so that the glycerol backbone dis- solves in the water phase and the fatty acid tails dis- solve in the oil phase. In cell membranes (see Fig. 1.2B), phospholipids orient so that the lipid-soluble fatty acid tails face each other and the water-soluble glycerol heads point away from each other, dissolving in the aqueous solutions of the ICF or ECF. This orienta- tion creates a lipid bilayer. Protein Component of Cell Membranes Proteins in cell membranes may be either integral or peripheral, depending on whether they span the mem- brane or whether they are present on only one side. The distribution of proteins in a phospholipid bilayer is illustrated in the fluid mosaic model, shown in Figure 1.3. ♦ Integral membrane proteins are embedded in, and anchored to, the cell membrane by hydrophobic interactions. To remove an integral protein from the cell membrane, its attachments to the lipid bilayer must be disrupted (e.g., by detergents). Some inte- gral proteins are transmembrane proteins, meaning they span the lipid bilayer one or more times; thus Concentration Differences Between Plasma and Interstitial Fluids As previously discussed, ECF consists of two subcom- partments: interstitial fluid and plasma. The most sig- nificant difference in composition between these two compartments is the presence of proteins (e.g., albumin) in the plasma compartment. Plasma proteins do not readily cross capillary walls because of their large molecular size and therefore are excluded from inter- stitial fluid. The exclusion of proteins from interstitial fluid has secondary consequences. The plasma proteins are negatively charged, and this negative charge causes a redistribution of small, permeant cations and anions across the capillary wall, called a Gibbs-Donnan equil- ibrium. The redistribution can be explained as follows: The plasma compartment contains the impermeant, negatively charged proteins. Because of the requirement for electroneutrality, the plasma compartment must have a slightly lower concentration of small anions (e.g., Cl−) and a slightly higher concentration of small cations (e.g., Na+ and K+) than that of interstitial fluid. The small concentration difference for permeant ions is expressed in the Gibbs-Donnan ratio, which gives the plasma concentration relative to the interstitial fluid concentration for anions and interstitial fluid relative to plasma for cations. For example, the Cl− concentration in plasma is slightly less than the Cl− concentration in interstitial fluid (due to the effect of the impermeant plasma proteins); the Gibbs-Donnan ratio for Cl− is 0.95, meaning that [Cl−]plasma/[Cl−]interstitial fluid equals 0.95. For Na+, the Gibbs-Donnan ratio is also 0.95, but Na+, being positively charged, is oriented the opposite way, and [Na+]interstitial fluid/[Na+]plasma equals 0.95. Generally, these minor differences in concentration for small cations and anions between plasma and interstitial fluid are ignored. CHARACTERISTICS OF CELL MEMBRANES Cell membranes are composed primarily of lipids and proteins. The lipid component consists of phospholip- ids, cholesterol, and glycolipids and is responsible for the high permeability of cell membranes to lipid-soluble substances such as carbon dioxide, oxygen, fatty acids, and steroid hormones. The lipid component of cell membranes is also responsible for the low permeability of cell membranes to water-soluble substances such as ions, glucose, and amino acids. The protein component of the membrane consists of transporters, enzymes, hormone receptors, cell-surface antigens, and ion and water channels. Water A Water Water Oil B Fig. 1.2 Orientation of phospholipid molecules at oil and water interfaces. Depicted are the orientation of phospholipid at an oil-water interface (A) and the orientation of phospholipid in a bilayer, as occurs in the cell membrane (B).Www.Medicalstudyzone.com
1—Cellular Physiology • 5 hydrogen bonds. One example of a peripheral mem- brane protein is ankyrin, which “anchors” the cytoskeleton of red blood cells to an integral mem- brane transport protein, the Cl−-HCO3− exchanger (also called band 3 protein). TRANSPORT ACROSS CELL MEMBRANES Several types of mechanisms are responsible for trans- port of substances across cell membranes (Table 1.2). Substances may be transported down an electro- chemical gradient (downhill) or against an electro- chemical gradient (uphill). Downhill transport occurs by diffusion, either simple or facilitated, and requires no input of metabolic energy. Uphill transport occurs by active transport, which may be primary or second- ary. Primary and secondary active transport processes transmembrane proteins are in contact with both ECF and ICF. Examples of transmembrane integral proteins are ligand-binding receptors (e.g., for hor- mones or neurotransmitters), transport proteins (e.g., Na+-K+ ATPase), pores, ion channels, cell adhesion molecules, and GTP-binding proteins (G proteins). A second category of integral proteins is embedded in the lipid bilayer of the membrane but does not span it. A third category of integral proteins is associated with membrane proteins but is not embedded in the lipid bilayer. ♦ Peripheral membrane proteins are not embedded in the membrane and are not covalently bound to cell membrane components. They are loosely attached to either the intracellular or extracellular side of the cell membrane by electrostatic interac- tions (e.g., with integral proteins) and can be removed with mild treatments that disrupt ionic or Lipid bilayer Intracellular fluid Peripheral protein Integral protein Gated ion channel Extracellular fluid Fig. 1.3 Fluid mosaic model for cell membranes. TABLE 1.2 Summary of Membrane Transport Type of Transport Active or Passive Carrier- Mediated Uses Metabolic Energy Dependent on Na+ Gradient Simple diffusion Passive; downhill No No No Facilitated diffusion Passive; downhill Yes No No Primary active transport Active; uphill Yes Yes; direct No Cotransport Secondary activea Yes Yes; indirect Yes (solutes move in same direction as Na+ across cell membrane) Countertransport Secondary activea Yes Yes; indirect Yes (solutes move in opposite direction as Na+ across cell membrane) aNa+ is transported downhill, and one or more solutes are transported uphill.Www.Medicalstudyzone.com
6 • Physiology ♦ Stereospecificity. The binding sites for solute on the transport proteins are stereospecific. For example, the transporter for glucose in the renal proximal tubule recognizes and transports the natural isomer D-glucose, but it does not recognize or transport the unnatural isomer L-glucose. In contrast, simple dif- fusion does not distinguish between the two glucose isomers because no protein carrier is involved. ♦ Competition. Although the binding sites for trans- ported solutes are quite specific, they may recognize, bind, and even transport chemically related solutes. For example, the transporter for glucose is specific for D-glucose, but it also recognizes and transports a closely related sugar, D-galactose. Therefore the presence of D-galactose inhibits the transport of D-glucose by occupying some of the binding sites and making them unavailable for glucose. Simple Diffusion Diffusion of Nonelectrolytes Simple diffusion occurs as a result of the random thermal motion of molecules, as shown in Figure 1.5. Two solutions, A and B, are separated by a membrane that is permeable to the solute. The solute concentra- tion in A is initially twice that of B. The solute molecules are in constant motion, with equal probability that a given molecule will cross the membrane to the other solution. However, because there are twice as many solute molecules in Solution A as in Solution B, there will be greater movement of molecules from A to B than from B to A. In other words, there will be net diffusion of the solute from A to B, which will continue until the solute concentrations of the two solutions become equal (although the random movement of molecules will go on forever). are distinguished by their energy source. Primary active transport requires a direct input of metabolic energy; secondary active transport utilizes an indirect input of metabolic energy. Further distinctions among transport mechanisms are based on whether the process involves a protein carrier. Simple diffusion is the only form of transport that is not carrier mediated. Facilitated diffusion, primary active transport, and secondary active trans- port all involve integral membrane proteins and are called carrier-mediated transport. All forms of carrier- mediated transport share the following three features: saturation, stereospecificity, and competition. ♦ Saturation. Saturability is based on the concept that carrier proteins have a limited number of binding sites for the solute. Figure 1.4 shows the relationship between the rate of carrier-mediated transport and solute concentration. At low solute concentrations, many binding sites are available and the rate of transport increases steeply as the concentration increases. However, at high solute concentrations, the available binding sites become scarce and the rate of transport levels off. Finally, when all of the binding sites are occupied, saturation is achieved at a point called the transport maximum, or Tm. The kinetics of carrier-mediated transport are similar to Michaelis-Menten enzyme kinetics—both involve proteins with a limited number of binding sites. (The Tm is analogous to the Vmax of enzyme kinetics.) Tm-limited glucose transport in the proximal tubule of the kidney is an example of saturable transport. Concentration Transport rate Simple diffusion Carrier-mediated transport Tm Fig. 1.4 Kinetics of carrier-mediated transport. Tm, Trans- port maximum. Membrane A B Fig. 1.5 Simple diffusion. The two solutions, A and B, are separated by a membrane, which is permeable to the solute (circles). Solution A initially contains a higher concentration of the solute than does Solution B.Www.Medicalstudyzone.com
1—Cellular Physiology • 7 THICKNESS OF THE MEMBRANE (ΔX) The thicker the cell membrane, the greater the distance the solute must diffuse and the lower the rate of diffusion. SURFACE AREA (A) The greater the surface area of membrane available, the higher the rate of diffusion. For example, lipid-soluble gases such as oxygen and carbon dioxide have particu- larly high rates of diffusion across cell membranes. These high rates can be attributed to the large surface area for diffusion provided by the lipid component of the membrane. To simplify the description of diffusion, several of the previously cited characteristics can be combined into a single term called permeability (P). Permeability includes the partition coefficient, the diffusion coeffi- cient, and the membrane thickness. Thus P KD x = ∆ By combining several variables into permeability, the rate of net diffusion is simplified to the following expression: J PA C CA B= −( ) where J Net rate of diffusion mmol/s P Permeability (cm/s A Surfa = = = ( ) ) cce area for diffusion cm C Concentration in Solution A (A ( )2 = mmmol/L) C Concentration in Solution B mmol/LB = ( ) Net diffusion of the solute is called flux, or flow (J), and depends on the following variables: size of the concentration gradient, partition coefficient, diffusion coefficient, thickness of the membrane, and surface area available for diffusion. CONCENTRATION GRADIENT (CA − CB) The concentration gradient across the membrane is the driving force for net diffusion. The larger the difference in solute concentration between Solution A and Solu- tion B, the greater the driving force and the greater the net diffusion. It also follows that, if the concentrations in the two solutions are equal, there is no driving force and no net diffusion. PARTITION COEFFICIENT (K) The partition coefficient, by definition, describes the solubility of a solute in oil relative to its solubility in water. The greater the relative solubility in oil, the higher the partition coefficient and the more easily the solute can dissolve in the cell membrane’s lipid bilayer. Nonpolar solutes tend to be soluble in oil and have high values for partition coefficient, whereas polar solutes tend to be insoluble in oil and have low values for partition coefficient. The partition coefficient can be measured by adding the solute to a mixture of olive oil and water and then measuring its concentration in the oil phase relative to its concentration in the water phase. Thus K Concentration in olive oil Concentration in water = DIFFUSION COEFFICIENT (D) The diffusion coefficient depends on such characteris- tics as size of the solute molecule and the viscosity of the medium. It is defined by the Stokes-Einstein equa- tion (see later). The diffusion coefficient correlates inversely with the molecular radius of the solute and the viscosity of the medium. Thus small solutes in nonviscous solutions have the largest diffusion coeffi- cients and diffuse most readily; large solutes in viscous solutions have the smallest diffusion coefficients and diffuse least readily. Thus D KT r = 6π η where D Diffusion coefficient K Boltzmann constant T Absolute temp = = = eerature K r Molecular radius Viscosity of the medium ( ) = =η SAMPLE PROBLEM. Solution A and Solution B are separated by a membrane whose permeability to urea is 2 × 10−5 cm/s and whose surface area is 1 cm2. The concentration of urea in A is 10 mg/mL, and the concentration of urea in B is 1 mg/mL. The partition coefficient for urea is 10−3, as measured in an oil-water mixture. What are the initial rate and direction of net diffusion of urea? SOLUTION. Note that the partition coefficient is extraneous information because the value for per- meability, which already includes the partition coefficient, is given. Net flux can be calculated by substituting the following values in the equation for net diffusion: Assume that 1 mL of water = 1 cm3. Thus J PA C CA B= −( )Www.Medicalstudyzone.com
8 • Physiology (In contrast, simple diffusion will proceed as long as there is a concentration gradient for the solute.) An excellent example of facilitated diffusion is the transport of D-glucose into skeletal muscle and adipose cells by the GLUT4 transporter. Glucose transport can proceed as long as the blood concentration of glucose is higher than the intracellular concentration of glucose and as long as the carriers are not saturated. Other monosaccharides such as D-galactose, 3-O-methyl glucose, and phlorizin competitively inhibit the trans- port of glucose because they bind to transport sites on the carrier. The competitive solute may itself be trans- ported (e.g., D-galactose), or it may simply occupy the binding sites and prevent the attachment of glucose (e.g., phlorizin). As noted previously, the nonphysio- logic stereoisomer, L-glucose, is not recognized by the carrier for facilitated diffusion and therefore is not bound or transported. Primary Active Transport In active transport, one or more solutes are moved against an electrochemical potential gradient (uphill). In other words, solute is moved from an area of low concentration (or low electrochemical potential) to an area of high concentration (or high electrochemical potential). Because movement of a solute uphill is work, metabolic energy in the form of ATP must be provided. In the process, ATP is hydrolyzed to adenos- ine diphosphate (ADP) and inorganic phosphate (Pi), releasing energy from the terminal high-energy phos- phate bond of ATP. When the terminal phosphate is released, it is transferred to the transport protein, initi- ating a cycle of phosphorylation and dephosphoryla- tion. When the ATP energy source is directly coupled to the transport process, it is called primary active transport. Three examples of primary active transport in physiologic systems are the Na+-K+ ATPase present in all cell membranes, the Ca2+ ATPase present in SR and endoplasmic reticulum, and the H+-K+ ATPase present in gastric parietal cells and renal α-intercalated cells. Na+-K+ ATPase (Na+-K+ Pump) Na+-K+ ATPase is present in the membranes of all cells. It pumps Na+ from ICF to ECF and K+ from ECF to ICF (Fig. 1.6). Each ion moves against its respective elec- trochemical gradient. The stoichiometry can vary but, typically, for every three Na+ ions pumped out of the cell, two K+ ions are pumped into the cell. This stoichi- ometry of three Na+ ions per two K+ ions means that, for each cycle of the Na+-K+ ATPase, more positive charge is pumped out of the cell than is pumped into the cell. Thus the transport process is termed electro- genic because it creates a charge separation and a potential difference. The Na+-K+ ATPase is responsible Diffusion of Electrolytes Thus far, the discussion concerning diffusion has assumed that the solute is a nonelectrolyte (i.e., it is uncharged). However, if the diffusing solute is an ion or an electrolyte, there are two additional consequences of the presence of charge on the solute. First, if there is a potential difference across the membrane, that potential difference will alter the net rate of diffusion of a charged solute. (A potential dif- ference does not alter the rate of diffusion of a nonelec- trolyte.) For example, the diffusion of K+ ions will be slowed if K+ is diffusing into an area of positive charge, and it will be accelerated if K+ is diffusing into an area of negative charge. This effect of potential difference can either add to or negate the effects of differences in concentrations, depending on the orientation of the potential difference and the charge on the diffusing ion. If the concentration gradient and the charge effect are oriented in the same direction across the membrane, they will combine; if they are oriented in opposite directions, they may cancel each other out. Second, when a charged solute diffuses down a concentration gradient, that diffusion can itself gener- ate a potential difference across a membrane called a diffusion potential. The concept of diffusion potential will be discussed more fully in a following section. Facilitated Diffusion Like simple diffusion, facilitated diffusion occurs down an electrochemical potential gradient; thus it requires no input of metabolic energy. Unlike simple diffusion, however, facilitated diffusion uses a membrane carrier and exhibits all the characteristics of carrier-mediated transport: saturation, stereospecificity, and competi- tion. At low solute concentration, facilitated diffusion typically proceeds faster than simple diffusion (i.e., is facilitated) because of the function of the carrier. However, at higher concentrations, the carriers will become saturated and facilitated diffusion will level off. where J cm/s cm mg/mL mg/mL J cm/s cm mg/ = × × × − = × × × − − 2 10 1 10 1 2 10 1 10 5 2 5 2 ( ) ( ccm mg/cm mg/s 3 3 4 1 1 8 10 − = × − ) . The magnitude of net flux has been calculated as 1.8 × 10−4 mg/s. The direction of net flux can be determine
1—Cellular Physiology • 9 glycosides inhibit the Na+-K+ ATPase by binding to the E2~P form near the K+-binding site on the extracellular side, thereby preventing the conversion of E2~P back to E1. By disrupting the cycle of phosphorylation- dephosphorylation, these drugs disrupt the entire enzyme cycle and its transport functions. Ca2+ ATPase (Ca2+ Pump) Most cell (plasma) membranes contain a Ca2+ ATPase, or plasma-membrane Ca2+ ATPase (PMCA), whose function is to extrude Ca2+ from the cell against an electrochemical gradient; one Ca2+ ion is extruded for each ATP hydrolyzed. PMCA is responsible, in part, for maintaining the very low intracellular Ca2+ concentra- tion. In addition, the sarcoplasmic reticulum (SR) of muscle cells and the endoplasmic reticulum of other cells contain variants of Ca2+ ATPase that pump two Ca2+ ions (for each ATP hydrolyzed) from ICF into the interior of the SR or endoplasmic reticulum (i.e., Ca2+ sequestration). These variants are called SR and endo- plasmic reticulum Ca2+ ATPase (SERCA). Ca2+ ATPase functions similarly to Na+-K+ ATPase, with E1 and E2 states that have, respectively, high and low affinities for Ca2+. For PMCA, the E1 state binds Ca2+ on the intracellular side, a conformational change to the E2 state occurs, and the E2 state releases Ca2+ to ECF. For SERCA, the E1 state binds Ca2+ on the intracellular side and the E2 state releases Ca2+ to the lumen of the SR or endoplasmic reticulum. H+-K+ ATPase (H+-K+ Pump) H+-K+ ATPase is found in the parietal cells of the gastric mucosa and in the α-intercalated cells of the renal collecting duct. In the stomach, it pumps H+ from the ICF of the parietal cells into the lumen of the stomach, where it acidifies the gastric contents. Omeprazole, an inhibitor of gastric H+-K+ ATPase, can be used thera- peutically to reduce the secretion of H+ in the treatment of some types of peptic ulcer disease. for maintaining concentration gradients for both Na+ and K+ across cell membranes, keeping the intracellular Na+ concentration low and the intracellular K+ concen- tration high. The Na+-K+ ATPase consists of α and β subunits. The α subunit contains the ATPase activity, as well as the binding sites for the transported ions, Na+ and K+. The Na+-K+ ATPase switches between two major con- formational states, E1 and E2. In the E1 state, the binding sites for Na+ and K+ face the ICF and the enzyme has a high affinity for Na+. In the E2 state, the binding sites for Na+ and K+ face the ECF and the enzyme has a high affinity for K+. The enzyme’s ion-transporting function (i.e., pumping Na+ out of the cell and K+ into the cell) is based on cycling between the E1 and E2 states and is powered by ATP hydrolysis. The transport cycle is illustrated in Figure 1.6. The cycle begins with the enzyme in the E1 state, bound to ATP. In the E1 state, the ion-binding sites face the ICF, and the enzyme has a high affinity for Na+; three Na+ ions bind, ATP is hydrolyzed, and the terminal phos- phate of ATP is transferred to the enzyme, producing a high-energy state, E1~P. Now, a major conformational change occurs, and the enzyme switches from E1~P to E2~P. In the E2 state, the ion-binding sites face the ECF, the affinity for Na+ is low, and the affinity for K+ is high. The three Na+ ions are released from the enzyme to ECF, two K+ ions are bound, and inorganic phosphate is released from E2. The enzyme now binds intracellular ATP, and another major conformational change occurs that returns the enzyme to the E1 state; the two K+ ions are released to ICF, and the enzyme is ready for another cycle. Cardiac glycosides (e.g., ouabain and digitalis) are a class of drugs that inhibits Na+-K+ ATPase. Treat- ment with this class of drugs causes certain predict- able changes in intracellular ionic concentration: The intracellular Na+ concentration will increase, and the intracellular K+ concentration will decrease. Cardiac ATPATP Extracellular fluidIntracellular fluid Extracellular fluidIntracellular fluid Cardiac glycosides 3Na+ Cardiac glycosides ADP + Pi ATP Na+ K+ 2K+ 3Na+ 2K+ E1 E1~P E2~P E2 Fig. 1.6 Na+-K+ pump of cell membranes. ADP, Adenosine diphosphate; ATP, adenosine tri- phosphate; E, Na+-K+ ATPase; E~P, phosphorylated Na+-K+ ATPase; Pi, inorganic phosphate.Www.Medicalstudyzone.com
10 • Physiology two specific recognition sites, one for Na+ ions and the other for glucose. When both Na+ and glucose are present in the lumen of the small intestine, they bind to the transporter. In this configuration, the cotransport protein rotates and releases both Na+ and glucose to the interior of the cell. (Subsequently, both solutes are transported out of the cell across the basolateral membrane—Na+ by the Na+-K+ ATPase and glucose by facilitated diffusion.) If either Na+ or glucose is missing from the intestinal lumen, the cotransporter cannot rotate. Thus both solutes are required, and neither can be transported in the absence of the other (Box 1.1). Finally, the role of the intestinal Na+-glucose cotrans- port process can be understood in the context of overall intestinal absorption of carbohydrates. Dietary carbo- hydrates are digested by gastrointestinal enzymes to an absorbable form, the monosaccharides. One of these monosaccharides is glucose, which is absorbed across the intestinal epithelial cells by a combination of Na+- glucose cotransport in the luminal membrane and facilitated diffusion of glucose in the basolateral mem- brane. Na+-glucose cotransport is the active step, allow- ing glucose to be absorbed into the blood against an electrochemical gradient. Countertransport Countertransport (antiport or exchange) is a form of secondary active transport in which solutes move in opposite directions across the cell membrane. Na+ moves into the cell on the carrier down its electrochemical gradient; the solutes that are countertransported or exchanged for Na+ move out of the cell. Countertrans- port is illustrated by Ca2+-Na+ exchange (Fig. 1.8) and by Na+-H+ exchange. As with cotransport, each process Secondary Active Transport Secondary active transport processes are those in which the transport of two or more solutes is coupled. One of the solutes, usually Na+, moves down its electro- chemical gradient (downhill), and the other solute moves against its electrochemical gradient (uphill). The downhill movement of Na+ provides energy for the uphill movement of the other solute. Thus metabolic energy, as ATP, is not used directly, but it is supplied indirectly in the Na+ concentration gradient across the cell membrane. (The Na+-K+ ATPase, utilizing ATP, creates and maintains this Na+ gradient.) The name secondary active transport therefore refers to the indi- rect utilization of ATP as an energy source. Inhibition of the Na+-K+ ATPase (e.g., by treatment with ouabain) diminishes the transport of Na+ from ICF to ECF, causing the intracellular Na+ concentration to increase and thereby decreasing the size of the trans- membrane Na+ gradient. Thus indirectly, all secondary active transport processes are diminished by inhibitors of the Na+-K+ ATPase because their energy source, the Na+ gradient, is diminished. There are two types of secondary active transport, distinguishable by the direction of movement of the uphill solute. If the uphill solute moves in the same direction as Na+, it is called cotransport, or symport. If the uphill solute moves in the opposite direction of Na+, it is called countertransport, antiport, or exchange. Cotransport Cotransport (symport) is a form of secondary active transport in which all solutes are transported in the same direction across the cell membrane. Na+ moves into the cell on the carrier down its electrochemical gradient; the solutes, cotransported with Na+, also move into the cell. Cotransport is involved in several critical physiologic processes, particularly in the absorbing epithelia of the small intestine and the renal tubule. For example, Na+-glucose cotransport (SGLT) and Na+-amino acid cotransport are present in the luminal membranes of the epithelial cells of both small intestine and renal proximal tubule. Another example of cotransport involving the renal tubule is Na+-K+-2Cl− cotransport, which is present in the luminal membrane of epithelial cells of the thick ascending limb. In each example, the Na+ gradient established by the Na+-K+ ATPase is used to transport solutes such as glucose, amino acids, K+, or Cl− against electrochemical gradients. Figure 1.7 illustrates the principles of cotransport using the example of Na+-glucose cotransport (SGLT1, or Na+-glucose transport protein 1) in intestinal epithe- lial cells. The cotransporter is present in the luminal membrane of these cells and can be visualized as having ATPATP Intestinal epithelial cellLumen Blood Na+ SGLT1 Glucose Glucose Basolateral membrane Luminal or apical membrane 2K+ 3Na+ Fig. 1.7 Na+-glucose cotransport in an intestinal epithelial cell. ATP, Adenosine triphosphate; SGLT1, Na+-glucose transport protein 1.Www.Medicalstudyzone.com
1—Cellular Physiology • 11 uses the Na+ gradient established by the Na+-K+ ATPase as an energy source; Na+ moves downhill and Ca2+ or H+ moves uphill. Ca2+-Na+ exchange is one of the transport mecha- nisms, along with the Ca2+ ATPase, that helps maintain the intracellular Ca2+ concentration at very low levels (≈10−7 molar). To accomplish Ca2+-Na+ exchange, active transport must be involved because Ca2+ moves out of the cell against its electrochemical gradient. Figure 1.8 illustrates the concept of Ca2+-Na+ exchange in a muscle cell membrane. The exchange protein has recognition sites for both Ca2+ and Na+. The protein must bind Ca2+ on the intracellular side of the membrane and, simul- taneously, bind Na+ on the extracellular side. In this configuration, the exchange protein rotates and delivers Ca2+ to the exterior of the cell and Na+ to the interior of the cell. The stoichiometry of Ca2+-Na+ exchange varies between different cell types and may even vary for a single cell type under different conditions. Usually, however, three Na+ ions enter the cell for each Ca2+ ion extruded from the cell. With this stoichiometry of three Na+ ions per one Ca2+ ion, three positive charges move into the cell in exchange for two positive charges leaving the cell, making the Ca2+-Na+ exchanger electrogenic. Osmosis Osmosis is the flow of water across a semipermeable membrane because of differences in solute concentra- tion. Concentration differences of impermeant solutes establish osmotic pressure differences, and this osmotic pressure difference causes water to flow by osmosis. Osmosis of water is not diffusion of water: Osmosis occurs because of a pressure difference, whereas diffu- sion occurs because of a concentration (or activity) difference of water. BOX 1.1 Clinical Physiology: Glucosuria Due to Diabetes Mellitus DESCRIPTION OF CASE. At his annual physical examination, a 14-year-old boy reports symptoms of frequent urination and severe thirst. A dipstick test of his urine shows elevated levels of glucose. The physician orders a glucose tolerance test, which indicates that the boy has type I diabetes mellitus. He is treated with insulin by injection, and his dipstick test is subsequently normal. EXPLANATION OF CASE. Although type I diabetes mellitus is a complex disease, this discussion is limited to the symptom of frequent urination and the finding of glucosuria (glucose in the urine). Glucose is normally handled by the kidney in the following manner: Glucose in the blood is filtered across the glomerular capillaries. The epithelial cells, which line the renal proximal tubule, then reabsorb all of the filtered glucose so that no glucose is excreted in the urine. Thus a normal dipstick test would show no glucose in the urine. If the epithelial cells in the proximal tubule do not reabsorb all of the filtered glucose back into the blood, the glucose that escapes reabsorption is excreted. The cellular mechanism for this glucose reabsorption is the Na+- glucose cotransporter in the luminal membrane of the proximal tubule cells. Because this is a carrier- mediated transporter, there is a finite number of binding sites for glucose. Once these binding sites are fully occupied, saturation of transport occurs (transport maximum). In this patient with type I diabetes mellitus, the hormone insulin is not produced in sufficient amounts by the pancreatic β cells. Insulin is required for normal uptake of glucose into liver, muscle, and other cells. Without insulin, the blood glucose concentration increases because glucose is not taken up by the cells. When the blood glucose concentra- tion increases to high levels, more glucose is filtered by the renal glomeruli and the amount of glucose filtered exceeds the capacity of the Na+-glucose cotransporter. The glucose that cannot be reabsorbed because of saturation of this transporter is then “spilled” in the urine. TREATMENT. Treatment of the patient with type I diabetes mellitus consists of administering exogenous insulin by injection. Whether secreted normally from the pancreatic β cells or adminis- tered by injection, insulin lowers the blood glucose concentration by promoting glucose uptake into cells. When this patient received insulin, his blood glucose concentration was reduced; thus the amount of glucose filtered was reduced, and the Na+-glucose cotransporters were no longer saturated. All of the filtered glucose could be reabsorbed, and there- fore no glucose was excreted, or “spilled,” in the urine. ATPATP 2K+ 3Na+ Muscle cell 3Na+ Ca2+ Fig. 1.8 Ca2+-Na+ countertransport (exchange) in a muscle cell. ATP, Adenosine triphosphate.Www.Medicalstudyzone.com
12 • Physiology Osmotic Pressure Osmosis is the flow of water across a semipermeable membrane due to a difference in solute concentration. The difference in solute concentration creates an osmotic pressure difference across the membrane and that pressure difference is the driving force for osmotic water flow. Figure 1.9 illustrates the concept of osmosis. Two aqueous solutions, open to the atmosphere, are shown in Figure 1.9A. The membrane separating the solutions is permeable to water but is impermeable to the solute. Initially, solute is present only in Solution 1. The solute in Solution 1 produces an osmotic pressure and causes, by the interaction of solute with pores in the membrane, a reduction in hydrostatic pressure of Solution 1. The resulting hydrostatic pressure difference across the membrane then causes water to flow from Solution 2 into Solution 1. With time, water flow causes the volume of Solution 1 to increase and the volume of Solution 2 to decrease. Figure 1.9B shows a similar pair of solutions; however, the preparation has been modified so that water flow into Solution 1 is prevented by applying pressure to a piston. The pressure required to stop the flow of water is the osmotic pressure of Solution 1. The osmotic pressure (π) of Solution 1 depends on two factors: the concentration of osmotically active particles and whether the solute remains in Solution 1 (i.e., whether the solute can cross the membrane or not). Osmotic pressure is calculated by the van’t Hoff equation (as follows), which converts the concentra- tion of particles to a pressure, taking into account whether the solute is retained in the original solution. Thus π σ= g C R T where π = = Osmotic pressure atm or mm Hg g Number of particles per ( ) mmole in solution (Osm/mol C Concentration (mmol/L Reflect ) )= =σ iion coefficient varies from to R Gas constant L atm ( ) ( . 0 1 0 082= − //mol K T Absolute temperature K − = ) ( ) The reflection coefficient (σ) is a dimensionless number ranging between 0 and 1 that describes the Osmolarity The osmolarity of a solution is its concentration of osmotically active particles, expressed as osmoles per liter or milliosmoles per liter. To calculate osmolarity, it is necessary to know the concentration of solute and whether the solute dissociates in solution. For example, glucose does not dissociate in solution; theoretically, NaCl dissociates into two particles and CaCl2 dissoci- ates into three particles. The symbol “g” gives the number of particles in solution and also takes into account whether there is complete or only partial dis- sociation. Thus if NaCl is completely dissociated into two particles, g equals 2.0; if NaCl dissociates only partially, then g falls between 1.0 and 2.0. Osmolarity is calculated as follows: Osmolarity g C= where Osmolarity Concentration of particles (mOsm/L g Number of p = = ) aarticles per mole in solution (Osm/mol C Concentration (mmol ) = //L) If two solutions have the same calculated osmolarity, they are called isosmotic. If two solutions have differ- ent calculated osmolarities, the solution with the higher osmolarity is called hyperosmotic and the solution with the lower osmolarity is called hyposmotic. Osmolality Osmolality is similar to osmolarity, except that it is the concentration of osmotically active particles, expressed as osmoles (or milliosmoles) per kilogram of water. Because 1 kg of water is approximately equivalent to 1 L of water, osmolarity and osmolality will have essentially the same numerical value. The two solutions do not have the same calcu- lated osmolarity; therefore they are not isosmotic. Solution A has a higher osmolarity than Solution B and is hyperosmotic; Solution B is hyposmotic. SAMPLE PROBLEM. Solution A is 2 mmol/L urea, and Solution B is 1 mmol/L NaCl. Assume that gNaCl = 1.85. Are the two solutions isosmotic? SOLUTION. Calculate the osmolarities of both solu- tions to compare them. Solution A contains urea, which does not dissociate in solution. Solution B contains NaCl, which dissociates partially in solu- tion but not completely (i.e., g < 2.0). Thus Osmolarity Osm/mol mmol/L mOsm/L Osmolarity Osm/mo A B = × = = 1 2 2 1 85. ll mmol/L mOsm/L × = 1 1 85.Www.Medicalstudyzone.com
1—Cellular Physiology • 13 Semipermeable membrane A Piston applies pressure to stop water flow 1 2 1 2 Time 1 2 1 2 atm Time B Fig. 1.9 Osmosis across a semipermeable membrane. A, Solute (circles) is present on one side of a semipermeable membrane; with time, the osmotic pressure created by the solute causes water to flow from Solution 2 to Solution 1. The resulting volume changes are shown. B, The solutions are closed to the atmosphere, and a piston is applied to stop the flow of water into Solution 1. The pressure needed to stop the flow of water is the effective osmotic pressure of Solution 1. atm, Atmosphere. ease with which a solute crosses a membrane. Reflec- tion coefficients can be described for the following three conditions (Fig. 1.10): ♦ σ = 1.0 (see Fig. 1.10A). If the membrane is imper- meable to the solute, σ is 1.0, and the solute will be retained in the original solution and exert its full osmotic effect. In this case, the effective osmotic pressure will be maximal and will cause maximal water flow. For example, serum albumin and intra- cellular proteins are solutes where σ = 1. ♦ σ = 0 (see Fig. 1.10C). If the membrane is freely permeable to the solute, σ is 0, and the solute will diffuse across the membrane down its concentration gradient until the solute concentrations of the two solutions are equal. In other words, the solute behaves as if it were water. In this case, there will be no effective osmotic pressure difference across the membrane and therefore no driving force for osmotic water flow. Refer again to the van’t Hoff equation and notice that, when σ = 0, the calculated effective osmotic pressure becomes zero. Urea is an example of a solute where σ = 0 (or nearly 0). ♦ σ = a value between 0 and 1 (see Fig. 1.10B). Most solutes are neither impermeant (σ = 1) nor freely permeant (σ = 0) across membranes, but the reflec- tion coefficient falls somewhere between 0 and 1. In such cases, the effective osmotic pressure lies between its maximal possible value (when the solute is completely impermeable) and zero (when the solute is freely permeable). Refer once again to the van’t Hoff equation and notice that, when σ is between 0 and 1, the calculated effective osmotic pressure will be less than its maximal possible value but greater than zero. When two solutions separated by a semipermeable membrane have the same effective osmotic pressure,Www.Medicalstudyzone.com
14 • Physiology they are isotonic; that is, no water will flow between them because there is no effective osmotic pressure difference across the membrane. When two solutions have different effective osmotic pressures, the solution with the lower effective osmotic pressure is hypotonic and the solution with the higher effective osmotic pres- sure is hypertonic. Water will flow from the hypotonic solution into the hypertonic solution (Box 1.2). A σ = 1 Membrane B σ = between 0 and 1 C σ = 0 Fig. 1.10 Reflection coefficient (σ). SAMPLE PROBLEM. A solution of 1 mol/L NaCl is separated from a solution of 2 mol/L urea by a semipermeable membrane. Assume that NaCl is completely dissociated, that σNaCl = 0.3, and σurea = 0.05. Are the two solutions isosmotic and/or isotonic? Is there net water flow, and what is its direction? SOLUTION Step 1. To determine whether the solutions are isosmotic, simply calculate the osmolarity of each solution (g × C) and compare the two values. It was stated that NaCl is completely dissociated (i.e., sepa- rated into two particles); thus for NaCl, g = 2.0. Urea does not dissociate in solution; thus for urea, g = 1.0. NaCl Osmolarity g C mol/L Osm/L : . = = × = 2 0 1 2 Urea Osmolarity g C mol/L Osm/L : . = = × = 1 0 2 2 Each solution has an osmolarity of 2 Osm/L— they are indeed isosmotic. Step 2. To determine whether the solutions are isotonic, the effective osmotic pressure of each solu- tion must be determined. Assume that at 37°C (310 K), RT = 25.45 L-atm/mol. Thus NaCl g C RT mol/L RT RT atm : . . . π σ= = × × × = = 2 1 0 3 0 6 15 3 Urea g C RT mol/L RT RT atm : . . . π σ= = × × × = = 1 2 0 05 0 1 2 5 Although the two solutions have the same calcu- lated osmolarities and are isosmotic (Step 1), they have different effective osmotic pressures and they are not isotonic (Step 2). This difference occurs because the reflection coefficient for NaCl is much higher than the reflection coefficient for urea and, thus NaCl creates the greater effective osmotic pres- sure. Water will flow from the urea solution into the NaCl solution, from the hypotonic solution to the hypertonic solution. DIFFUSION POTENTIALS AND EQUILIBRIUM POTENTIALS Ion Channels Ion channels are integral, membrane-spanning proteins that, when open, permit the passage of certain ions. Thus ion channels are selective and allow ions with specific characteristics to move through them. This selectivity is based on both the size of the channel and the charges lining it. For example, channels lined with negative charges typically permit the passage of cations but exclude anions; channels lined with positive charges permit the passage of anions but exclude cations. Chan- nels also discriminate on the basis of size. For example, a cation-selective channel lined with negative charges might permit the passage of Na+ but exclude K+; anotherWww.Medicalstudyzone.com
1—Cellular Physiology • 15 The gates on ion channels are controlled by three types of sensors. One type of gate has sensors that respond to changes in membrane potential (i.e., voltage-gated channels); a second type of gate responds to changes in signaling molecules (i.e., second messenger–gated channels); and a third type of gate responds to changes in ligands such as hormones or neurotransmitters (i.e., ligand-gated channels). ♦ Voltage-gated channels have gates that are con- trolled by changes in membrane potential. For example, the activation gate on the nerve Na+ channel is opened by depolarization of the nerve cell membrane; opening of this channel is responsible for the upstroke of the action potential. Interestingly, another gate on the Na+ channel, an inactivation gate, is closed by depolarization. Because the activa- tion gate responds more rapidly to depolarization than the inactivation gate, the Na+ channel first opens and then closes. This difference in response times of the two gates accounts for the shape and time course of the action potential. ♦ Second messenger–gated channels have gates that are controlled by changes in levels of intracellular signaling molecules such as cyclic adenosine mono- phosphate (cAMP) or inositol 1,4,5-triphosphate (IP3). Thus the sensors for these gates are on the intracellular side of the ion channel. For example, the gates on Na+ channels in cardiac sinoatrial node are opened by increased intracellular cAMP. ♦ Ligand-gated channels have gates that are controlled by hormones and neurotransmitters. The sensors for these gates are located on the extracellular side of the ion channel. For example, the nicotinic receptor on the motor end plate is actually an ion channel that opens when acetylcholine (ACh) binds to it; when open, it is permeable to Na+ and K+ ions. Diffusion Potentials A diffusion potential is the potential difference gener- ated across a membrane when a charged solute (an ion) diffuses down its concentration gradient. Therefore a diffusion potential is caused by diffusion of ions. It follows, then, that a diffusion potential can be gener- ated only if the membrane is permeable to that ion. Furthermore, if the membrane is not permeable to the ion, no diffusion potential will be generated no matter how large a concentration gradient is present. The magnitude of a diffusion potential, measured in millivolts (mV), depends on the size of the concen- tration gradient, where the concentration gradient is the driving force. The sign of the diffusion potential depends on the charge of the diffusing ion. Finally, as noted, diffusion potentials are created by the cation-selective channel (e.g., nicotinic receptor on the motor end plate) might have less selectivity and permit the passage of several different small cations. Ion channels are controlled by gates, and, depend- ing on the position of the gates, the channels may be open or closed. When a channel is open, the ions for which it is selective can flow through it by passive diffusion, down the existing electrochemical gradient. In the open state, there is a continuous path between ECF and ICF, through which ions can flow. When the channel is closed, the ions cannot flow through it, no matter what the size of the electrochemical gradient. The conductance of a channel depends on the probabil- ity that it is open. The higher the probability that the channel is open, the higher is its conductance or permeability. BOX 1.2 Clinical Physiology: Hyposmolarity With Brain Swelling DESCRIPTION OF CASE. A 72-year-old man was diagnosed recently with oat cell carcinoma of the lung. He tried to stay busy with consulting work, but the disease sapped his energy. One evening, his wife noticed that he seemed confused and lethargic, and suddenly he suffered a grand mal seizure. In the emergency department, his plasma Na+ concentra- tion was 113 mEq/L (normal, 140 mEq/L) and his plasma osmolarity was 230 mOsm/L (normal, 290 mOsm/L). He was treated immediately with an infusion of hypertonic NaCl and was released from the hospital a few days later, with strict instructions to limit his water intake. EXPLANATION OF CASE. The man’s oat cell carci- noma autonomously secretes antidiuretic hormone (ADH), which causes syndrome of inappropriate antidiuretic hormone (SIADH). In SIADH, the high circulating levels of ADH cause excessive water reabsorption by the principal cells of the late distal tubule and collecting ducts. The excess water that is reabsorbed and retained in the body dilutes the Na+ concentration and osmolarity of the ECF. The decreased osmolarity means there is also decreased effective osmotic pressure of ECF and, briefly, osmotic pressure of ECF is less than osmotic pres- sure of ICF. The effective osmotic pressure difference across cell membranes causes osmotic water flow from ECF to ICF, which results in cell swelling. Because the brain is contained in a fixed structure (the skull), swelling of brain cells can cause
16 • Physiology The positivity in Solution 2 opposes further diffusion of Na+, and eventually it is large enough to prevent further net diffusion. The potential difference that exactly balances the tendency of Na+ to diffuse down its concentration gradient is the Na+ equilibrium potential. When the chemical and electrical driving forces on Na+ are equal and opposite, Na+ is said to be at electrochemical equilibrium. This diffusion of a few Na+ ions, sufficient to create the diffusion potential, does not produce any change in Na+ concentration in the bulk solutions. Example of Cl− Equilibrium Potential Figure 1.12 shows the same pair of solutions as in Figure 1.11; however, in Figure 1.12, the theoretical membrane is permeable to Cl− rather than to Na+. Cl− will diffuse from Solution 1 to Solution 2 down its concentration gradient, but Na+ will not accompany it. A diffusion potential will be established, and Solution 2 will become negative relative to Solution 1. The potential difference that exactly balances the tendency of Cl− to diffuse down its concentration gradient is the Cl− equilibrium potential. When the chemical and electrical driving forces on Cl− are equal and opposite, then Cl− is at electrochemical equilibrium. Again, diffusion of these few Cl− ions will not change the Cl− concentration in the bulk solutions. Nernst Equation The Nernst equation is used to calculate the equilibrium potential for an ion at a given concentration difference across a membrane, assuming that the membrane is permeable to that ion. By definition, the equilibrium potential is calculated for one ion at a time. Thus E RT zF C C x i e = −2 3 10 . log [ ] [ ] movement of only a few ions, and they do not cause changes in the concentration of ions in bulk solution. Equilibrium Potentials The concept of equilibrium potential is simply an extension of the concept of diffusion potential. If there is a concentration difference for an ion across a mem- brane and the membrane is permeable to that ion, a potential difference (the diffusion potential) is created. Eventually, net diffusion of the ion slows and then stops because of that potential difference. In other words, if a cation diffuses down its concentration gradi- ent, it carries a positive charge across the membrane, which will retard and eventually stop further diffusion of the cation. If an anion diffuses down its concentra- tion gradient, it carries a negative charge, which will retard and then stop further diffusion of the anion. The equilibrium potential is the diffusion potential that exactly balances or opposes the tendency for diffusion down the concentration difference. At electrochemical equilibrium, the chemical and electrical driving forces acting on an ion are equal and opposite, and no further net diffusion occurs. The following examples of a diffusing cation and a diffusing anion illustrate the concepts of equilibrium potential and electrochemical equilibrium. Example of Na+ Equilibrium Potential Figure 1.11 shows two solutions separated by a theoreti- cal membrane that is permeable to Na+ but not to Cl−. The NaCl concentration is higher in Solution 1 than in Solution 2. The permeant ion, Na+, will diffuse down its concentration gradient from Solution 1 to Solution 2, but the impermeant ion, Cl−, will not accompany it. As a result of the net movement of positive charge to Solution 2, an Na+ diffusion potential develops and Solution 2 becomes positive with respect to Solution 1. – – – – + + + + Na+ Cl– Na+ Cl– 1 2 1 2 Na+-selective membrane Na+ Cl– Na+ Cl– Time Fig. 1.11 Generation of an Na+ diffusion potential.Www.Medicalstudyzone.com
1—Cellular Physiology • 17 where E Equilibrium potential mV for a given ion X RT F Consta X = = ( ) , .2 3 nnt mV at C z Charge on the ion for Na for Ca 60 37 1 2 2 ° = + + − ( ) + + ( ; ; 11 for Cl C Intracellular concentration of X mmol/L C Ex i e − = = ) ( ) ttracellular concentration of X mmol/L( ) In words, the Nernst equation converts a concentra- tion difference for an ion into a voltage. This conversion is accomplished by the various constants: R is the gas constant, T is the absolute temperature, and F is Faraday constant; multiplying by 2.3 converts natural logarithm to log10. By convention, membrane potential is expressed as intracellular potential relative to extracellular potential. Hence, a transmembrane potential difference of −70 mV means 70 mV, cell interior negative. Typical values for equilibrium potential for common ions in skeletal muscle, calculated as previously described and assuming typical concentration gradients across cell membranes, are as follows: E mV E mV E mV E mV Na Ca K Cl + + + − = + = + = − = − 65 120 95 90 2 It is useful to keep these values in mind when considering the concepts of resting membrane potential and action potentials. Na+ Cl– Na+ Cl– 1 2 1 2 Cl–-selective membrane Na+ Cl– Na+ Cl– Time – – – – + + + + Fig. 1.12 Generation of a Cl− diffusion potential. SAMPLE PROBLEM. If the intracellular [Ca2+] is 10−7 mol/L and the extracellular [Ca2+] is 2 × 10−3 mol/L, at what potential difference across the cell membrane will Ca2+ be at electrochemical equi- librium? Assume that 2.3RT/F = 60 mV at body temperature (37°C). SOLUTION. Another way of posing the question is to ask what the membrane potential will be, given this concentration gradient across the membrane, if Ca2+ is the only permeant ion. Remember, Ca2+ is divalent, so z = +2. Thus E mV z C C mV mol/L mol/L Ca i e 2 60 60 2 10 2 10 30 10 10 7 3 + = − = − + × = − − − log log mmV mV mV log ( . ) 10 5 5 10 30 4 3 129 × = − − = + − Because this is a log function, it is not necessary to remember which concentration goes in the numerator. Simply complete the calculation either way to arrive at 129 mV, and then determine the correct sign with an intuitive approach. The intuitive approach depends on the knowledge that, because the [Ca2+] is much higher in ECF than in ICF, Ca2+ will tend to diffuse down this concentration gradient from ECF into ICF, making the inside of the cell positive. Thus Ca2+ will be at electrochemical equi- librium when the membrane potential is +129 mV (cell interior positive). Be aware that the equilibrium potential has been calculated at a given concentration gradient for Ca2+ ions. With a different concentration gradient, the calculated equilibrium potential would be different.Www.Medicalstudyzone.com
18 • Physiology I G E EX X m X= −( ) where I ionic current mAmp G ionic conductance /ohm where co X X = = ( ) ( ),1 nnductance is the reciprocal of resistance E E driving form X− = cce on ion X mV( ) You will notice that the equation for ionic current is simply a rearrangement of Ohm’s law, where V = IR or I = V/R (where V is the same thing as E). Because conductance (G) is the reciprocal of resistance (R), I = G × V. The direction of ionic current is determined by the direction of the driving force, as described in the previ- ous section. The magnitude of ionic current is deter- mined by the size of the driving force and the conductance of the ion. For a given conductance, the greater the driving force, the greater the current flow. For a given driving force, the greater the conductance, the greater the current flow. Lastly, if either the driving force or the conductance of an ion is zero, there can be no net diffusion of that ion across the cell membrane and no current flow. RESTING MEMBRANE POTENTIAL The resting membrane potential is the potential differ- ence that exists across the membrane of excitable cells such as nerve and muscle in the period between action potentials (i.e., at rest). As stated previously, in expressing the membrane potential, it is conventional to refer the intracellular potential to the extracellular potential. The resting membrane potential is established by diffusion potentials, which result from the concentra- tion differences for various ions across the cell mem- brane. (Recall that these concentration differences have been established by primary and secondary active transport mechanisms.) Each permeant ion attempts to drive the membrane potential toward its own equilib- rium potential. Ions with the highest permeabilities or conductances at rest will make the greatest contribu- tions to the resting membrane potential, and those with the lowest permeabilities will make little or no contribution. The resting membrane potential of most excitable cells falls in the range of −70 to −80 mV. These values can best be explained by the concept of relative perme- abilities of the cell membrane. Thus the resting mem- brane potential is close to the equilibrium potentials for K+ and Cl− because the permeability to these ions at rest is high. The resting membrane potential is far from Driving Force When dealing with uncharged solutes, the driving force for net diffusion is simply the concentration difference of the solute across the cell membrane. However, when dealing with charged solutes (i.e., ions), the driving force for net diffusion must consider both concentra- tion difference and electrical potential difference across the cell membrane. The driving force on a given ion is the difference between the actual, measured membrane potential (Em) and the ion’s calculated equilibrium potential (EX). In other words, it is the difference between the actual Em and the value the ion would “like” the membrane potential to be. (The ion would “like” the membrane potential to be its equilibrium potential, as calculated by the Nernst equation.) The driving force on a given ion, X, is therefore calculated as: Net driving force mV E Em x( ) = − where Driving force Driving force mV E Actual membrane potentiam = = ( ) ll mV E Equilibrium potential for X mVX ( ) ( )= When the driving force is negative (i.e., Em is more negative than the ion’s equilibrium potential), that ion X will enter the cell if it is a cation and will leave the cell if it is an anion. In other words, ion X “thinks” the membrane potential is too negative and tries to bring the membrane potential toward its equilibrium poten- tial by diffusing in the appropriate direction across the cell membrane. Conversely, if the driving force is posi- tive (Em is more positive than the ion’s equilibrium potential), then ion X will leave the cell if it is a cation and will enter the cell if it is an anion; in this case, ion X “thinks” the membrane potential is too positive and tries to bring the membrane potential toward its equi- librium potential by diffusing in the appropriate direc- tion across the cell membrane. Finally, if Em is equal to the ion’s equilibrium potential, then the driving force on the ion is zero, and the ion is, by definition, at electrochemical equilibrium; since there is no driving force, there will be no net movement of the ion in either direction. Ionic Current Ionic current (IX), or current flow, occurs when there is movement of an ion across the cell membrane. Ions will move across the cell membrane through ion chan- nels when two conditions are met: (1) there is a driving force on the ion, and (2) the membrane has a conduc- tance to that ion (i.e., its ion channels are open). ThusWww.Medicalstudyzone.com
1—Cellular Physiology • 19 the membrane potential. Action potentials are the basic mechanism for transmission of information in the nervous system and in all types of muscle. Terminology The following terminology will be used for discussion of the action potential, the refractory periods, and the propagation of action potentials: ♦ Depolarization is the process of making the mem- brane potential less negative. As noted, the usual resting membrane potential of excitable cells is ori- ented with the cell interior negative. Depolarization makes the interior of the cell less negative, or it may even cause the cell interior to become positive. Such a change in membrane potential should not be described as “increasing” or “decreasing” because those terms are ambiguous. (For example, when the membrane potential depolarizes, or becomes less negative, has the membrane potential increased or decreased?) ♦ Hyperpolarization is the process of making the membrane potential more negative. As with depolar- ization, the terms “increasing” or “decreasing” should not be used to describe a change that makes the membrane potential more negative. ♦ Inward current is the flow of positive charge into the cell. Thus inward currents depolarize the mem- brane potential. An example of an inward current is the flow of Na+ into the cell during the upstroke of the action potential. ♦ Outward current is the flow of positive charge out of the cell. Outward currents hyperpolarize the membrane potential. An example of an outward current is the flow of K+ out of the cell during the repolarization phase of the action potential. ♦ Threshold potential is the membrane potential at which occurrence of the action potential is inevitable. Because the threshold potential is less negative than the resting membrane potential, an inward current is required to depolarize the membrane potential to threshold. At threshold potential, net inward current (e.g., inward Na+ current) becomes larger than net outward current (e.g., outward K+ current), and the resulting depolarization becomes self-sustaining, giving rise to the upstroke of the action potential. If net inward current is less than net outward current, the membrane will not be depolarized to threshold and no action potential will occur (see all-or-none response). ♦ Overshoot is that portion of the action potential where the membrane potential is positive (cell interior positive). the equilibrium potentials for Na+ and Ca2+ because the permeability to these ions at rest is low. One way of evaluating the contribution each ion makes to the membrane potential is by using the chord conductance equation, which weights the equilibrium potential for each ion (calculated by the Nernst equa- tion) by its relative conductance. Ions with the highest conductance drive the membrane potential toward their equilibrium potentials, whereas those with low conduc- tance have little influence on the membrane potential. (An alternative approach to the same question applies the Goldman equation, which considers the contribu- tion of each ion by its relative permeability rather than by its conductance.) The chord conductance equation is written as follows: E g g E g g E g g E g g Em K T K Na T Na Cl T Cl Ca T Ca = + + + + + + + − − + + 2 2 where E Membrane potential mV g etc K conductance etc mho re m K = =+ + ( ) . . ( , cciprocal of resistance g Total conductance mho E etc K T K ) ( ) . = =+ + eequilibrium potential etc mV. ( ) At rest, the membranes of excitable cells are far more permeable to K+ and Cl− than to Na+ and Ca2+. These differences in permeability account for the resting membrane potential. What role, if any, does the Na+-K+ ATPase play in creating the resting membrane potential? The answer has two parts. First, there is a small direct electrogenic contribution of the Na+-K+ ATPase, which is based on the stoichiometry of three Na+ ions pumped out of the cell for every two K+ ions pumped into the cell. Second, the more important indirect contribution is in maintain- ing the concentration gradient for K+ across the cell membrane, which then is responsible for the K+ diffu- sion potential that drives the membrane potential toward the K+ equilibrium potential. Thus the Na+-K+ ATPase is necessary to create and maintain the K+ concentration gradient, which establishes the resting membrane potential. (A similar argument can be made for the role of the Na+-K+ ATPase in the upstroke of the action potential, where it maintains the ionic gradient for Na+ across the cell membrane.) ACTION POTENTIALS The action potential is a phenomenon of excitable cells such as nerve and muscle and consists of a rapid depolarization (upstroke) followed by repolarization ofWww.Medicalstudyzone.com
20 • Physiology action potentials from one site to the next is nondecremental. ♦ All-or-none response. An action potential either occurs or does not occur. If an excitable cell is depolarized to threshold in a normal manner, then the occurrence of an action potential is inevitable. On the other hand, if the membrane is not depolar- ized to threshold, no action potential can occur. Indeed, if the stimulus is applied during the refrac- tory period, then either no action potential occurs, or the action potential will occur but not have the stereotypical size and shape. Ionic Basis of the Action Potential The action potential is a fast depolarization (the upstroke), followed by repolarization back to the resting membrane potential. Figure 1.13 illustrates the events of the action potential in nerve and skeletal muscle, which occur in the following steps: 1. Resting membrane potential. At rest, the membrane potential is approximately −70 mV (cell interior ♦ Undershoot, or hyperpolarizing afterpotential, is that portion of the action potential, following repo- larization, where the membrane potential is actually more negative than it is at rest. ♦ Refractory period is a period during which another normal action potential cannot be elicited in an excitable cell. Refractory periods can be absolute or relative. (In cardiac muscle cells, there is an addi- tional category called effective refractory period.) Characteristics of Action Potentials Action potentials have three basic characteristics: ste- reotypical size and shape, propagation, and all-or-none response. ♦ Stereotypical size and shape. Each normal action potential for a given cell type looks identical, depo- larizes to the same potential, and repolarizes back to the same resting potential. ♦ Propagation. An action potential at one site causes depolarization at adjacent sites, bringing those adjacent sites to threshold. Propagation of Action potential Na+ conductance Na+ equilibrium potential Absolute refractory period Relative refractory period Resting membrane potential K+ equilibrium potential Time (milliseconds) 1.0 2.0 Voltage or conductance +65 mV 0 mV –70 mV –85 mV K+ conductance Fig. 1.13 Time course of voltage and conductance changes during the action potential of nerve.Www.Medicalstudyzone.com
1—Cellular Physiology • 21 but does not quite reach, the Na+ equilibrium poten- tial of +65 mV. Tetrodotoxin (a toxin from the Japa- nese puffer fish) and the local anesthetic lidocaine block these voltage-sensitive Na+ channels and prevent the occurrence of nerve action potentials. 3. Repolarization of the action potential. The upstroke is terminated, and the membrane potential repolar- izes to the resting level as a result of two events. First, the inactivation gates on the Na+ channels respond to depolarization by closing, but their response is slower than the opening of the activation gates. Thus after a delay, the inactivation gates close, which closes the Na+ channels and terminates the upstroke. Second, depolarization opens K+ chan- nels and increases K+ conductance to a value even higher than occurs at rest. The combined effect of closing of the Na+ channels and greater opening of the K+ channels makes the K+ conductance much higher than the Na+ conductance. Thus an outward K+ current results, and the membrane is repolarized. Tetraethylammonium (TEA) blocks these voltage- gated K+ channels, the outward K+ current, and repolarization. negative). The K+ conductance or permeability is high and K+ channels are almost fully open, allowing K+ ions to diffuse out of the cell down the existing concentration gradient. This diffusion creates a K+ diffusion potential, which drives the membrane potential toward the K+ equilibrium potential. The conductance to Cl− (not shown) also is high, and, at rest, Cl− also is near electrochemical equilibrium. At rest, the Na+ conductance is low, and thus the resting membrane potential is far from the Na+ equilibrium potential, and Na+ is far from electro- chemical equilibrium. 2. Upstroke of the action potential. An inward current, usually the result of current spread from action potentials at neighboring sites, causes depolarization of the nerve cell membrane to threshold, which occurs at approximately −60 mV. This initial depo- larization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance promptly increases and becomes even higher than the K+ conductance (Fig. 1.14). The increase in Na+ conductance results in an inward Na+ current; the membrane potential is further depolarized toward, Closed, but available Inactivation gate Activation gate Open Inactivated Na+ 321 Fig. 1.14 States of activation and inactivation gates on the nerve Na+ channel. 1, In the closed but available state, at the resting membrane potential, the activation gate is closed, the inactivation gate is open, and the channel is closed (but available, if depolarization occurs). 2, In the open state, during the upstroke of the action potential, both the activation and inactivation gates are open and the channel is open. 3, In the inactivated state, at the peak of the action potential, the activation gate is open, the inactivation gate is closed, and the channel is closed.Www.Medicalstudyzone.com
22 • Physiology that they are ready to fire another action potential? Repolarization back to the resting membrane potential causes the inactivation gates to open. The Na+ channels now return to the closed, but available state and are ready and “available” to fire another action potential if depolarization occurs. Refractory Periods During the refractory periods, excitable cells are inca- pable of producing normal action potentials (see Fig. 1.13). The refractory period includes an absolute refrac- tory period and a relative refractory period. Absolute Refractory Period The absolute refractory period overlaps with almost the entire duration of the action potential. During this period, no matter how great the stimulus, another action potential cannot be elicited. The basis for the absolute refractory period is closure of the inactivation gates of the Na+ channel in response to depolarization. These inactivation gates are in the closed position until the cell is repolarized back to the resting membrane potential and the Na+ channels have recovered to the “closed, but available” state (see Fig. 1.14). Relative Refractory Period The relative refractory period begins at the end of the absolute refractory period and overlaps primarily with the period of the hyperpolarizing afterpotential. During this period, an action potential can be elicited, but only if a greater than usual depolarizing (inward) current is applied. The basis for the relative refractory period is the higher K+ conductance than is present at rest. Because the membrane potential is closer to the K+ equilibrium potential, more inward current is needed to bring the membrane to threshold for the next action potential to be initiated. Accommodation When a nerve or muscle cell is depolarized slowly or is held at a depolarized level, the usual threshold potential may pass without an action potential having been fired. This process, called accommodation, occurs because depolarization closes inactivation gates on the Na+ channels. If depolarization occurs slowly enough, the Na+ channels close and remain closed. The upstroke of the action potential cannot occur because there are insufficient available Na+ channels to carry inward current. An example of accommodation is seen in persons who have an elevated serum K+ concentration, or hyperkalemia. At rest, nerve and muscle cell mem- branes are very permeable to K+; an increase in extra- cellular K+ concentration causes depolarization of the resting membrane (as dictated by the Nernst equation). This depolarization brings the cell membrane closer to 4. Hyperpolarizing afterpotential (undershoot). For a brief period following repolarization, the K+ conduc- tance is higher than at rest and the membrane potential is driven even closer to the K+ equilibrium potential (hyperpolarizing afterpotential). Eventu- ally, the K+ conductance returns to the resting level, and the membrane potential depolarizes slightly, back to the resting membrane potential. The mem- brane is now ready, if stimulated, to generate another action potential. The Nerve Na+ Channel A voltage-gated Na+ channel is responsible for the upstroke of the action potential in nerve and skeletal muscle. This channel is an integral membrane protein, consisting of a large α subunit and two β subunits. The α subunit has four domains, each of which has six transmembrane α-helices. The repeats of transmem- brane α-helices surround a central pore, through which Na+ ions can flow (if the channel’s gates are open). A conceptual model of the Na+ channel demonstrating the function of the activation and inactivation gates is shown in Figure 1.14. The basic assumption of this model is that in order for Na+ to move through the channel, both gates on the channel must be open. Recall how these gates respond to changes in voltage. The activation gates open quickly in response to depolariza- tion. The inactivation gates close in response to depo- larization, but slowly, after a time delay. Thus when depolarization occurs, the activation gates open quickly, followed by slower closing of the inactivation gates. The figure shows three combinations of the gates’ posi- tions and the resulting effect on Na+ channel opening. 1. Closed, but available. At the resting membrane potential, the activation gates are closed and the inactivation gates are open. Thus the Na+ channels are closed. However, they are “available” to fire an action potential if depolarization occurs. (Depolar- ization would open the activation gates and, because the inactivation gates are already open, the Na+ channels would then be open.) 2. Open. During the upstroke of the action potential, depolarization quickly opens the activation gates and both the activation and inactivation gates are briefly open. Na+ can flow through the channels into the cell, causing further depolarization. 3. Inactivated. At the peak of the action potential, the slow inactivation gates finally close in response to depolarization;
1—Cellular Physiology • 23 the cell interior becomes positive. The adjacent region of the axon remains inactive, with its cell interior negative. Figure 1.15B illustrates the spread of local current from the depolarized active region to the adjacent inac- tive region. At the active site, positive charges inside the cell flow toward negative charges at the adjacent inactive site. This current flow causes the adjacent region to depolarize to threshold. In Figure 1.15C the adjacent region of the nerve axon, having been depolarized to threshold, now fires an action potential. The polarity of its membrane potential is reversed, and the cell interior becomes positive. At this time, the original active region has been repolarized back to the resting membrane poten- tial and restored to its inside-negative polarity. The process continues, transmitting the action potential sequentially down the axon. Conduction Velocity The speed at which action potentials are conducted along a nerve or muscle fiber is the conduction velocity. This property is of great physiologic importance because threshold and would seem to make it more likely to fire an action potential. However, the cell is actually less likely to fire an action potential because this sustained depolarization closes the inactivation gates on the Na+ channels (Box 1.3). Propagation of Action Potentials Propagation of action potentials down a nerve or muscle fiber occurs by the spread of local currents from active regions to adjacent inactive regions. Figure 1.15 shows a nerve cell body with its dendritic tree and an axon. At rest, the entire nerve axon is at the resting membrane potential, with the cell interior negative. Action potentials are initiated in the initial segment of the axon, nearest the nerve cell body. They propagate down the axon by spread of local currents, as illustrated in the figure. In Figure 1.15A the initial segment of the nerve axon is depolarized to threshold and fires an action potential (the active region). As the result of an inward Na+ current, at the peak of the action potential, the polarity of the membrane potential is reversed and BOX 1.3 Clinical Physiology: Hyperkalemia With Muscle Weakness DESCRIPTION OF CASE. A 48-year-old woman with insulin-dependent diabetes mellitus reports to her physician that she is experiencing severe muscle weak- ness. She is being treated for hypertension with pro- pranolol, a β-adrenergic blocking agent. Her physician immediately orders blood studies, which reveal a serum [K+] of 6.5 mEq/L (normal, 4.5 mEq/L) and elevated BUN (blood urea nitrogen). The physician tapers off the dosage of propranolol, with eventual discontinua- tion of the drug. He adjusts her insulin dosage. Within a few days, the patient’s serum [K+] has decreased to 4.7 mEq/L, and she reports that her muscle strength has returned to normal. EXPLANATION OF CASE. This diabetic patient has severe hyperkalemia caused by several factors: (1) Because her insulin dosage is insufficient, the lack of adequate insulin has caused a shift of K+ out of cells into blood (insulin promotes K+ uptake into cells). (2) Propranolol, the β-blocking agent used to treat the woman’s hypertension, also shifts K+ out of cells into blood. (3) Elevated BUN suggests that the woman is developing renal failure; her failing kidneys are unable to excrete the extra K+ that is accumulating in her blood. These mechanisms involve concepts related to renal physiology and endocrine physiology. It is important to understand that this woman has a severely elevated blood [K+] (hyperkalemia) and that her muscle weakness results from this hyperkalemia. The basis for this weakness can be explained as follows: The resting membrane potential of muscle cells is determined by the concentration gradient for K+ across the cell membrane (Nernst equation). At rest, the cell membrane is very permeable to K+, and K+ diffuses out of the cell down its concentration gradient, creating a K+ diffusion potential. This K+ diffusion potential is responsible for the resting membrane potential, which is cell interior negative. The larger the K+ concentration gradient, the greater the negativity in the cell. When the blood [K+] is elevated, the concentration gradient across the cell membrane is less than normal; resting membrane potential will therefore be less negative (i.e., depolarized). It might be expected that this depolarization would make it easier to generate action potentials in the muscle because the resting membrane potential would be closer to threshold. A more important effect of depolarization, however, is that it closes the inactiva- tion gates on Na+ channels. When these inactivation gates are closed, no action potentials can be generated, even if the activation gates are open. Without action potentials in the muscle, there can be no contraction. TREATMENT. Treatment of this patient is based on shifting K+ back into the cells by increasing the woman’s insulin dosages and by disco
24 • Physiology membrane capacitance (Cm), is the ability of the cell membrane to store charge. When Cm is high, the time constant is increased because injected current first must discharge the membrane capacitor before it can depolarize the membrane. Thus the time constant is greatest (i.e., takes longest) when Rm and Cm are high. The length constant (λ) is the distance from the site of current injection where the potential has fallen by 63% of its original value. The length constant indicates how far a depolarizing current will spread along a nerve. In other words, the longer the length constant, the farther the current spreads down the nerve fiber. Thus λ ∝ R /Rm i where λ = = = Length constant R Membrane resistance R Internal resista m i nnce Again, Rm represents membrane resistance. Internal resistance, Ri, is inversely related to the ease of current flow in the cytoplasm of the nerve fiber. Therefore the length constant will be greatest (i.e., current will travel the farthest) when the diameter of the nerve is large, when membrane resistance is high, and when internal it determines the speed at which information can be transmitted in the nervous system. To understand conduction velocity in excitable tissues, two major concepts must be explained: the time constant and the length constant. These concepts, called cable proper- ties, explain how nerves and muscles act as cables to conduct electrical activity. The time constant (τ) is the amount of time it takes following the injection of current for the potential to change to 63% of its final value. In other words, the time constant indicates how quickly a cell membrane depolarizes in response to an inward current or how quickly it hyperpolarizes in response to an outward current. Thus τ = R Cm m where τ = = = Time constant R Membrane resistance C Membrane capacitan m m cce Two factors affect the time constant. The first factor is membrane resistance (Rm). When Rm is high, current does not readily flow across the cell membrane, which makes it difficult to change the membrane potential, thus increasing the time constant. The second factor, + + + + + + + + – – – – – – – – – + + – + + + + + + + + – – – – – – – – – + + – + + + + + + + + – – – – – – – – + – – + Active region A B C Fig. 1.15 Spread of depolarization down a nerve fiber by local currents. A, The initial segment of the axon has fired an action potential, and the potential difference across the cell membrane has reversed to become inside positive. The adjacent area is inactive and remains at the resting membrane potential, inside negative. B, At the active site, positive charges inside the nerve flow to the adjacent inactive area. C, Local current flow causes the adjacent area to be depolarized to threshold and to fire action potentials; the original active region has repolarized back to the resting membrane potential.Www.Medicalstudyzone.com
1—Cellular Physiology • 25 current spreads farthest from the active region to propagate action potentials. Increasing nerve fiber size is certainly an important mechanism for increas- ing conduction velocity in the nervous system, but anatomic constraints limit how large nerves can become. Therefore a second mechanism, myelina- tion, is invoked to increase conduction velocity. ♦ Myelination. Myelin is a lipid insulator of nerve axons that increases membrane resistance and decreases membrane capacitance. The increased membrane resistance forces current to flow along the path of least resistance of the axon interior rather than across the high resistance path of the axonal membrane. The decreased membrane capacitance produces a decrease in time constant; thus at breaks in the myelin sheath (see following), the axonal membrane depolarizes faster in response to inward current. Together, the effects of increased membrane resistance and decreased membrane capacitance result in increased conduction velocity (Box 1.4). resistance is low. In other words, current flows along the path of least resistance. Changes in Conduction Velocity There are two mechanisms that increase conduction velocity along a nerve: increasing the size of the nerve fiber and myelinating the nerve fiber. These mecha- nisms can best be understood in terms of the cable properties of time constant and length constant. ♦ Increasing nerve diameter. Increasing the size of a nerve fiber increases conduction velocity, a relation- ship that can be explained as follows: Internal resistance, Ri, is inversely proportional to the cross- sectional area (A = πr2). Therefore the larger the fiber, the lower the internal resistance. The length constant is inversely proportional to the square root of Ri (refer to the equation for length constant). Thus the length constant (λ) will be large when internal resistance (Ri) is small (i.e., fiber size is large). The largest nerves have the longest length constants, and BOX 1.4 Clinical Physiology: Multiple Sclerosis DESCRIPTION OF CASE. A 32-year-old woman had her first episode of blurred vision 5 years ago. She had trouble reading the newspaper and the fine print on labels. Her vision returned to normal on its own, but 10 months later, the blurred vision recurred, this time with other symptoms including double vision, and a “pins and needles” feeling and severe weakness in her legs. She was too weak to walk even a single flight of stairs. She was referred to a neurologist, who ordered a series of tests. Magnetic Resonance Imaging (MRI) of the brain showed lesions typical of multiple sclerosis. Visual evoked potentials had a prolonged latency that was consistent with decreased nerve conduction veloc- ity. Since the diagnosis, she has had two relapses and she is currently being treated with interferon beta. EXPLANATION OF CASE. Action potentials are propa- gated along nerve fibers by spread of local currents as follows: When an action potential occurs, the inward current of the upstroke of the action potential depolar- izes the membrane at that site and reverses the polarity (i.e., that site briefly becomes inside positive). The depolarization then spreads to adjacent sites along the nerve fiber by local current flow. Importantly, if these local currents depolarize an adjacent region to thresh- old, it will fire an action potential (i.e., the action potential will be propagated). The speed of propagation of the action potential is called conduction velocity. The further local currents can spread without decay (expressed as the length constant), the faster the con- duction velocity. There are two main factors that increase length constant and therefore increase conduc- tion velocity in nerves: increased nerve diameter and myelination. Myelin is an insulator of axons that increases mem- brane resistance and decreases membrane capacitance. By increasing membrane resistance, current is forced to flow down the axon interior and less current is lost across the cell membrane (increasing length constant); because more current flows down the axon, conduction velocity is increased. By decreasing membrane capaci- tance, local currents depolarize the membrane more rapidly, which also increases conduction velocity. In order for action potentials to be conducted in myelin- ated nerves, there must be periodic breaks in the myelin sheath (at the nodes of Ranvier), where there is a concentration of Na+ and K+ channels. Thus at the nodes, the ionic currents necessary for the action potential can flow across the membrane (e.g., the inward Na+ current necessary for the upstroke of the action potential). Between nodes, membrane resistance is very high and current is forced to flow rapidly down the nerve axon to the next node, where the next action potential can be generated. Thus the action potential appears to “jump” from one node of Ranvier to the next. This is called saltatory conduction. Multiple sclerosis is the most common demyelinat
26 • Physiology tory, depending on the nature of the neurotransmitter released from the presynaptic nerve terminal. If the neurotransmitter is excitatory, it causes depolarization of the postsynaptic cell; if the neurotransmitter is inhibitory, it causes hyperpolarization of the postsyn- aptic cell. In contrast to electrical synapses, neurotransmission across chemical synapses is unidirectional (from pre- synaptic cell to postsynaptic cell). The synaptic delay is the time required for the multiple steps in chemical neurotransmission to occur. Neuromuscular Junction—Example of a Chemical Synapse Motor Units Motoneurons are the nerves that innervate muscle fibers. A motor unit comprises a single motoneuron and the muscle fibers it innervates. Motor units vary considerably in size: A single motoneuron may activate a few muscle fibers or thousands of muscle fibers. Predictably, small motor units are involved in fine motor activities (e.g., facial expressions), and large motor units are involved in gross muscular activities (e.g., quadriceps muscles used in running). Sequence of Events at the Neuromuscular Junction The synapse between a motoneuron and a muscle fiber is called the neuromuscular junction (Fig. 1.16). An action potential in the motoneuron produces an action potential in the muscle fibers it innervates by the fol- lowing sequence of events: The numbered steps cor- relate with the circled numbers in Figure 1.16. 1. Action potentials are propagated down the motoneu- ron, as described previously. Local currents depolar- ize each adjacent region to threshold. Finally, the presynaptic terminal is depolarized, and this depo- larization causes voltage-gated Ca2+ channels in the presynaptic membrane to open. 2. When these Ca2+ channels open, the Ca2+ permeabil- ity of the presynaptic terminal increases, and Ca2+ flows into the terminal down its electrochemical gradient. 3. Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine (ACh), which has been previously synthesized and stored in synaptic vesicles. To release ACh, the synaptic vesicles fuse with the plasma membrane and empty their contents into the synaptic cleft by exocytosis. ACh is formed from acetyl coenzyme A (acetyl CoA) and choline by the action of the enzyme choline acetyltransferase (Fig. 1.17). ACh is stored in vesicles with ATP and proteoglycan for subsequent If the entire nerve were coated with the lipid myelin sheath, however, no action potentials could occur because there would be no low resistance breaks in the membrane across which depolarizing current could flow. Therefore it is important to note that at intervals of 1 to 2 mm, there are breaks in the myelin sheath, at the nodes of Ranvier. At the nodes, membrane resis- tance is low, current can flow across the membrane, and action potentials can occur. Thus conduction of action potentials is faster in myelinated nerves than in unmyelinated nerves because action potentials “jump” long distances from one node to the next, a process called saltatory conduction. SYNAPTIC AND NEUROMUSCULAR TRANSMISSION A synapse is a site where information is transmitted from one cell to another. The information can be trans- mitted either electrically (electrical synapse) or via a chemical transmitter (chemical synapse). Types of Synapses Electrical Synapses Electrical synapses allow current to flow from one excitable cell to the next via low resistance pathways between the cells called gap junctions. Gap junctions are found in cardiac muscle and in some types of smooth muscle and account for the very fast conduc- tion in these tissues. For example, rapid cell-to-cell conduction occurs in cardiac ventricular muscle, in the uterus, and in the bladder, allowing cells in these tissues to be activated simultaneously and ensuring that contraction occurs in a coordinated manner. Chemical Synapses In chemical synapses, there is a gap between the pre- synaptic cell membrane and the postsynaptic cell membrane, known as the synaptic cleft. Information is transmitted across the synaptic cleft via a neurotrans- mitter, a substance that is released from the presynaptic terminal and binds to receptors on the postsynaptic terminal. The following sequence of events occurs at chemical synapses: An action potential in the presynaptic cell causes Ca2+ channels to open. An influx of Ca2+ into the presynaptic terminal causes the neurotransmitter, which is stored in synaptic vesicles, to be released by exocytosis. The neurotransmitter diffuses across the synaptic cleft, binds to receptors on the postsynaptic membrane, and produces a change in membrane poten- tial on the postsynaptic cell. The change in membrane potential on the postsyn- aptic cell membrane can be either excitatory or inhibi-Www.Medicalstudyzone.com
1—Cellular Physiology • 27 the α subunits of the nicotinic receptor and causes a conformational change. It is important to note that the nicotinic receptor for ACh is an example of a ligand-gated ion channel: It also is an Na+ and K+ channel. When the conformational change occurs, the central core of the channel opens, and the per- meability of the motor end plate to both Na+ and K+ increases. 5. When these channels open, both Na+ and K+ flow down their respective electrochemical gradients, Na+ moving into the end plate and K+ moving out, each ion attempting to drive the motor end plate potential (EPP) to its equilibrium potential. Indeed, if there were no other ion channels in the motor end plate, the end plate would depolarize to a value about halfway between the equilibrium potentials for Na+ and K+, or approximately 0 mV. (In this case, zero is not a “magic number”—it simply happens to be the value about halfway between the two equilib- rium potentials.) In practice, however, because other ion channels that influence membrane potential are present in the end plate, the motor end plate only depolarizes to about −50 mV, which is the EPP. The EPP is not an action potential but is simply a local depolarization of the specialized motor end plate. The content of a single synaptic vesicle produces the smallest possible change in membrane potential of the motor end plate, the miniature end plate release. On stimulation, the entire content of a synaptic vesicle is released into the synaptic cleft. The smallest possible amount of ACh that can be released is the content of one synaptic vesicle (one quantum), and for this reason, the release of ACh is said to be quantal. 4. ACh diffuses across the synaptic cleft to the postsyn- aptic membrane. This specialized region of the muscle fiber is called the motor end plate, which contains nicotinic receptors for ACh. ACh binds to 1 AChE Na+ Choline Acetate ACh ACh ACh ACh ACh ACh Presynaptic nerve terminal Motor end plate Ca2+ Action potential in nerve Depolarization of motor end plate Action potential in muscle 2 3 4 7 6 MOTONEURON MUSCLE K+ Na+ 5 Fig. 1.16 Sequence of events in neuromuscular transmission. 1, Action potential travels down the motoneuron to the presynaptic terminal. 2, Depolarization of the presynaptic terminal opens Ca2+ channels, and Ca2+ flows into the terminal. 3, Acetylcholine (ACh) is extruded into the synapse by exocytosis. 4, ACh binds to its receptor on the motor end plate. 5, Channels for Na+ and K+ are opened in the motor end plate. 6, Depolarization of the motor end plate causes action potentials to be generated in the adjacent muscle tissue. 7, ACh is degraded to choline and acetate by acetylcholinesterase (AChE); choline is taken back into the presynaptic terminal on an Na+- choline cotransporter. Choline + Acetyl CoA Choline + Acetate choline acetyltransferase acetylcholinesterase Synthesis Degradation Reuptake into nerve terminal Acetylcholine Fig. 1.17 Synthesis and degradation of acetylcholine.Acetyl CoA, Acetyl coenzyme A.Www.Medicalstudyzone.com
28 • Physiology muscle, and, eventually, death from respiratory failure. ♦ Curare competes with ACh for the nicotinic recep- tors on the motor end plate, decreasing the size of the EPP. When administered in maximal doses, curare causes paralysis and death. D-Tubocurarine, a form of curare, is used therapeutically to cause relaxation of skeletal muscle during anesthesia. A related substance, α-bungarotoxin, binds irre- versibly to ACh receptors. Binding of radioactive α-bungarotoxin has provided an experimental tool for measuring the density of ACh receptors on the motor end plate. ♦ AChE inhibitors (anticholinesterases) such as neo- stigmine prevent degradation of ACh in the synaptic cleft, and they prolong and enhance the action of ACh at the motor end plate. AChE inhibitors can be used in the treatment of myasthenia gravis, a disease characterized by skeletal muscle weakness and fatigability, in which ACh receptors are blocked by antibodies (Box 1.5). ♦ Hemicholinium blocks choline reuptake into pre- synaptic terminals, thus depleting choline stores from the motoneuron terminal and decreasing the synthesis of ACh. Types of Synaptic Arrangements There are several types of relationships between the input to a synapse (the presynaptic element) and the output (the postsynaptic element): one-to-one, one-to- many, or many-to-one. ♦ One-to-one synapses. The one-to-one synapse is illustrated by the neuromuscular junction (see Fig. 1.16). A single action potential in the presynaptic cell, the motoneuron, causes a single action potential in the postsynaptic cell, the muscle fiber. ♦ One-to-many synapses. The one-to-many synapse is uncommon, but it is found, for example, at the potential (MEPP). MEPPs summate to produce the full-fledged EPP. The spontaneous appearance of MEPPs proves the quantal nature of ACh release at the neuromuscular junction. Each MEPP, which represents the content of one synaptic vesicle, depolarizes the motor end plate by about 0.4 mV. An EPP is a multiple of these 0.4-mV units of depolarization. How many such quanta are required to depolarize the motor end plate to the EPP? Because the motor end plate must be depolarized from its resting potential of −90 mV to the threshold potential of −50 mV, it must therefore depolarize by 40 mV. Depolarization by 40 mV requires 100 quanta (because each quantum or vesicle depolarizes the motor end plate by 0.4 mV). 6. Depolarization of the motor end plate (the EPP) then spreads by local currents to adjacent muscle fibers, which are depolarized to threshold and fire action potentials. Although the motor end plate itself cannot fire action potentials, it depolarizes sufficiently to initiate the process in the neighboring “regular” muscle cell membranes. Action potentials are propa- gated down the muscle fiber by a continuation of this process. 7. The EPP at the motor end plate is terminated when ACh is degraded to choline and acetate by acetyl- cholinesterase (AChE) on the motor end plate. Approximately 50% of the choline is returned to the presynaptic terminal by Na+-choline cotransport, to be used again in the synthesis of new ACh. Agents That Alter Neuromuscular Function Several agents interfere with normal activity at the neuromuscular junction, and their mechanisms of action can be readily understood by considering the steps involved in neuromuscular transmission (Table 1.3; see Fig. 1.16). ♦ Botulinus toxin blocks the release of ACh from presynaptic terminals, causing total blockade of neuromuscular transmission, paralysis of skeletal TABLE 1.3 Agents Affecting Neuromuscular Transmission Example Action Effect on Neuromuscular Transmission Botulinus toxin Blocks ACh release from presynaptic terminals Total blockade, paralysis of respiratory muscles, and death Curare Competes with ACh for receptors on motor end plate Decreases size of EPP; in maximal doses produces paralysis of respiratory muscles and death Neostigmine AChE inhibitor (anticholinesterase) Prolongs and enhances action of ACh at motor end plate Hemicholinium Blocks reuptake of choline into presynaptic terminal Depletes ACh stores from presynaptic terminal ACh, Acetylcholine; AChE, acetylcholinesterase; EPP, end plate potential.Www.Medicalstudyzone.com
1—Cellular Physiology • 29 presynaptic cell is insufficient to produce an action potential in the postsynaptic cell. Instead, many presynaptic cells converge on the postsynaptic cell, these inputs summate, and the sum of the inputs determines whether the postsynaptic cell will fire an action potential. Synaptic Input—Excitatory and Inhibitory Postsynaptic Potentials The many-to-one synaptic arrangement is a common configuration in which many presynaptic cells converge on a single postsynaptic cell, with the inputs being either excitatory or inhibitory. The postsynaptic cell integrates all the converging information, and if the sum of the inputs is sufficient to bring the postsynaptic cell to threshold, it will then fire an action potential. Excitatory Postsynaptic Potentials Excitatory postsynaptic potentials (EPSPs) are synaptic inputs that depolarize the postsynaptic cell, bringing the membrane potential closer to threshold and closer to firing an action potential. EPSPs are produced by opening Na+ and K+ channels, similar to the nicotinic ACh receptor. The membrane potential is driven to a value approximately halfway between the equilibrium potentials for Na+ and K+, or 0 mV, which is a depolar- ized state. Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin. Inhibitory Postsynaptic Potentials Inhibitory postsynaptic potentials (IPSPs) are synaptic inputs that hyperpolarize the postsynaptic cell, taking the membrane potential away from threshold and farther from firing an action potential. IPSPs are pro- duced by opening Cl− channels. The membrane potential is driven toward the Cl− equilibrium potential (approximately −90 mV), which is a hyperpolarized state. Inhibitory neurotransmitters are γ-aminobutyric acid (GABA) and glycine. Integration of Synaptic Information The presynaptic information that arrives at the synapse may be integrated in one of two ways, spatially or temporally. Spatial Summation Spatial summation occurs when two or more presyn- aptic inputs arrive at a postsynaptic cell simultaneously. If both inputs are excitatory, they will combine to produce greater depolarization than either input would produce separately. If one input is excitatory and the other is inhibitory, they will cancel each other out. Spatial summation may occur, even if the inputs are far synapses of motoneurons on Renshaw cells of the spinal cord. An action potential in the presynaptic cell, the motoneuron, causes a burst of action poten- tials in the postsynaptic cells. This arrangement causes amplification of activity. ♦ Many-to-one synapses. The many-to-one synapse is a very common arrangement in the nervous system. In these synapses, an action potential in the BOX 1.5 Clinical Physiology: Myasthenia Gravis DESCRIPTION OF CASE. An 18-year-old college woman comes to the student health service com- plaining of progressive weakness. She reports that occasionally her eyelids “droop” and that she tires easily, even when completing ordinary daily tasks such as brushing her hair. She has fallen several times while climbing a flight of stairs. These symp- toms improve with rest. The physician orders blood studies, which reveal elevated levels of antibodies to ACh receptors. Nerve stimulation studies show decreased responsiveness of skeletal muscle on repeated stimulation of motoneurons. The woman is diagnosed with myasthenia gravis and is treated with the drug pyridostigmine. After treatment, she reports a return of muscle strength. EXPLANATION OF CASE. This young woman has classic myasthenia gravis. In the autoimmune form of the disease, antibodies are produced to ACh receptors on the motor end plates of skeletal muscle. Her symptoms of severe muscle weakness (eye muscles; arms and legs) are explainable by the presence of antibodies that block ACh receptors. Although ACh is released in normal amounts from the terminals of motoneurons, binding of ACh to its receptors on the motor end plates is impaired. Because ACh cannot bind, depolarization of the motor end plate (EPP) will not occur and normal action potentials cannot be generated in the skeletal muscle. Muscle weakness and fatigability ensue. TREATMENT. Treatment of the patient with myas- thenia gravis depends on a clear understanding of the physiology of the neuromuscular junction. Because this patient’s condition improved with the administration of pyridostigmine (a long-acting AChE inhibitor), the success of the treatment con- firmed the diagnosis of myasthenia gravis. AChE on the motor end plate normally degrades ACh (i.e., AChE terminates the action of ACh). By inhibiting the ACh-degradative enzyme with pyridostigmine, ACh levels in the neuromuscular junction are main- tained at a high level, prolonging the time available for ACh to activate its receptors on the motor end plate. Thus a more normal EPP in the muscle fiber can be produced even though many of the ACh receptors are blocked by antibodies.Www.Medical
30 • Physiology Neurotransmitters The transmission of information at chemical synapses involves the release of a neurotransmitter from a pre- synaptic cell, diffusion across the synaptic cleft, and binding of the neurotransmitter to specific receptors on the postsynaptic membrane to produce a change in membrane potential. The following criteria are used to formally designate a substance as a neurotransmitter: The substance must be synthesized in the presynaptic cell; the substance must be released by the presynaptic cell on stimulation; and, if the substance is applied exogenously to the postsynaptic membrane at physiologic concentration, the response of the postsynaptic cell must mimic the in vivo response. Neurotransmitter substances can be grouped into the following categories: ACh, biogenic amines, amino acids, and neuropeptides (Table 1.4). Acetylcholine The role of ACh as a neurotransmitter is vitally impor- tant for several reasons. ACh is the only neurotransmitter that is utilized at the neuromuscular junction. It is the neurotransmitter released from all preganglionic and most postganglionic neurons in the parasympathetic apart on the nerve cell body, because EPSPs and IPSPs are conducted so rapidly over the cell membrane. Temporal Summation Temporal summation occurs when two presynaptic inputs arrive at the postsynaptic cell in rapid succes- sion. Because the inputs overlap in time, they summate. Other Phenomena That Alter Synaptic Activity Facilitation, augmentation, and post-tetanic potentia- tion are phenomena that may occur at synapses. In each instance, repeated stimulation causes the response of the postsynaptic cell to be greater than expected. The common underlying mechanism is believed to be an increased release of neurotransmitter into the synapse, possibly caused by accumulation of Ca2+ in the presynaptic terminal. Long-term potentiation occurs in storage of memories and involves both increased release of neurotransmitter from presynaptic terminals and increased sensitivity of postsynaptic membranes to the transmitter. Synaptic fatigue may occur where repeated stimula- tion produces a smaller than expected response in the postsynaptic cell, possibly resulting from the deple- tion of neurotransmitter stores from the presynaptic terminal. TABLE 1.4 Classification of Neurotransmitter Substances Choline Esters Biogenic Amines Amino Acids Neuropeptides Acetylcholine (ACh) Dopamine Epinephrine Histamine Norepinephrine Serotonin γ-Aminobutyric acid (GABA) Glutamate Glycine Adrenocorticotropin (ACTH) Cholecystokinin Dynorphin Endorphins Enkephalins Gastrin-releasing peptide (GRP) Glucose-dependent insulinotropic peptide (GIP) Glucagon Neurophysin II Neurotensin Oxytocin Secretin Somatostatin Substance P Thyrotropin-releasing hormone (TRH) Vasopressin, or antidiuretic hormone (ADH) Vasoactive intestinal peptide (VIP)Www.Medicalstudyzone.com
1—Cellular Physiology • 31 ACh at the postsynaptic membrane. Approximately one-half of the choline that is released from the degra- dation of ACh is taken back into the presynaptic terminal to be reutilized for synthesis of new ACh. Norepinephrine, Epinephrine, and Dopamine Norepinephrine, epinephrine, and dopamine are members of the same family of biogenic amines: They share a common precursor, tyrosine, and a common biosynthetic pathway (Fig. 1.18). Tyrosine is converted to L-dopa by tyrosine hydroxylase, and L-dopa is con- verted to dopamine by dopa decarboxylase. If dopamine β-hydroxylase is present in small dense-core vesicles of nervous system and from all preganglionic neurons in the sympathetic nervous system. It is also the neuro- transmitter that is released from presynaptic neurons of the adrenal medulla. Figure 1.17 illustrates the synthetic and degradative pathways for ACh. In the presynaptic terminal, choline and acetyl CoA combine to form ACh, catalyzed by choline acetyltransferase. When ACh is released from the presynaptic nerve terminal, it diffuses to the post- synaptic membrane, where it binds to and activates nicotinic ACh receptors. AChE is present on the post- synaptic membrane, where it degrades ACh to choline and acetate. This degradation terminates the action of Tyrosine 3-Methoxytyramine Homovanillic acid (HVA) Dihydroxyphenylacetic acid tyrosine hydroxylase L-Dopa dopa decarboxylase dopamine β-hydroxylase Dopamine phenylethanolamine-N-methyltransferase Synthesis Degradation Dopaminergic neurons Adrenergic neurons Adrenal medulla COMT MAO MAO + COMT Normetanephrine 3-Methoxy-4-hydroxymandelic acid (VMA) Dihydroxymandelic acid Metanephrine 3-Methoxy-4-hydroxymandelic acid (VMA) Dihydroxymandelic acid Norepinephrine Epinephrine COMT MAO MAO + COMT COMT MAO MAO + COMT Fig. 1.18 Synthesis and degradation of dopamine, norepinephrine, and epinephrine. COMT, Catechol- O-methyltransferase; MAO, monoamine oxidase.Www.Medicalstudyzone.com
32 • Physiology normetanephrine. The major metabolite of epinephrine is metanephrine. Both norepinephrine and epineph- rine are degraded to 3-methoxy-4-hydroxymandelic acid (VMA). Serotonin Serotonin, another biogenic amine, is produced from tryptophan in serotonergic neurons in the brain and in the gastrointestinal tract (Fig. 1.19). Following its release from presynaptic neurons, serotonin may be returned intact to the nerve terminal, or it may be degraded in the presynaptic terminal by MAO to 5-hydroxyindoleacetic acid. Additionally, serotonin serves as the precursor to melatonin in the pineal gland. Histamine Histamine, a biogenic amine, is synthesized from his- tidine, catalyzed by histidine decarboxylase. It is present in neurons of the hypothalamus, as well as in nonneural tissue such as mast cells of the gastrointestinal tract. Glutamate Glutamate, an amino acid, is the major excitatory neurotransmitter in the central nervous system. It plays a significant role in the spinal cord and cerebellum. There are four subtypes of glutamate receptors. Three of the subtypes are ionotropic receptors, or ligand-gated ion channels including the NMDA (N-methyl-D-aspartate) receptor that is widely distributed throughout the central nervous system. A fourth subtype comprises metabotropic receptors, which are coupled via het- erotrimeric guanosine triphosphate (GTP)–binding proteins (G proteins) to ion channels. the nerve terminal, dopamine is converted to norepi- nephrine. If phenylethanolamine-N-methyl transferase (PNMT) is present (with S-adenosylmethionine as the methyl donor), then norepinephrine is methylated to form epinephrine. The specific neurotransmitter secreted depends on which portion, or portions, of the enzymatic pathway are present in a particular type of nerve or gland. Thus dopaminergic neurons secrete dopamine because the presynaptic nerve terminal contains tyrosine hydroxy- lase and dopa decarboxylase but not the other enzymes. Adrenergic neurons secrete norepinephrine because they contain dopamine β-hydroxylase, in addition to tyrosine hydroxylase and dopa decarboxylase, but not PNMT. The adrenal medulla contains the complete enzymatic pathway; therefore it secretes primarily epinephrine. The degradation of dopamine, norepinephrine, and epinephrine to inactive substances occurs via two enzymes: catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). COMT, a methylating enzyme, is not found in nerve terminals, but it is dis- tributed widely in other tissues including the liver. MAO is located in presynaptic nerve terminals and catalyzes oxidative deamination. If a neurotransmitter is to be degraded by MAO, there must be reuptake of the neurotransmitter from the synapse. Each of the biogenic amines can be degraded by MAO alone, by COMT alone, or by both MAO and COMT (in any order). Thus there are three possible degradative products from each neurotransmitter, and typically these products are excreted in the urine (see Fig. 1.8). The major metabolite of norepinephrine is 5-Hydroxytryptophan 5-Hydroxyindoleacetic acid 5-hydroxytryptophan decarboxylase Tryptophan tryptophan hydroxylase MAO + aldehyde dehydrogenase Serotonin Melatonin Synthesis Degradation Reuptake into nerve terminal Pineal gland Fig. 1.19 Synthesis and degradation of serotonin. MAO, Monoamine oxidase.Www.Medicalstudyzone.com
1—Cellular Physiology • 33 is metabotropic. When stimulated, it increases K+ conductance and hyperpolarizes the postsynaptic cell. Huntington disease is associated with GABA defi- ciency. The disease is characterized by hyperkinetic choreiform movements related to a deficiency of GABA in the projections from the striatum to the globus palli- dus. The characteristic uncontrolled movements are, in part, attributed to lack of GABA-dependent inhibition of neural pathways. Nitric Oxide Nitric oxide (NO) is a short-acting inhibitory neuro- transmitter in the gastrointestinal tract and the central nervous system. In presynaptic nerve terminals, the enzyme NO synthase converts arginine to citrulline and NO. Then, NO, a permeant gas, simply diffuses from the presynaptic terminal to its target cell (instead of the usual packaging of neurotransmitter in synaptic vesicles and release by exocytosis). In addition to serving as a neurotransmitter, NO also functions in signal transduction of guanylyl cyclase in a variety of tissues including vascular smooth muscle (see Chapter 4). Neuropeptides There is a long and growing list of neuropeptides that function as neuromodulators, neurohormones, and neurotransmitters (see Table 1.4 for a partial list). ♦ Neuromodulators are substances that act on the presynaptic cell to alter the amount of neurotrans- mitter released in response to stimulation. Alterna- tively, a neuromodulator may be cosecreted with a neurotransmitter and alter the response of the postsynaptic cell to the neurotransmitter. ♦ Neurohormones, like other hormones, are released from secretory cells (in these cases, neurons) into the blood to act at a distant site. ♦ In several instances, neuropeptides are copackaged and cosecreted from presynaptic vesicles along with the classical neurotransmitters. For example, vasoac- tive intestinal peptide (VIP) is stored and secreted with ACh, particularly in neurons of the gastro- intestinal tract. Somatostatin, enkephalin, and neu- rotensin are secreted with norepinephrine. Substance P is secreted with serotonin. In contrast to classical neurotransmitters, which are synthesized in presynaptic nerve terminals, neuropep- tides are synthesized in the nerve cell body. As occurs in all protein synthesis, the cell’s DNA is transcribed into specific messenger RNA, which is translated into polypeptides on the ribosomes. Typically, a preliminary polypeptide containing a signal peptide sequence is synthesized first. The signal peptide is removed in the endoplasmic reticulum, and the final peptide is Glycine Glycine, an amino acid, is an inhibitory neurotransmit- ter that is found in the spinal cord and brain stem. Its mechanism of action is to increase Cl− conductance of the postsynaptic cell membrane. By increasing Cl− con- ductance, the membrane potential is driven closer to the Cl− equilibrium potential. Thus the postsynaptic cell membrane is hyperpolarized or inhibited. γ-Aminobutyric Acid (GABA) GABA is an amino acid and an inhibitory neurotrans- mitter that is distributed widely in the central nervous system in GABAergic neurons. GABA is synthesized from glutamic acid, catalyzed by glutamic acid decar- boxylase, an enzyme that is unique to GABAergic neurons (Fig. 1.20). Following its release from presyn- aptic nerves and its action at the postsynaptic cell membrane, GABA can be either recycled back to the presynaptic terminal or degraded by GABA transami- nase to enter the citric acid cycle. Unlike the other amino acids that serve as neurotransmitters (e.g., glu- tamate and glycine), GABA does not have any metabolic functions (i.e., it is not incorporated into proteins). The two types of GABA receptors on postsynaptic membranes are the GABAA and the GABAB receptors. The GABAA receptor is directly linked to a Cl− channel and thus is ionotropic. When stimulated, it increases Cl− conductance and thus hyperpolarizes (inhibits) the postsynaptic cell. The GABAA receptor is the site of action of benzodiazepines and barbiturates in the central nervous system. The GABAB receptor is coupled via a G protein to a K+ channel and thus GABA-transaminase Succinate semialdehyde Citric acid cycle Glutamate glutamate decarboxylase Synthesis Degradation Reuptake into nerve terminal γ-Aminobutyric acid (GABA) Fig. 1.20 Synthesis and degradation of γ-aminobutyric acid (GABA).Www.Medicalstudyzone.com
34 • Physiology Muscle Filaments Each muscle fiber behaves as a single unit, is multinucle- ate, and contains myofibrils. The myofibrils are sur- rounded by SR and are invaginated by transverse tubules (T tubules). Each myofibril contains interdigi- tating thick and thin filaments, which are arranged longitudinally and cross-sectionally in sarcomeres (Fig. 1.21). The repeating units of sarcomeres account for the unique banding pattern seen in striated muscle (which includes both skeletal and cardiac muscle). Thick Filaments The thick filaments comprise a large molecular weight protein called myosin, which has six polypeptide chains including one pair of heavy chains and two pairs of light chains (see Fig. 1.21A). Most of the heavy-chain myosin has an α-helical structure, in which the two chains coil around each other to form the “tail” of the myosin molecule. The four light chains and the N terminus of each heavy chain form two globular “heads” on the myosin molecule. These globu- lar heads have an actin-binding site, which is necessary for cross-bridge formation, and a site that binds and hydrolyzes ATP (myosin ATPase). Thin Filaments The thin filaments are composed of three proteins: actin, tropomyosin, and troponin (see Fig. 1.21B). Actin is a globular protein and, in this globular form, is called G-actin. In the thin filaments, G-actin is polym- erized into two strands that are twisted into an α-helical structure to form filamentous actin, called F-actin. Actin has myosin-binding sites. When the muscle is at rest, the myosin-binding sites are covered by tropomyo- sin so that actin and myosin cannot interact. delivered to secretory vesicles. The secretory vesicles are then moved rapidly down the nerve by axonal transport to the presynaptic terminal, where they become the synaptic vesicles. Purines ATP and adenosine function as neuromodulators in the autonomic and central nervous systems. For example, ATP is synthesized in the sympathetic neurons that innervate vascular smooth muscle. It is costored and cosecreted with the “regular” neurotransmitter of these neurons, norepinephrine. When stimulated, the neuron releases both ATP and norepinephrine and both transmitters cause contraction of the smooth muscle; in fact, the ATP-induced contraction precedes the norepinephrine-induced contraction. SKELETAL MUSCLE Contraction of skeletal muscle is under voluntary or reflex control. Each skeletal muscle cell is innervated by a branch of a motoneuron. Action potentials are propagated along the motoneurons, leading to release of ACh at the neuromuscular junction, depolarization of the motor end plate, and initiation of action poten- tials in the muscle fiber. What events, then, elicit contraction of the muscle fiber? These events, occurring between the action potential in the muscle fiber and contraction of the muscle fiber, are called excitation-contraction coupling. The mechanisms of excitation-contraction coupling in skeletal muscle and smooth muscle are discussed in this chapter, and the mechanisms of excitation-contraction coupling in cardiac muscle are discussed in Chapter 4. Tail Heads Heavy chains Light chains Thick filaments (myosin) A Actin Tropomyosin Troponin Thin filaments (actin, tropomyosin, troponin) T I C B Fig. 1.21 Structure of thick (A) and thin (B) filaments of skeletal muscle. Troponin is a complex of three proteins: I, Troponin I; T, troponin T; and C, troponin C.Www.Medicalstudyzone.com
1—Cellular Physiology • 35 The I bands are located on either side of the A band and appear light when viewed under polarized light. They contain the thin (actin) filaments, intermediate filamentous proteins, and Z disks. They have no thick filaments. The Z disks are darkly staining structures that run down the middle of each I band, delineating the ends of each sarcomere. The bare zone is located in the center of each sar- comere. There are no thin filaments in the bare zone; thus there can be no overlap of thick and thin filaments or cross-bridge formation in this region. The M line bisects the bare zone and contains darkly staining proteins that link the central portions of the thick filaments together. Cytoskeletal Proteins Cytoskeletal proteins establish the architecture of the myofibrils, ensuring that the thick and thin filaments are aligned correctly and at proper distances with respect to each other. Transverse cytoskeletal proteins link thick and thin filaments, forming a “scaffold” for the myofibrils and linking sarcomeres of adjacent myofibrils. A system of intermediate filaments holds the myofibrils together, side by side. The entire myofibrillar array is anchored to the cell membrane by an actin-binding protein called dystrophin. (In patients with muscular dystrophy, dystrophin is defective or absent.) Longitudinal cytoskeletal proteins include two large proteins called titin and nebulin. Titin, which is associ- ated with thick filaments, is a large molecular weight protein that extends from the M lines to the Z disks. Part of the titin molecule passes through the thick Tropomyosin is a filamentous protein that runs along the groove of each twisted actin filament. At rest, its function is to block the myosin-binding sites on actin. If contraction is to occur, tropomyosin must be moved out of the way so that actin and myosin can interact. Troponin is a complex of three globular proteins (troponin T, troponin I, and troponin C) located at regular intervals along the tropomyosin filaments. Troponin T (T for tropomyosin) attaches the troponin complex to tropomyosin. Troponin I (I for inhibition), along with tropomyosin, inhibits the interaction of actin and myosin by covering the myosin-binding site on actin. Troponin C (C for Ca2+) is a Ca2+-binding protein that plays a central role in the initiation of contraction. When the intracellular Ca2+ concentration increases, Ca2+ binds to troponin C, producing a con- formational change in the troponin complex. This conformational change moves tropomyosin out of the way, permitting the binding of actin to the myosin heads. Arrangement of Thick and Thin Filaments in Sarcomeres The sarcomere is the basic contractile unit, and it is delineated by the Z disks. Each sarcomere contains a full A band in the center and one-half of two I bands on either side of the A band (Fig. 1.22). The A bands are located in the center of the sarco- mere and contain the thick (myosin) filaments, which appear dark when viewed under polarized light. Thick and thin filaments may overlap in the A band; these areas of overlap are potential sites of cross-bridge formation. Z disk M line Thin filaments Titin Thick filaments Z disk Bare zone A band Sarcomere I band + +– – Fig. 1.22 Arrangement of thick and thin filaments of skeletal muscle in sarcomeres.Www.Medicalstudyzone.com
36 • Physiology interior of the SR, keeping the intracellular Ca2+ con- centration low when the muscle fiber is at rest. Within the SR, Ca2+ is bound to calsequestrin, a low-affinity, high-capacity Ca2+-binding protein. Calsequestrin, by binding Ca2+, helps to maintain a low free Ca2+ concen- tration inside the SR, thereby reducing the work of the Ca2+ ATPase pump. Thus a large quantity of Ca2+ can be stored inside the SR in bound form, while the intra- sarcoplasmic reticulum free Ca2+ concentration remains extremely low. Excitation-Contraction Coupling in Skeletal Muscle The mechanism that translates the muscle action potential into the production of tension is excitation- contraction coupling. Figure 1.24 shows the temporal relationships between an action potential in the skeletal muscle fiber, the subsequent increase in intracellular free Ca2+ concentration (which is released from the SR), and contraction of the muscle fiber. These temporal relationships are critical in that the action potential always precedes the rise in intracellular Ca2+ concentra- tion, which always precedes contraction. The steps involved in excitation-contraction coupling are described as follows and illustrated in Figure 1.25 (Step 6 is illustrated in Fig. 1.26): 1. Action potentials in the muscle cell membrane are propagated to the T tubules by the spread of local currents. Thus the T tubules are continuous with the sarcolemmal membrane and carry the depolariza- tion from the surface to the interior of the muscle fiber. 2a. and b. Depolarization of the T tubules causes a criti- cal conformational change in their voltage-sensitive dihydropyridine receptors. This conformational filament; the rest of the molecule, which is elastic or springlike, is anchored to the Z disk. As the length of the sarcomere changes, so does the elastic portion of the titin molecule. Titin also helps center the thick fila- ments in the sarcomere. Nebulin is associated with thin filaments. A single nebulin molecule extends from one end of the thin filament to the other. Nebulin serves as a “molecular ruler,” setting the length of thin filaments during their assembly. α-Actinin anchors the thin fila- ments to the Z disk. Transverse Tubules and the Sarcoplasmic Reticulum The transverse (T) tubules are an extensive network of muscle cell membrane (sarcolemmal membrane) that invaginates deep into the muscle fiber. The T tubules are responsible for carrying depolarization from action potentials at the muscle cell surface to the interior of the fiber. The T tubules make contact with the terminal cisternae of the SR and contain a voltage- sensitive protein called the dihydropyridine receptor, named for the drug that inhibits it (Fig. 1.23). The sarcoplasmic reticulum (SR) is an internal tubular structure, which is the site of storage and release of Ca2+ for excitation-contraction coupling. As previously noted, the terminal cisternae of the SR make contact with the T tubules in a triad arrangement. The SR contains a Ca2+-release channel called the ryanodine receptor (named for the plant alkaloid that opens this release channel). The significance of the physical relationship between the T tubules (and their dihydro- pyridine receptor) and the SR (and its ryanodine recep- tor) is described in the section on excitation-contraction coupling. Ca2+ is accumulated in the SR by the action of Ca2+ ATPase (SERCA) in the SR membrane. The Ca2+ ATPase pumps Ca2+ from the ICF of the muscle fiber into the Terminal cisternae of sarcoplasmic reticulum Sarcolemmal membrane Longitudinal sarcoplasmic reticulum Transverse tubules Fig. 1.23 Transverse tubules and sarcoplasmic reticulum (SR) of skeletal muscle. The transverse tubules are continuous with the sarcolemmal membrane and invaginate deep into the muscle fiber, making contact with terminal cisternae of the SR.Www.Medicalstudyzone.com
1—Cellular Physiology • 37 6. Cross-bridge cycling. With Ca2+ bound to troponin C and tropomyosin moved out of the way, myosin heads can now bind to actin and form so-called cross-bridges. Formation of cross-bridges is associ- ated with hydrolysis of ATP and generation of force. The sequence of events in the cross-bridge cycle is shown in Figure 1.26. A, At the beginning of the cycle, no ATP is bound to myosin, and myosin is tightly attached to actin in a “rigor” position. In rapidly contracting muscle, this state is brief. However, in the absence of ATP, this state is perma- nent (i.e., rigor mortis). B, The binding of ATP to a cleft on the back of the myosin head produces a conformational change in myosin that decreases its affinity for actin; thus myosin is released from the original actin-binding site. C, The cleft closes around the bound ATP molecule, producing a further change opens Ca2+-release channels (ryanodine receptors) on the nearby SR. (As an aside, although the T tubules’ dihydropyridine receptors are L-type voltage-gated Ca2+ channels, Ca2+ influx into the cell through these channels is not required for excitation- contraction coupling in skeletal muscle.) 3. When these Ca2+-release channels open, Ca2+ is released from its storage site in the SR into the ICF of the muscle fiber, resulting in an increase in intracellular Ca2+ concentration. At rest, the intra- cellular free Ca2+ concentration is less than 10−7 M. After its release from the SR, intracellular free Ca2+ concentration increases to levels between 10−7 M and 10−6 M. 4. Ca2+ binds to troponin C on the thin filaments, causing a conformational change in the troponin complex. Troponin C can bind as many as four Ca2+ ions per molecule of protein. Because this binding is cooperative, each molecule of bound Ca2+ increases the affinity of troponin C for the next Ca2+. Thus even a small increase in Ca2+ concentration increases the likelihood that all of the binding sites will be occu- pied to produce the necessary conformational change in the troponin complex. 5. The conformational change in troponin causes tropomyosin (which was previously blocking the interaction of actin and myosin) to be moved out of the way so that cross-bridge cycling can begin. When tropomyosin is moved away, the myosin-binding sites on actin, previously covered, are exposed. Action potential Intracellular [Ca2+] Tension Time Response Fig. 1.24 Temporal sequence of events in excitation- contraction coupling in skeletal muscle. The muscle action potential precedes a rise in intracellular [Ca2+], which precedes contraction. 1 Action potential in muscle membrane 2a Depolarization of T tubules 2b Opens SR Ca2+ release channels (ryanodine receptors) 3 Intracellular Ca2+ concentration 4 Ca2+ binds troponin C 5 Tropomyosin moves and allows interaction of actin and myosin 6 Cross-bridge cycling and force-generation 7 Ca2+ reaccumulated by SR relaxation EXCITATION – CONTRACTION IN SKELETAL MUSCLE Fig. 1.25 Steps in excitation-contraction in skeletal muscle. SR, Sarcoplasmic reticulum; T tubules, transverse tubules. See text for explanation of the circled numbers.Www.Medicalstudyzone.com
38 • Physiology ADP ADP Pi ATP + Events ATP/ADP Actin filament A Myosin head Myosin filament – + Position of Actin and Myosin During Cross-Bridge Cycling No nucleotides bound ATP bound ADP bound Rigor No nucleotides bound Conformational change in myosin ATP binds to cleft on myosin head Decreased affinity of myosin for actin Power stroke = force Myosin head binds new site on actin Myosin released Conformational change Cleft closes around ATP Myosin head displaced toward end of actin ATP hydrolysis ATP ADP + Pi ADP + Pi bound Rigor ADP released– + – + – + – + B C D E Fig. 1.26 Cross-bridge cycle in skeletal muscle. Mechanism by which myosin “walks” toward the plus end of the actin filament. A–E, See the discussion in the text. ADP, Adenosine diphos- phate; ATP, adenosine triphosphate; Pi, inorganic phosphate.Www.Medicalstudyzone.com
1—Cellular Physiology • 39 elastic elements remain stretched out and thus force transmission to the muscle surface continues after intracellular Ca2+ has fallen and cross-bridge cycling has ceased. Mechanism of Tetanus A single action potential results in the release of a fixed amount of Ca2+ from the SR, which produces a single twitch. The twitch is terminated (relaxation occurs) when the SR reaccumulates this Ca2+. However, if the muscle is stimulated repeatedly, there is insufficient time for the SR to reaccumulate Ca2+, and the intracel- lular Ca2+ concentration never returns to the low levels that exist during relaxation. Instead, the level of intra- cellular Ca2+ concentration remains high, resulting in continued binding of Ca2+ to troponin C and continued cross-bridge cycling. In this state, there is a sustained contraction called tetanus, rather than just a single twitch. Length-Tension Relationship The length-tension relationship in muscle refers to the effect of muscle fiber length on the amount of tension the fiber can develop (Fig. 1.27). The amount of tension is determined for a muscle undergoing an isometric contraction, in which the muscle is allowed to develop tension at a preset length (called preload) but is not allowed to shorten. (Imagine trying to lift a 500-lb barbell. The tension developed would be great, but no shortening or movement of muscle would occur!) The conformational change that causes myosin to be displaced toward the plus end of actin. ATP is hydro- lyzed to ADP and Pi, which remain attached to myosin. D, Myosin binds to a new site on actin (toward the plus end), constituting the force- generating, or power, stroke. Each cross-bridge cycle “walks” the myosin head 10 nanometers (10−8 meters) along the actin filament. E, ADP is released, and myosin is returned to its original state with no nucleotides bound (A). Cross-bridge cycling contin- ues, with myosin “walking” toward the plus end of the actin filament, as long as Ca2+ is bound to tro- ponin C. 7. Relaxation occurs when Ca2+ is reaccumulated in the SR by the Ca2+ ATPase of the SR membrane (SERCA). When the intracellular Ca2+ concentration decreases to less than 10−7 M, there is insufficient Ca2+ for binding to troponin C. When Ca2+ is released from troponin C, tropomyosin returns to its resting position, where it blocks the myosin-binding site on actin. As long as the intracellular Ca2+ is low, cross- bridge cycling cannot occur and the muscle will relax. The cross-bridge cycle produces force (tension) at the level of the contractile elements. In order for this force to be transmitted to the muscle surface, the series elastic elements (e.g., titin) must first be stretched out. As a result, there is a delay in transmission of force from the cross-bridges to the muscle surface (see Fig. 1.24). Once cross-bridge cycling has concluded, there is also a delay in the fall of muscle tension; the series Muscle length or preload Tension Length at maximum cross-bridge overlap Total Passive Active Fig. 1.27 Length-tension relationship in skeletal muscle. Maximal active tension occurs at muscle lengths where there is maximal overlap of thick and thin filaments.Www.Medicalstudyzone.com
40 • Physiology length-tension relationship, the force-velocity relation- ship is determined by allowing the muscle to shorten. The force, rather than the length, is fixed, and therefore it is called an isotonic contraction. The velocity of shortening reflects the speed of cross-bridge cycling. As is intuitively obvious, the velocity of shortening will be maximal (Vmax) when the afterload on the muscle is zero. As the afterload on the muscle increases, the velocity will be decreased because cross-bridges can cycle less rapidly against the higher resistance. As the afterload increases to even higher levels, the veloc- ity of shortening is reduced to zero. (Imagine how quickly you can lift a feather as opposed to a ton of bricks!) The effect of afterload on the velocity of shortening can be further demonstrated by setting the muscle to a preset length (preload) and then measuring the veloc- ity of shortening at various levels of afterload (see Fig. 1.28, right). A “family” of curves is generated, each one representing a different fixed preload. The curves always intersect at Vmax, the point where afterload is zero and where velocity of shortening is maximal. SMOOTH MUSCLE Smooth muscle lacks striations, which distinguishes it from skeletal and cardiac muscle. The striations found in skeletal and cardiac muscle are created by the banding patterns of thick and thin filaments in the sarcomeres. In smooth muscle, there are no striations because the thick and thin filaments, while present, are not organized in sarcomeres. Smooth muscle is found in the walls of hollow organs such as the gastrointestinal tract, the bladder, and the uterus, as well as in the vasculature, the ureters, the bronchioles, and the muscles of the eye. The func- tions of smooth muscle are twofold: to produce motility following measurements of tension can be made as a function of preset length (or preload): ♦ Passive tension is the tension developed by simply stretching a muscle to different lengths. (Think of the tension produced in a rubber band as it is pro- gressively stretched to longer lengths.) ♦ Total tension is the tension developed when a muscle is stimulated to contract at different preloads. It is the sum of the active tension developed by the cross-bridge cycling in the sarcomeres and the passive tension caused by stretching the muscle. ♦ Active tension is determined by subtracting the passive tension from the total tension. It represents the active force developed during cross-bridge cycling. The unusual relationship between active tension and muscle length is the length-tension relation- ship and can be explained by the mechanisms involved in the cross-bridge cycle (see Fig. 1.27). The active tension developed is proportional to the number of cross-bridges that cycle. Therefore the active tension is maximal when there is maximal overlap of thick and thin filaments and maximal possible cross-bridges. When the muscle is stretched to longer lengths, the number of possible cross- bridges is reduced and active tension is reduced. Likewise, when muscle length is decreased, the thin filaments collide with each other in the center of the sarcomere, reducing the number of possible cross- bridges and reducing active tension. Force-Velocity Relationship The force-velocity relationship, shown in Figure 1.28, describes the velocity of shortening when the force against which the muscle contracts, the after- load, is varied (see Fig. 1.28, left). In contrast to the Afterload Normal Initial velocity of shortening Vmax Afterload Changing afterload at fixed muscle length Initial velocity of shortening Vmax V = 0 Fig. 1.28 Initial velocity of shortening as a function of afterload in skeletal muscle.Www.Medicalstudyzone.com
1—Cellular Physiology • 41 Steps in Excitation-Contraction Coupling in Smooth Muscle The steps involved in excitation-contraction coupling in smooth muscle are illustrated in Figure 1.29 and occur as follows: 1. Depolarization of smooth muscle opens voltage- gated Ca2+ channels in the sarcolemmal membrane. With these Ca2+ channels open, Ca2+ flows into the cell down its electrochemical gradient. This influx of (e.g., to propel chyme along the gastrointestinal tract or to propel urine along the ureter) and to maintain tension (e.g., smooth muscle in the walls of blood vessels). Types of Smooth Muscle Smooth muscles are classified as multiunit or unitary, depending on whether the cells are electrically coupled. Unitary smooth muscle has gap junctions between cells, which allow for the fast spread of electrical activ- ity throughout the organ, followed by a coordinated contraction. Multiunit smooth muscle has little or no coupling between cells. A third type, a combination of unitary and multiunit smooth muscle, is found in vascular smooth muscle. Unitary Smooth Muscle Unitary (single unit) smooth muscle is present in the gastrointestinal tract, bladder, uterus, and ureter. The smooth muscle in these organs contracts in a coordi- nated fashion because the cells are linked by gap junctions. Gap junctions are low-resistance pathways for current flow, which permit electrical coupling between cells. For example, action potentials occur simultaneously in the smooth muscle cells of the bladder so that contraction (and emptying) of the entire organ can occur at once. Unitary smooth muscle is also characterized by spontaneous pacemaker activity, or slow waves. The frequency of slow waves sets a characteristic pattern of action potentials within an organ, which then deter- mines the frequency of contractions. Multiunit Smooth Muscle Multiunit smooth muscle is present in the iris, in the ciliary muscles of the lens, and in the vas deferens. Each muscle fiber behaves as a separate motor unit (similar to skeletal muscle), and there is little or no coupling between cells. Multiunit smooth muscle cells are densely innervated by postganglionic fibers of the parasympathetic and sympathetic nervous systems, and it is these innervations that regulate function. Excitation-Contraction Coupling in Smooth Muscle The mechanism of excitation-contraction coupling in smooth muscle differs from that of skeletal muscle. Recall that in skeletal muscle, binding of actin and myosin is permitted when Ca2+ binds troponin C. In smooth muscle, however, there is no troponin. Rather, the interaction of actin and myosin is controlled by the binding of Ca2+ to another protein, calmodulin. In turn, Ca2+-calmodulin regulates myosin-light-chain kinase, which regulates cross-bridge cycling. [Ca2+] Ca2+-calmodulin (CaM) Phosphorylation of myosin light chains Ca2+-induced Ca2+ release from SR Tension myosin-light-chain kinase Myosin ATPase Myosin~P + actin Hormones or neurotransmitters Hormones or neurotransmitters Ca2+ release from SR Depolarization Opens voltage-gated Ca2+ channels Open ligand-gated Ca2+ channels IP3 Cross-bridge cycling Fig. 1.29 The sequence of molecular events in contraction of smooth muscle. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; IP3, inositol 1,4,5-triphosphate; Myosin~P, phosphorylated myosin; Pi, inor- ganic phosphate; SR, sarcoplasmic reticulum.Www.Medicalstudyzone.com
42 • Physiology facilitating the formation of cross-bridges between actin and myosin. 6. Relaxation of smooth muscle occurs when the intracellular Ca2+ concentration falls below the level needed to form Ca2+-calmodulin complexes. A fall in intracellular Ca2+ concentration can occur by a variety of mechanisms including hyperpolarization (which closes voltage-gated Ca2+ channels); direct inhibition of Ca2+ channels by ligands such as cAMP and cyclic guanosine monophosphate (cGMP); inhi- bition of IP3 production and decreased release of Ca2+ from SR; and increased Ca2+ ATPase activity in SR. Additionally, relaxation of smooth muscle can involve activation of myosin-light-chain phospha- tase, which dephosphorylates myosin light chain, leading to inhibition of myosin ATPase. Mechanisms That Increase Intracellular Ca2+ Concentration in Smooth Muscle Depolarization of smooth muscle opens sarcolemmal voltage-gated Ca2+ channels and Ca2+ enters the cell from ECF. As already noted, this is only one source of Ca2+ for contraction. Ca2+ also can enter the cell through ligand-gated channels in the sarcolemmal membrane, or it can be released from the SR by second messenger (IP3)-gated mechanisms (Fig. 1.30). (In contrast, recall that in skeletal muscle the rise in intracellular Ca2+ concentration is caused exclusively by release from the SR—Ca2+ does not enter the cell from the ECF.) The three mechanisms involved in Ca2+ entry in smooth muscle are described as follows: ♦ Voltage-gated Ca2+ channels are sarcolemmal Ca2+ channels that open when the cell membrane poten- tial depolarizes. Thus action potentials in the smooth muscle cell membrane cause voltage-gated Ca2+ channels to open, allowing Ca2+ to flow into the cell down its electrochemical potential gradient. ♦ Ligand-gated Ca2+ channels also are present in the sarcolemmal membrane. They are not regulated by changes in membrane potential but by receptor- mediated events. Various hormones and neurotrans- mitters interact with specific receptors in the sarcolemmal membrane, which are coupled via a GTP-binding protein (G protein) to the Ca2+ channels. When the channel is open, Ca2+ flows into the cell down its electrochemical gradient. (See Chapters 2 and 9 for further discussion of G proteins.) ♦ IP3-gated Ca2+ channels are present in the SR mem- brane. The process begins at the cell membrane, but the source of the Ca2+ is the SR rather than the ECF. Hormones or neurotransmitters interact with specific receptors on the sarcolemmal membrane Ca2+ from the ECF causes an increase in intracel- lular Ca2+ concentration. In contrast to skeletal muscle, where action potentials are required to produce contraction, in smooth muscle, subthresh- old depolarization (which does not lead to an action potential) can open these voltage-gated Ca2+ chan- nels and cause an increase in intracellular Ca2+ concentration. If the depolarization of the smooth muscle membrane reaches threshold, then action potentials can occur, causing even greater depolar- ization and even greater opening of voltage-gated Ca2+ channels. Ca2+ that enters the smooth muscle cells through voltage-gated Ca2+ channels releases additional Ca2+ from the SR (called Ca2+-induced Ca2+ release). Thus the rise in intracellular Ca2+ is partly due to Ca2+ entry across the sarcolemmal membrane and partly due to Ca2+ release from intracellular SR stores. 2. Two additional mechanisms may contribute to the increase in intracellular Ca2+ concentration: ligand- gated Ca2+ channels and IP3-gated Ca2+ release chan- nels. Ligand-gated Ca2+ channels in the sarcolemmal membrane may be opened by various hormones and neurotransmitters, permitting the entry of additional Ca2+ from the ECF. IP3-gated Ca2+ release channels in the membrane of the SR may be opened by hor- mones and neurotransmitters. Either of these mecha- nisms may augment the rise in intracellular Ca2+ concentration caused by depolarization. 3. The rise in intracellular Ca2+ concentration causes Ca2+ to bind to calmodulin. Like troponin C in skeletal muscle, calmodulin binds four ions of Ca2+ in a cooperative fashion. The Ca2+-calmodulin complex binds to and activates myosin-light-chain kinase. 4. When activated, myosin-light-chain kinase phos- phorylates myosin light chain. When myosin light chain is phosphorylated, the conformation of the myosin head is altered, greatly increasing its ATPase activity. (In contrast, skeletal muscle myosin ATPase activity is always high.) The increase in myosin ATPase activity allows myosin to bind actin, thus initiating cross-bridge cycling and production of tension. The amount of tension is proportional to the intracellular Ca2+ concentration. 5. Ca2+-calmodulin, in addition to the effects on myosin described earlier, also has effects on two thin fila- ment proteins, calponin and caldesmon. At low levels of intracellular Ca2+, calponin and caldesmon bind actin, inhibiting myosin ATPase and preventing the interaction of actin and myosin. Wh
1—Cellular Physiology • 43 fewer cross-bridges will cycle and less tension will be produced (Ca2+-desensitization). SUMMARY ■ Water, a major component of the body, is distributed among two major compartments, ICF and ECF. ECF is further distributed among the plasma and the interstitial fluid. The differences in composition of ICF and ECF are created and maintained by transport proteins in the cell membranes. ■ Transport may be either passive or active. If transport occurs down an electrochemical gradient, it is passive and does not consume energy. If transport occurs against an electrochemical gradient, it is active. The energy for active transport may be primary (using ATP) or secondary (using energy from the Na+ gradient). Osmosis occurs when an impermeable solute creates an osmotic pressure difference across a membrane, which drives water flow. (e.g., norepinephrine with α1 receptors). These receptors are coupled, via a G protein, to phos- pholipase C (PLC). PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to IP3 and diacylglycerol (DAG). IP3 then diffuses to the SR, where it opens Ca2+ release channels (similar to the mechanism of the ryanodine receptor in skeletal muscle). When these Ca2+ channels are open, Ca2+ flows from its storage site in the SR into the ICF. (See Chapter 9 for discussion of IP3-mediated hormone action.) Ca2+-Independent Changes in Smooth Muscle Contraction In addition to the contractile mechanisms in smooth muscle that depend on changes in intracellular Ca2+ concentration, the degree of contraction also can be regulated by Ca2+-independent mechanisms. For example, in the presence of a constant level of intracel- lular Ca2+, if there is activation of myosin-light-chain kinase, more cross-bridges will cycle and more tension will be produced (Ca2+-sensitization); conversely, if there is activation of myosin-light-chain phosphatase, Hormone or neurotransmitter IP3-gated Ca2+ channels SMOOTH MUSCLE CELL Sarcoplasmic reticulum Ryanodine receptor IP3 PIP2 [Ca2+] Hormone or neurotransmitter Ca2+ Ca2+ Voltage-gated Ca2+ channel Ligand-gated Ca2+ channel Ca2+ Ca2+ G G PLC R R ATP Fig. 1.30 Mechanisms for increasing intracellular [Ca2+] in smooth muscle. ATP, Adenosine triphosphate; G, GTP-binding protein (G protein); IP3, inositol 1,4,5-triphosphate; PIP2, phosphati- dylinositol 4,5-diphosphate; PLC, phospholipase C; R, receptor for hormone or neurotransmitter.Www.Medicalstudyzone.com
44 • Physiology ■ Ion channels provide routes for charged solutes to move across cell membranes. The conductance of ion channels is controlled by gates, which are regu- lated by voltage, second messengers, or ligands. Diffusion of a permeable ion down a concentration gradient creates a diffusion potential, which, at electrochemical equilibrium, is calculated by the Nernst equation. When several ions are permeable, each attempts to drive the membrane toward its equilibrium potential. Ions with the highest perme- abilities make the greatest contribution to the resting membrane potential. ■ Action potentials in nerve and muscle consist of rapid depolarization (upstroke), followed by repolar- ization caused by the opening and closing of ion channels. Action potentials are propagated down nerve and muscle fibers by the spread of local cur- rents, with the speed of conduction depending on the tissue’s cable properties. Conduction velocity is increased by increasing fiber size and by myelination. ■ Synapses between cells may be electrical or, more commonly, chemical. The prototype of the chemical synapse is the neuromuscular junction, which uses ACh as a neurotransmitter. ACh is released from presynaptic nerve terminals and diffuses across the synapse to cause depolarization of the motor end plate. Neurotransmitters at other synapses may be either excitatory (causing depolarization) or inhibi- tory (causing hyperpolarization). ■ In muscle, action potentials precede contraction. The mechanisms that translate the action potential into contraction are called excitation-contraction cou- pling. In both skeletal and smooth muscle, Ca2+ plays a central role in the coupling. ■ In skeletal muscle, the action potential is carried to the cell interior by the T tubules, where depolariza- tion releases Ca2+ from terminal cisternae of the nearby SR. Ca2+ then binds to troponin C on the thin filaments, causing a conformational change, which removes the inhibition of myosin-binding sites. When actin and myosin bind, cross-bridge cycling begins, producing tension. ■ In smooth muscle, Ca2+ enters the cell during the action potential via voltage-gated Ca2+ channels. Ca2+ then binds to calmodulin, and the Ca2+-calmodulin complex activates myosin-light-chain kinase, which phosphorylates myosin. Myosin~P can bind actin, form cross-bridges, and generate tension. Other sources of intracellular Ca2+ in smooth muscle are ligand-gated Ca2+ channels in the sarcolemmal mem- brane and IP3-gated Ca2+ channels in the SR membrane. Challenge Yourself Answer each question with a word, phrase, sentence, or numerical solution. When a list of possible answers is supplied with the question, one, more than one, or none of the choices may be correct. Correct answers are provided at the end of the book. 1 Solution A contains 100 mM NaCl, Solution B contains 10 mM NaCl, and the membrane separating them is permeable to Cl− but not Na+. What is the orientation of the potential difference that will be established across the membrane? 2 The osmolarity of a solution of 50 mmol/L CaCl2 is closest to the osmolarity of which of the following: 50 mmol/L NaCl, 100 mmol/L urea, 150 mmol/L NaCl, or 150 mmol/L urea? 3 How does the intracellular Na+ concentration change following inhibition of Na+-K+ ATPase? 4 Which phase of the nerve action potential is responsible for propagation of the action potential to neighboring sites? 5 How many quanta of acetylcholine (ACh) are required to depolarize the motor end plate from −80 mV to −70 mV if a miniature end plate potential (MEPP) is 0.4 mV? 6 A man is poisoned with curare. Which of the following agents would worsen his condition: neostigmine, nicotine, botulinus toxin, ACh? 7 Put these events in the correct temporal order: end plate potential (EPP), action potential in muscle fiber, ACh release from presynaptic terminal, MEPP, opening ligand-gated ion channels, opening Ca2+ channels in presynaptic terminal, binding of ACh to nicotinic receptors, action potential in nerve fiber. 8 In skeletal muscle, at muscle lengths less than the length that generates maximum active tension, is active tension greater than, less than, or approximately equal to total tension? 9 Which of the following neurotransmitters would be inactivated by peptidases: ACh, substance P, dopamine, glutamate, GABA, histamine, vasopressin, nitric oxide (NO)? 10 Solution A contains 10 mmol/L glucose, and Solution B contains 1 mmol/L glucose. If the glucose concentration in both solutions is doubled, by how much will the flux (flow) of glucose between the two solutions change (e.g.,Www.Medicalstudyzone.com
1—Cellular Physiology • 45 halve, remain unchanged, double, triple, quadruple)? 11 Adrenergic neurons synthesize which of the following: norepinephrine, epinephrine, ACh, dopamine, L-dopa, serotonin? 12 What effect would each of the following have on conduction velocity: increasing nerve diameter, increasing internal resistance (Ri), increasing membrane resistance (Rm), decreasing membrane capacitance (Cm), increasing length constant, increasing time constant? 13 How does hyperkalemia alter resting membrane potential (depolarizes, hyperpolarizes, or has no effect), and why does this cause muscle weakness? 14 During which of the following steps in cross-bridge cycling in skeletal muscle is ATP bound to myosin: rigor, conformational change in myosin that reduces its affinity for actin, power stroke? 15 Which of the following classes of drugs are contraindicated in a patient with myasthenia gravis: nicotinic receptor antagonist, inhibitor of choline reuptake, acetylcholinesterase (AChE) inhibitor, inhibitor of ACh release? 16 Solution A contains 100 mmol/L glucose and Solution B contains 50 mmol/L NaCl. Assume that gNaCl is 2.0, σglucose is 0.5, and σNaCl is 0.8. If a semipermeable membrane separates the two solutions, what is the direction of water flow across the membrane?Www.Medicalstudyzone.com
47 CHAPTER 2 Autonomic Nervous System Organization and General Features of the Autonomic Nervous System, 47 Autonomic Receptors, 59 Summary, 66 Challenge Yourself, 66 The motor (efferent) nervous system has two compo- nents: the somatic and the autonomic. These two systems differ in a number of ways but are chiefly distinguished by the types of effector organs they innervate and the types of functions they control. The somatic nervous system is a voluntary motor system under conscious control. Each of its pathways consists of a single motoneuron and the skeletal muscle fibers it innervates. The cell body of the motoneuron is located in the central nervous system, in either the brain stem or spinal cord, and its axon synapses directly on skeletal muscle, the effector organ. The neurotransmitter acetylcholine is released from presynaptic terminals of the motoneurons and activates nicotinic receptors located on the motor end plates of the skeletal muscle. An action potential in the motoneuron causes an action potential in the muscle fiber, which causes the muscle to contract. (For a complete discussion of the somatic nervous system, see Chapter 1.) The autonomic nervous system is an involuntary system that controls and modulates the functions primarily of visceral organs. Each pathway in the autonomic nervous system consists of two neurons: a preganglionic neuron and a postganglionic neuron. The cell body of each preganglionic neuron resides in the central nervous system. The axons of these preganglionic neurons synapse on the cell bodies of postganglionic neurons in one of several autonomic ganglia located outside the central nervous system. The axons of the postganglionic neurons then travel to the periphery, where they synapse on visceral effector organs such as the heart, bronchioles, vascular smooth muscle, gastrointestinal tract, bladder, and genitalia. All preganglionic neurons of the autonomic nervous system release acetylcholine. Postganglionic neurons release either acetylcholine or norepinephrine or, in some cases, neuropeptides. ORGANIZATION AND GENERAL FEATURES OF THE AUTONOMIC NERVOUS SYSTEM The autonomic nervous system has two major divisions: the sympathetic and the parasympathetic, which often complement each other in the regulation of organ system function. A third division of the autonomic nervous system, the enteric nervous system, is located in plexuses of the gastrointestinal tract. (The enteric nervous system is dis- cussed in Chapter 8.) The organization of the autonomic nervous system is described in Figure 2.1 and its companion, Table 2.1. The sympathetic and parasympathetic divisions are included and, for comparison, so is the somatic nervous system.Www.Medicalstudyzone.com
48 • Physiology postganglionic parasympathetic neurons of the gastro- intestinal tract that release peptides [e.g., substance P] or other substances [e.g., nitric oxide (NO)] as their neurotransmitter rather than ACh.) To summarize, whether located in the sympathetic division or in the parasympathetic division, all pregan- glionic neurons release ACh and therefore are called cholinergic. Postganglionic neurons may be either adrenergic (they release norepinephrine) or cholinergic (they release ACh). Most postganglionic parasympa- thetic neurons are cholinergic; postganglionic sympa- thetic neurons may be either adrenergic or cholinergic. Neuroeffector Junctions of the Autonomic Nervous System The junctions between postganglionic autonomic neurons and their effectors (target tissues), the neuro effector junctions, are analogous to the neuromuscular junctions of the somatic nervous system. There are, however, several structural and functional differ- ences with the neuromuscular junction. (1) The Terminology The terms sympathetic and parasympathetic are strictly anatomic terms and refer to the anatomic origin of the preganglionic neurons in the central nervous system (CNS; see Table 2.1). Preganglionic neurons in the sympathetic division originate in the thoracolumbar spinal cord. Preganglionic neurons in the parasympa thetic division originate in the brain stem and sacral spinal cord. The terms adrenergic and cholinergic are used to describe neurons of either division, according to which neurotransmitter they synthesize and release. Adrenergic neurons release norepinephrine; receptors for norepinephrine on the effector organs are called adrenoreceptors. Adrenoreceptors may be activated by norepinephrine, which is released from adrenergic neurons, or by epinephrine, which is secreted into the circulation by the adrenal medulla. Cholinergic neurons release acetylcholine (ACh); receptors for ACh are called cholinoreceptors. (A third term is nonadrenergic, noncholinergic, which describes some EFFECTOR ORGANSCENTRAL NERVOUS SYSTEM Somatic Sympathetic Parasympathetic Adrenal medulla Skeletal muscle Smooth muscle, glands Sweat glands* Smooth muscle, glands Preganglionic ACh ACh Epinephrine (80%)To circulation Norepinephrine (20%) Adrenal medulla M M NE Postganglionic Postganglionic ACh Preganglionic α1 α2 β1 β2 ACh Preganglionic Postganglionic ACh N2 N2 N1 ACh Motoneuron N2 N2 Fig. 2.1 Organization of the autonomic nervous system. The somatic nervous system is included for comparison. ACh, Acetylcholine; M, muscarinic receptor; N, nicotinic receptor; NE, norepinephrine. *Sweat glands have sympathetic cholinergic innervation.Www.Medicalstudyzone.com
2—Autonomic Nervous System • 49 and alertness. Although this response, per se, is rarely employed, the sympathetic nervous system operates continuously to modulate the functions of many organ systems such as heart, blood vessels, gastrointestinal tract, bronchi, and sweat glands. Figure 2.2 depicts the organization of the sympa- thetic nervous system in relation to the spinal cord, the sympathetic ganglia, and the effector organs in the periphery. The preganglionic sympathetic neurons originate in nuclei of the thoracolumbar spinal cord, leave the spinal cord via the ventral motor roots and white rami, and project either to the paravertebral ganglia of the sympathetic chain or to a series of pre- vertebral ganglia. Thus one category of preganglionic neuron synapses on postganglionic neurons in paraver tebral ganglia (e.g., superior cervical ganglion) of the sympathetic chain. These synapses may occur in ganglia at the same segmental level of the chain, or the preganglionic fibers may turn in the cranial or caudal direction and innervate ganglia at higher or lower levels in the chain, thereby permitting synapses in multiple ganglia (consistent with the diffuseness of sympathetic functions). The other category of preganglionic neuron passes through the sympathetic chain without synaps- ing and continues on to synapse in prevertebral ganglia (celiac, superior mesenteric, and inferior mesenteric) that supply visceral organs, glands, and the enteric nervous system of the gastrointestinal tract. In the neuromuscular junction (discussed in Chapter 1) has a discrete arrangement, whereby the “effector,” a skeletal muscle fiber, is innervated by a single motoneuron. In contrast, in the autonomic nervous system, the post- ganglionic neurons that innervate target tissues form diffuse, branching networks. Beads, or varicosities, line these branches and are the sites of neurotransmitter synthesis, storage, and release. The varicosities are therefore analogous to the presynaptic nerve terminals of the neuromuscular junction. (2) There is overlap in the branching networks from different postganglionic neurons, such that target tissues may be innervated by many postganglionic neurons. (3) In the autonomic nervous system, postsynaptic receptors are widely distributed on the target tissues, and there is no special- ized region of receptors analogous to the motor end plate of skeletal muscle. Sympathetic Nervous System The overall function of the sympathetic nervous system is to mobilize the body for activity. In the extreme, if a person is exposed to a stressful situation, the sym- pathetic nervous system is activated with a response known as “fight or flight,” which includes increased arterial pressure, increased blood flow to active muscles, increased metabolic rate, increased blood glucose concentration, and increased mental activity TABLE 2.1 Organization of the Autonomic Nervous System Characteristics Sympathetic Division Parasympathetic Division Somatic Nervous Systema Origin of preganglionic neurons Spinal cord segments T1–L3 (thoracolumbar) Nuclei of CN III, VII, IX, and X; spinal cord segments S2–S4 (craniosacral) — Location of autonomic ganglia Paravertebral and prevertebral In or near effector organs — Length of preganglionic axons Short Long — Length of postganglionic axons Long Short — Effector organs Smooth muscle; cardiac muscle; glands Smooth muscle; cardiac muscle; glands Skeletal muscle Neuroeffector junctions Diffuse, branching; receptors not concentrated in one region Diffuse, branching; receptors not concentrated in one region Discrete, organized; ACh receptors localized on motor end plate Neurotransmitter and receptor type in ganglion ACh/nicotinic receptor ACh/nicotinic receptor — Neurotransmitter in effector organs Norepinephrine (except sweat glands) ACh Ach Receptor types in effector organs α1, α2, β1, β2 Muscarinic Nicotinic aSomatic nervous system is included for comparison. ACh, Acetylcholine; CN, cranial nerve.Www.Medicalstudyzone.com
50 • Physiology Spinal cord Superior cervical ganglion Sympathetic chain Sympathetic chain To blood vessels, pilomotor muscles, and sweat glands Male genitalia Inferior mesenteric plexus Large intestine Stomach Bronchial tree Parotid gland Submandibular and sublingual glands Tarsal muscle Lacrimal gland Radial muscle: dilates pupil Small intestine L3 T1 Superior mesenteric plexus Celiac plexus Adrenal medulla Heart SYMPATHETIC NERVOUS SYSTEM Fig. 2.2 Innervation of the sympathetic nervous system. Preganglionic neurons originate in thoracic and lumbar segments of the spinal cord (T1–L3).Www.Medicalstudyzone.com
2—Autonomic Nervous System • 51 with nicotinic (N2) receptors on the cell bodies of postganglionic neurons. Postganglionic neurons of the sympathetic division are adrenergic in all of the effector organs, except in the thermoregulatory sweat glands (where they are cholinergic). The effector organs that are innervated by sympathetic adrenergic neurons have one or more of the following types of adreno- receptors: alpha1, alpha2, beta1, or beta2 (α1, α2, β1, or β2). The thermoregulatory sweat glands innervated by sympathetic cholinergic neurons have muscarinic cholinoreceptors. Sympathetic Adrenergic Varicosities As described previously, sympathetic postganglionic adrenergic nerves release their neurotransmitters from varicosities onto their target tissues (e.g., vascular smooth muscle). The sympathetic adrenergic varicosi ties contain both the classic neurotransmitter (norepi- nephrine) and nonclassic neurotransmitters (adenosine triphosphate [ATP] and neuropeptide Y). The classic neurotransmitter, norepinephrine, is synthesized from tyrosine in the varicosities (see Fig. 1.18) and stored in small dense core vesicles, ready for release; these small dense-core vesicles also contain dopamine β-hydroxylase, which catalyzes the conversion of dopa- mine to norepinephrine (the final step in the synthetic pathway), and ATP. ATP is said to be “colocalized” with norepinephrine. A separate group of large dense core vesicles contain neuropeptide Y. When sympathetic postganglionic adrenergic neurons are stimulated, norepinephrine and ATP are released from the small dense-core vesicles. Both nor- epinephrine and ATP serve as neurotransmitters at the neuroeffector junction, binding to and activating their respective receptors on the target tissue (e.g., vascular smooth muscle). Actually, ATP acts first, binding to purinergic receptors on the target tissue and causing a physiologic effect (e.g., contraction of the vascular smooth muscle). The action of norepinephrine follows ATP; norepinephrine binds to its receptors on the target tissue (e.g., α1-adrenergic receptors on vascular smooth muscle) and causes a second, more prolonged contraction. Finally, with more intense or higher- frequency stimulation, the large dense-core vesicles release neuropeptide Y, which binds to its receptor on the target tissue, causing a third, slower phase of contraction. Adrenal Medulla The adrenal medulla is a specialized ganglion in the sympathetic division of the autonomic nervous system. The cell bodies of its preganglionic neurons are located in the thoracic spinal cord. The axons of these pre- ganglionic neurons travel in the greater splanchnic nerve to the adrenal medulla, where they synapse on chromaffin cells and release ACh, which activates ganglia, the preganglionic neurons synapse on postgan- glionic neurons, which travel to the periphery and innervate the effector organs. The features of the sympathetic nervous system discussed in the following sections are listed in Table 2.1 and are illustrated in Figure 2.2. Origin of Preganglionic Neurons The preganglionic neurons of the sympathetic division arise from nuclei in the thoracic and lumbar spinal cord segments, specifically from the first thoracic segment to the third lumbar segment (T1–L3). Thus the sympa- thetic division is referred to as thoracolumbar. Generally, the origin of preganglionic neurons in the spinal cord is anatomically consistent with the projec- tion to the periphery. Thus the sympathetic pathways to organs in the thorax (e.g., heart) have preganglionic neurons originating in the upper thoracic spinal cord. Sympathetic pathways to organs in the pelvis (e.g., colon, genitals) have preganglionic neurons that origi- nate in the lumbar spinal cord. Blood vessels, thermo- regulatory sweat glands, and pilomotor muscles of the skin have preganglionic neurons that synapse on multiple postganglionic neurons up and down the sympathetic chain, reflecting their broad distribution throughout the body. Location of Autonomic Ganglia The ganglia of the sympathetic nervous system are located near the spinal cord, either in the paravertebral ganglia (known as the sympathetic chain) or in the prevertebral ganglia. Again, the anatomy is logical. The superior cervical ganglion projects to organs in the head such as the eyes and the salivary glands. The celiac ganglion projects to the stomach and the small intestine. The superior mesenteric ganglion projects to the small and large intestine, and the inferior mesen- teric ganglion projects to the lower large intestine, anus, bladder, and genitalia. The adrenal medulla is simply a specialized sympa- thetic ganglion whose preganglionic neurons originate in the thoracic spinal cord (T5–T9), pass through the sympathetic chain and the celiac ganglion without synapsing, and travel in the greater splanchnic nerve to the adrenal gland. Length of Preganglionic and Postganglionic Axons Because the sympathetic ganglia are located near the spinal co
52 • Physiology mainly epinephrine, a pheochromocytoma secretes mainly norepinephrine, which is explained by the fact that the tumor is located too far from the adrenal cortex to receive the cortisol that is required by PNMT. Fight or Flight Response The body responds to fear, extreme stress, and intense exercise with a massive, coordinated activation of the sympathetic nervous system including the adrenal medulla. This activation, the fight or flight response, ensures that the body can respond appropriately to a stressful situation (e.g., take a difficult exam, run away from a burning house, fight an attacker). The response includes increases in heart rate, cardiac output, and blood pressure; redistribution of blood flow away from skin, kidneys, and splanchnic regions and toward skeletal muscle; increased ventilation, with dilation of the airways; decreased gastrointestinal motility and secretions; and increased blood glucose concentration. nicotinic receptors. When activated, the chromaffin cells of the adrenal medulla secrete catecholamines (epinephrine and norepinephrine) into the general circulation. In contrast with sympathetic postganglionic neurons, which release only norepinephrine, the adrenal medulla secretes mainly epinephrine (80%) and a small amount of norepinephrine (20%). The reason for this difference is the presence of phenylethanolamine N methyltransferase (PNMT) in the adrenal medulla but not in sympathetic postganglionic adrenergic neurons (see Fig. 1.18). PNMT catalyzes the conversion of norepinephrine to epinephrine, a step that, interest- ingly, requires cortisol from the nearby adrenal cortex; cortisol is supplied to the adrenal medulla in venous effluent from the adrenal cortex. A tumor of the adrenal medulla, or pheochromocy toma, may be located on or near the adrenal medulla, or at a distant (ectopic) location in the body (Box 2.1). Unlike the normal adrenal medulla, which secretes BOX 2.1 Clinical Physiology: Pheochromocytoma DESCRIPTION OF CASE. A 48-year-old woman visits her physician complaining of what she calls “panic attacks.” She reports that she has experienced a racing heart and that she can feel (and even see) her heart pounding in her chest. She also complains of throbbing headaches, cold hands and cold feet, feeling hot, visual disturbances, and nausea and vomiting. In the physi- cian’s office, her blood pressure is severely elevated (230/125). She is admitted to the hospital for evalua- tion of her hypertension. A 24-hour urine sample reveals elevated levels of metanephrine, normetanephrine, and 3-methoxy-4- hydroxymandelic acid (VMA). After the physician rules out other causes for hypertension, he concludes that she has a tumor of the adrenal medulla, called a pheo- chromocytoma. A computerized tomographic scan of the abdomen reveals a 3.5-cm mass on her right adrenal medulla. The patient is administered an α1 antagonist, and surgery is performed. The woman recovers fully; her blood pressure returns to normal, and her other symptoms disappear. EXPLANATION OF CASE. The woman has a classic pheochromocytoma, a tumor of the chromaffin cells of the adrenal medulla. The tumor secretes excessive amounts of norepinephrine and epinephrine, which produce all of the woman’s symptoms and result in elevated levels of catecholamine metabolites in her urine. In contrast to normal adrenal medulla, which secretes mainly epinephrine, pheochromocytomas secrete mainly norepinephrine. The patient’s symptoms can be interpreted by under- standing the physiologic effects of catecholamines. Any tissue where adrenoreceptors are present will be activated by the increased levels of epinephrine and norepinephrine, which reach the tissues via the circula- tion. The woman’s most prominent symptoms are cardiovascular: pounding heart, increased heart rate, increased blood pressure, and cold hands and feet. These symptoms can be understood by considering the functions of adrenoreceptors in the heart and blood vessels. The increased amounts of circulating catechol- amines activated β1 receptors in the heart, increasing the heart rate and increasing contractility (pounding of the heart). Activation of α1 receptors in vascular smooth muscle of the skin produced vasoconstriction, which presented as cold hands and feet. The patient felt hot, however, because this vasoconstriction in the skin impaired the ability to dissipate heat. Her extremely elevated blood pressure was caused by the combination of increased heart rate, increased contractility, and increased constriction (resistance) of the blood vessels. The patient’s headache was secondary to her elevated blood pressure. The woman’s other symptoms also can be explained by the activation of adrenoreceptors in other organ systems (i.e., gastrointestinal symptoms of nausea and vomiting and visual disturbances). TREATMENT. The patient’s treatment consisted of locating and excising the tumor, thereby removing the source of excess catecholamines. Alternat
2—Autonomic Nervous System • 53 Parasympathetic Nervous System The overall function of the parasympathetic nervous system is restorative, to conserve energy. Figure 2.3 depicts the organization of the parasympathetic nervous system in relation to the CNS (brain stem and spinal cord), the parasympathetic ganglia, and the effector organs. Preganglionic neurons of the parasympathetic division have their cell bodies in either the brain stem (midbrain, pons, and medulla) or the sacral spinal cord. Preganglionic axons project to a series of ganglia located near or in the effector organs. The following features of the parasympathetic nervous system can be noted and compared with the sympathetic nervous system (see Table 2.1 and Fig. 2.3). Origin of Preganglionic Neurons Preganglionic neurons of the parasympathetic division arise from nuclei of cranial nerves (CNs) III, VII, IX, and X or from sacral spinal cord segments S2–S4; therefore the parasympathetic division is called cranio sacral. As in the sympathetic division, the origin of the preganglionic neurons in the CNS is consistent with the projection to effector organs in the periphery. For example, the parasympathetic innervation of eye muscles originates in the Edinger-Westphal nucleus in the midbrain and travels to the periphery in CN III; the parasympathetic innervation of the heart, bronchioles, and gastrointestinal tract originates in nuclei of the medulla and travels to the periphery in CN X (vagus nerve); and the parasympathetic innervation of the genitourinary organs originates in the sacral spinal cord and travels to the periphery in the pelvic nerves. Location of Autonomic Ganglia In contrast to the sympathetic ganglia, which are located near the CNS, the ganglia of the parasympa- thetic nervous system are located near, on, or in the effector organs (e.g., ciliary, pterygopalatine, subman- dibular, otic). Length of Preganglionic and Postganglionic Axons The relative length of preganglionic and postganglionic axons in the parasympathetic division is the reverse of the relative lengths in the sympathetic division. This difference reflects the location of the ganglia. The parasympathetic ganglia are located near or in the effector organs; therefore the preganglionic neurons have long axons and the postganglionic neurons have short axons. Neurotransmitters and Types of Receptors As in the sympathetic division, all preganglionic neurons are cholinergic and release ACh, which inter- acts at nicotinic (N2) receptors on the cell bodies of postganglionic neurons. Most postganglionic neurons of the parasympathetic division are also cholinergic. Receptors for ACh in the effector organs are muscarinic receptors rather than nicotinic receptors. Thus ACh released from preganglionic neurons of the para- sympathetic division activates nicotinic receptors, whereas ACh released from postganglionic neurons of the parasympathetic division activates muscarinic receptors. These receptors and their functions are distinguished by the drugs that activate or inhibit them (Table 2.2). Parasympathetic Cholinergic Varicosities As described previously, parasympathetic postgangli onic cholinergic nerves release their neurotransmitters from varicosities onto their target tissues (e.g., smooth muscle). The parasympathetic cholinergic varicosities release both the classic neurotransmitter (ACh) and nonclassic neurotransmitters (e.g., vasoactive intestinal peptide [VIP], NO). The classic neurotransmitter, ACh, is synthesized in the varicosities from choline and acetyl coenzyme A (acetyl CoA) (see Fig. 1.17) and stored in small, clear vesicles. A separate group of large dense core vesicles contains peptides such as VIP. Lastly, the varicosities contain nitric oxide syn- thase and can synthesize NO on demand. TABLE 2.2 Prototypes of Agonists and Antagonists to Autonomic Receptors Receptor Agonists Antagonists Adrenoreceptors α1 Norepinephrine Phenoxybenzamine Phenylephrine Prazosin α2 Clonidine Yohimbine β1 Norepinephrine Propranolol Epinephrine Metoprolol Isoproterenol Dobutamine β2 Epinephrine Propranolol Norepinephrine Butoxamine Isoproterenol Albuterol Cholinoreceptors Nicotinic ACh Nicotine Curare (blocks neuromuscular N1 receptors) Hexamethonium (blocks ganglionic N2 receptors) Muscarinic ACh Atropine Muscarine ACh, Acetylcholine.Www.Medicalstudyzone.com
54 • Physiology Heart Parotid gland Submandibular and sublingual glands Lacrimal and nasal glands Circular muscle: constricts pupil Ciliary muscle: near vision Midbrain Pons Medulla Inferior salivatory nucleus Dorsal motor nucleus of vagal nerve Lacrimal nucleus Superior salivatory nucleus Edinger-Westphal nucleus PARASYMPATHETIC NERVOUS SYSTEM Otic ganglionCN IX Spinal cord Pelvic splanchnic nerves S2 S3 S4 Male genitalia Large intestine Stomach Bronchial tree Small intestine Urinary bladder CN X CN III CN VII Submandibular ganglion Pterygopalatine ganglion Ciliary ganglion Fig. 2.3 Innervation of the parasympathetic nervous system. Preganglionic neurons originate in nuclei of the brain stem (midbrain, pons, medulla) and in sacral segments (S2–S4) of the spinal cord. CN, Cranial nerve.Www.Medicalstudyzone.com
2—Autonomic Nervous System • 55 sympathetic and parasympathetic innervations, which function reciprocally to modulate the heart rate. Thus an increase in sympathetic activity increases heart rate, and an increase in parasympathetic activity decreases heart rate. These reciprocal functions are illustrated as follows: If there is a decrease in blood pressure, vasomotor centers in the brain stem respond to this decrease and produce, simultaneously, an increase in sympathetic activity to the SA node and a decrease in parasympathetic activity. Each of these actions, directed and coordinated by the brain stem vasomotor center, has the effect of increasing heart rate. The sym- pathetic and parasympathetic actions do not compete with each other but work synergistically to increase the heart rate (which helps restore normal blood pressure). URINARY BLADDER The urinary bladder is another example of reciprocal innervations by sympathetic and parasympathetic divi- sions (Fig. 2.4). In adults, micturition, or emptying of the bladder, is under voluntary control because the external sphincter is composed of skeletal muscle. However, the micturition reflex itself is controlled by the autonomic nervous system. This reflex occurs when the bladder is sensed as being “full.” The detrusor muscle of the bladder wall and the internal bladder sphincter are composed of smooth muscle; each has both sympathetic and parasympathetic innervations. The sympathetic innervation of the detrusor muscle and the internal sphincter originates in the lumbar spinal cord (L1–L3), and the parasympathetic innerva- tion originates in the sacral spinal cord (S2–S4). When the bladder is filling with urine, sympathetic control predominates. This sympathetic activity pro- duces relaxation of the detrusor muscle, via β2 recep- tors, and contraction of the internal sphincter muscle, via α1 receptors. The external sphincter is simultane- ously closed by trained voluntary action. When the muscle wall is relaxed and the sphincters are closed, the bladder can fill with urine. When the bladder is full, this fullness is sensed by mechanoreceptors in the bladder wall, and afferent neurons transmit this information to the spinal cord and then to the brain stem. The micturition reflex is coordinated by centers in the midbrain, and now para sympathetic control predominates. Parasympathetic activity produces contraction of the detrusor muscle (to increase pressure and eject urine) and relaxation of the internal sphincters. Simultaneously, the external sphincter is relaxed by a voluntary action. Clearly, the sympathetic and parasympathetic actions on the bladder structures are opposite but coordinated: The sympathetic actions dominate for bladder filling, and the parasympathetic actions dominate for bladder emptying. When parasympathetic postganglionic cholinergic neurons are stimulated, ACh is released from the vari- cosities and binds to muscarinic receptors on the target tissue, which direct its physiologic action. With intense or high-frequency stimulation, the large dense-core vesicles release their peptides (e.g., VIP), which bind to receptors on the target tissues and augment the actions of ACh. Autonomic Innervation of the Organ Systems Table 2.3 serves as a reference for information concern- ing autonomic control of organ system function. This table lists the sympathetic and parasympathetic inner- vations of the major organ systems and the receptor types that are present in these tissues. Table 2.3 will be most valuable if the information it contains is seen as a set of recurring themes rather than as a random list of actions and receptors. Reciprocal Functions—Sympathetic and Parasympathetic Most organs have both sympathetic and parasympa- thetic innervation. These innervations operate recip rocally or synergistically to produce coordinated responses. For example, the heart has both sympathetic and parasympathetic innervations that function recip- rocally to regulate heart rate and conduction velocity. The smooth muscle walls of the gastrointestinal tract and the bladder have both sympathetic innervation (which produces relaxation) and parasympathetic innervation (which produces contraction); the sphinc- ters of the gastrointestinal tract and the bladder also have both sympathetic innervation (which produces contraction) and parasympathetic innervation (which produces relaxation). The radial muscles of the iris are responsible for dilation of the pupil (mydriasis) and have sympathetic innervation; the circular muscle of the iris is responsible for constriction of the pupil (miosis) and has parasympathetic innervation. In this example of the eye muscles, different muscles control pupil size, but the overall effects of sympathetic and parasympathetic activity are reciprocal. In the male genitalia, sympathetic activity controls ejaculation and parasympathetic activity controls erection, which, together, are responsible for the male sexual response. The followin
56 • Physiology innervation through α1 receptors. Activation of these α1 receptors causes constriction of the radial muscle, which causes dilation of the pupil, or mydriasis. The pupillary constrictor muscle is controlled by parasym- pathetic innervation through muscarinic receptors. PUPIL The size of the pupil is reciprocally controlled by two muscles of the iris: the pupillary dilator (radial) muscle and pupillary constrictor (sphincter) muscle. The pupillary dilator muscle is controlled by sympathetic TABLE 2.3 Effects of the Autonomic Nervous System on Organ System Function Organ Sympathetic Parasympathetic Action Receptor Action Receptor Heart SA node, heart rate ↑ β1 ↓ M AV nodal conduction ↑ β1 ↓ M Contractility ↑ β1 ↓ (atria only) M Vascular Smooth Muscle Skin; splanchnic Constricts α1 Skeletal muscle Dilates β2 Skeletal muscle Constricts α1 Endothelium Releases EDRF M Bronchioles Dilates β2 Constricts M Gastrointestinal Tract Smooth muscle, walls Relaxes α2, β2 Contracts M Smooth muscle, sphincters Contracts α1 Relaxes M Saliva secretion ↑ β1 ↑ M Gastric acid secretion ↑ M Pancreatic secretion ↑ M Bladder Wall, detrusor muscle Relaxes β2 Contracts M Sphincter Contracts α1 Relaxes M Male Genitalia Ejaculation α Erection M Eye Radial muscle, iris Dilates pupil (mydriasis) α1 Circular sphincter muscle, iris Constricts pupil (miosis) M Ciliary muscle Dilates (far vision) β Contracts (near vision) M Skin Sweat glands, thermoregulatory ↑ Ma Sweat glands, stress ↑ α Pilomotor muscle (goose bumps) Contracts α Lacrimal Glands Secretion M Liver Gluconeogenesis; glycogenolysis α, β2 Adipose Tissue Lipolysis β1 Kidney Renin secretion β1 aSympathetic cholinergic neurons. AV, Atrioventricular; EDRF, endothelial-derived relaxing factor; M, muscarinic receptor; SA, sinoatrial.Www.Medicalstudyzone.com
2—Autonomic Nervous System • 57 activity of the detrusor muscle in the bladder wall and in the sphincters (see Fig. 2.4). Thus sympathetic activ- ity dominates when the bladder is filling to produce relaxation of the bladder wall and, simultaneously, contraction of the internal bladder sphincter. The bladder can fill because the bladder wall is relaxed and the sphincter is closed. During micturition, parasympa- thetic activity dominates, producing contraction of the bladder wall and, simultaneously, relaxation of the sphincter. Similar reasoning can be applied to the autonomic control of the gastrointestinal tract: Contraction of the wall of the gastrointestinal tract is accompanied by relaxation of the sphincters (parasympathetic), allow- ing the contents of the gastrointestinal tract to be propelled forward. Relaxation of the wall of the gastrointestinal tract is accompanied by contraction of the sphincters (sympathetic); the combined effect of these actions is to slow or stop movement of the contents. Types of Receptors Inspection of Table 2.3 permits some generalizations about types of receptors and their mechanisms of action. These generalizations are as follows: (1) In the parasympathetic division, effector organs have musca- rinic receptors. (2) In the sympathetic division, there are multiple receptor types in effector organs including the four adrenoreceptors (α1, α2, β1, β2); and in tissues Activation of these muscarinic receptors causes con striction of the sphincter muscle, which causes con striction of the pupil, or miosis. For example, in the pupillary light reflex, light strikes the retina and, through a series of CNS connec- tions, activates parasympathetic preganglionic nerves in the Edinger-Westphal nucleus; activation of these parasympathetic fibers causes contraction of the sphincter muscle and pupillary constriction. In the accommodation response, a blurred retinal image activates parasympathetic preganglionic neurons in the Edinger-Westphal nuclei and leads to contraction of the sphincter muscle and pupillary constriction. At the same time, the ciliary muscle contracts, causing the lens to “round up” and its refractive power to increase. There are some notable exceptions to the generaliza- tion of reciprocal innervation. Several organs have only sympathetic innervation: sweat glands, vascular smooth muscle, pilomotor muscles of the skin, liver, adipose tissue, and kidney. Coordination of Function Within Organs Coordination of function within the organ systems, as orchestrated by the autonomic nervous system, is another recurring physiologic theme (Boxes 2.2 and 2.3). This control is exquisitely clear, for example, when considering the function of the urinary bladder. In this organ, there must be a timely coordination between β2 α1 M M β2 Filling of Bladder Emptying of Bladder Muscle Detrusor muscle Internal sphincter External sphincter State Relaxed Contracted Contracted Control Mechanism Sympathetic Sympathetic Voluntary State Contracted Relaxed Relaxed Control Mechanism Parasympathetic Parasympathetic Voluntary Parasympathetic Sympathetic α1 M M Spinal cord L1 L2 L3 S2 S3 S4 Fig. 2.4 Autonomic control of bladder function. During filling of the bladder, sympathetic control predominates, causing relaxation of the detrusor muscle and contraction of the internal sphincter. During micturition, parasympathetic control predominates, causing contraction of the detrusor muscle and relaxation of the internal sphincter. Dashed lines represent sympathetic innervation; solid lines represent parasympathetic innervation. α1, Adrenoreceptor in internal sphincter; β2, adrenoreceptor in detrusor muscle; L1–L3, lumbar segments; M, muscarinic cholino- receptor in detrusor muscle and internal sphincter; S2–S4, sacral segments.Www.Medicalstudyzone.com
58 • Physiology BOX 2.3 Clinical Physiology: Shy-Drager Syndrome DESCRIPTION OF CASE. A 58-year old man in seem- ingly good health begins to experience alarming symptoms. He is occasionally impotent, and recently his impotence has progressed to “every time.” In addi- tion, he has enormous urgency to urinate but has dif- ficulty producing a urinary stream. He has been reluctant to seek medical attention for these issues, but one morning, he faints when he arises from bed. By the time he schedules an appointment with his physi- cian, he is dizzy every morning and has a wide array of symptoms, including double vision, indigestion, diarrhea, and heat intolerance. The man is referred to a neurologist, who performs an ocular test that involves instilling methacholine into the conjunctival sac; in this man, the methacholine causes exaggerated miosis (constriction of the pupil due to contraction of circular muscle of the iris). Because of the global nature of the man’s symptoms and the results of this ocular test, the neurologist diagnoses him with Shy-Drager syndrome. EXPLANATION OF CASE. Shy-Drager syndrome is a rare, progressive disease of the central autonomic nervous system associated with degeneration of pre- ganglionic neurons of the intermediolateral cell column of the spinal cord, peripheral autonomic ganglia, and hypothalamic autonomic centers. Consequently, there is severe impairment of both the sympathetic and parasympathetic divisions of the autonomic nervous system. The symptoms of impotence, difficulty urinating, and heat intolerance are all explained by sympathetic and parasympathetic failures. The male sexual response consists of erection (parasympathetic, muscarinic receptors) and ejaculation (sympathetic, α1 receptors). The detrusor muscle of the bladder wall is composed of smooth muscle with both sympathetic (β2 receptors) and parasympathetic (muscarinic receptors) innerva- tion; the internal bladder sphincter is also composed of smooth muscle with sympathetic (α1 receptors) and parasympathetic (muscarinic receptors) innervation. Thermoregulatory sweat glands are under sympathetic control. The exaggerated ocular response to methacholine (a cholinergic muscarinic agonist) is perhaps surprising, since the man’s parasympathetic nervous system is impaired; however, the test results make sense because the loss of parasympathetic innervation to circular muscle of the iris causes up-regulation of choliner- gic receptors and thus an enhanced response to an exogenously applied cholinergic agonist (denervation hypersensitivity). The man experienced orthostatic hypotension, or a decrease in blood pressure upon standing up. Upon standing, blood pools in the lower extremities, which decreases arterial pressure. In normal persons, the fall in arterial pressure evokes the baroreceptor reflex, which involves both the sympathetic and parasympa- thetic nervous systems; together, these autonomic responses work to restore arterial pressure to normal. The man’s baroreceptor mechanism was severely impaired and his blood pressure could not be corrected by autonomic reflexes; therefore he felt dizzy and even fainted. TREATMENT. The man was instructed to elevate his head during sleep (to lessen the orthostatic effects on blood pressure upon standing), to wear compression stockings to prevent blood from pooling in his legs, and to take an aldosterone analogue to increase his blood volume. Each of these measures was an attempt to ameliorate dizziness and fainting upon standing up. The treatments were palliative; there is no cure for this ultimately fatal, degenerative disease. BOX 2.2 Clinical Physiology: Horner Syndrome DESCRIPTION OF CASE. A 66-year-old man who suf- fered a stroke on the right side has a drooping right eyelid (ptosis), constriction of his right pupil (miosis), and lack of sweating on the right side of his face (anhidrosis). His physician orders a test with cocaine eye drops. When a solution of 10% cocaine is applied in the left eye, it causes dilation of the pupil (mydria- sis). However, when the cocaine solution is applied in the right eye, it fails to cause dilation of that pupil. EXPLANATION OF CASE. The man has a classic case of Horner syndrome, secondary to his stroke. In this syndrome, there is loss of sympathetic innervation on the affected side of the face. Thus the loss of sympa- thetic innervation to smooth muscle elevating the right eyelid caused ptosis on the right side. The loss of sympathetic innervation of the right pupillary dilator muscle caused constriction of the right pupil. And loss of sympathetic innervation of the sweat glands of the right side of the face caused anhidrosis on the right side. When cocaine drops were instilled in the left eye (the unaffected side), the cocaine blocked reuptake of norepinephrine into sympathetic nerves innervating the pupillary dilator muscle; with higher norepinephrine levels in those adrenergic synapses, there was constric- tion of the radial musc
2—Autonomic Nervous System • 59 with sympathetic cholinergic innervation, there are muscarinic receptors. (3) Among the sympathetic adrenoreceptors, receptor type is related to function. The α1 receptors cause contraction of smooth muscle such as vascular smooth muscle, gastrointestinal and bladder sphincters, pilomotor muscles, and the radial muscle of the iris. The β1 receptors are involved in metabolic functions such as gluconeogenesis, lipolysis, renin secretion, and in all functions in the heart. The β2 receptors cause relaxation of smooth muscle in bronchioles, wall of the bladder, and wall of the gastrointestinal tract. Hypothalamic and Brain Stem Centers Centers in the hypothalamus and brain stem coordinate the autonomic regulation of organ system functions. Figure 2.5 summarizes the locations of these centers, which are responsible for temperature regulation, thirst, food intake (satiety), micturition, breathing, and car- diovascular (vasomotor) function. For example, the vasomotor center receives information about blood pressure from baroreceptors in the carotid sinus and compares this information to a blood pressure set point. If corrections are necessary, the vasomotor center orchestrates changes in output of both the sympathetic and the parasympathetic innervation of the heart and blood vessels to bring about the necessary change in blood pressure. These higher autonomic centers are discussed throughout this book in the context of each organ system. AUTONOMIC RECEPTORS As noted in the preceding discussion, autonomic recep- tors are present at the neuromuscular junction, on the cell bodies of postganglionic neurons, and in the effec- tor organs. The type of receptor and its mechanism of action determine the nature of the physiologic response. Furthermore, the physiologic responses are tissue spe- cific and cell type specific. To illustrate this specificity, compare the effect of activating adrenergic β1 receptors in the SA node to the effect of activating β1 receptors in ventricular muscle. Both the SA node and the ventricular muscle Vasomotor center (cardiovascular) Pneumotaxic center Micturition center Food intake Thirst Temperature regulation Respiratory center Swallowing, coughing, vomiting centers CI Midbrain Hypothalamus Pons Medulla Spinal cord Fig. 2.5 Autonomic centers in the hypothalamus and brain stem. CI, First cervical spinal cord segment.Www.Medicalstudyzone.com
60 • Physiology are located in the heart, and their adrenergic receptors and mechanisms of action are the same. The resulting physiologic actions, however, are entirely different. The β1 receptor in the SA node is coupled to mechanisms that increase the spontaneous rate of depolarization and increase heart rate; binding of an agonist such as norepinephrine to this β1 receptor increases the heart rate. The β1 receptor in ventricular muscle is coupled to mechanisms that increase intracellular Ca2+ concentration and contractility; binding of an agonist such as norepinephrine to this β1 receptor increases contractility, but it has no direct effect on the heart rate. The type of receptor also predicts which pharmaco- logic agonists or antagonists will activate it or block it. The effects of such drugs can be readily predicted by understanding the normal physiologic responses. For example, drugs that are β1 agonists are expected to cause increased heart rate and increased contractility, and drugs that are β1 antagonists are expected to cause decreased heart rate and decreased contractility. Table 2.4 summarizes the features of adrenergic and cholinergic receptors, their target tissues, and their mechanisms of action. Table 2.2, its companion, is arranged similarly by receptor type and lists the prototypical drugs that either activate (agonists) or block (antagonists) the receptors. Together, the two tables should be used as a reference for the following discussion about mechanisms of action. These mecha- nisms involving guanosine triphosphate (GTP)–binding proteins (G proteins), adenylyl cyclase, and inositol 1,4,5-triphosphate (IP3) also are discussed in Chapter 9 in the context of hormone action. G Proteins Autonomic receptors are coupled to GTP-binding pro- teins (G proteins) and therefore are called G protein– linked receptors. G protein–linked receptors, including those in the autonomic nervous system, are composed of a single polypeptide chain that winds back and forth across the cell membrane seven times; thus they are also known as seven-pass transmembrane receptor proteins. The ligand (e.g., ACh, norepinephrine) binds to the extracellular domain of its G protein–linked receptor. The intracellular domain of the receptor binds to (is “linked” to) a G protein. These G proteins are heterotrimeric. In other words, they have three different subunits: α, β, and γ. The α subunit binds either guanosine diphosphate (GDP) or GTP. When GDP is bound, the α subunit is inactive; when GTP is bound, the α subunit is active. Thus activity of the G protein resides in its α subunit, and the G protein switches between active and inactive states according to whether it is bound to GDP or GTP. For example, when the G protein releases GDP and binds GTP, it switches from the inactive state to the active state; when GTP is converted back to GDP through intrinsic GTPase activity of the G protein, it switches from the active state to the inactive state. G proteins couple G protein–linked autonomic receptors to enzymes that execute physiologic actions. These enzymes are adenylyl cyclase and phospholipase C, which, when activated, generate a second messen- ger (cyclic adenosine monophosphate [cAMP] or IP3, respectively). The second messenger then amplifies the message and executes the final physiologic action. In some cases (e.g., certain muscarinic receptors), the G protein directly alters the function of an ion channel without the mediation of a second messenger. Adrenoreceptors Adrenoreceptors are found in target tissues of the sympathetic nervous system and are activated by the catecholamines norepinephrine and epinephrine. Nor- epinephrine is released from postganglionic neurons of the sympathetic nervous system. Epinephrine is secreted by the adrenal medulla and reaches the target tissues via the circulation. Adrenoreceptors are divided into two types, α and β, which are further designated as α1, α2, β1, and β2 receptors. Each of the receptor types has a different mechanism of action (except the β1 and β2 receptors, which have the same mechanism of action), resulting in different physiologic effects (see Tables 2.3 and 2.4). α1 Receptors α1 Receptors are found in vascular smooth muscle of the skin, skeletal muscle, and the splanchnic region, in the sphincters of the gastrointestinal tract and bladder, and in the radial muscle of the iris. Activation of α1 receptors leads to contraction in each of these tissues. The mechanism of action involves a G protein called Gq and activation of phospholipase C, illustrated in Figure 2.6. The circled numbers in the figure correspond to the steps discussed as follows: 1. The α1 receptor is embedded in the cell membrane, where it is coupled, via the Gq protein, to phospho- lipase C. In the inactive state, the αq subunit of the heterotrimeric Gq protein is bound to GDP. 2. When an agonist such as norepinephrine binds to the α1 receptor (Step 1), a conformational change occurs in the αq subunit
2—Autonomic Nervous System • 61 further release of norepinephrine from the same termi- nals; this negative feedback conserves norepinephrine in states of high stimulation of the sympathetic nervous system. Interestingly, the adrenal medulla does not have α2 receptors and therefore is not subject to feed- back inhibition; consequently, the adrenal medulla can become depleted of catecholamines during periods of prolonged stress. α2 Receptors present on parasympathetic postgangli- onic nerve terminals of the gastrointestinal tract are called heteroreceptors. Norepinephrine is released from sympathetic postganglionic fibers that synapse on these parasympathetic postganglionic fibers. When activated by norepinephrine, the α2 receptors cause inhibition of release of ACh from the parasympathetic postganglionic nerve terminals. In this way, the sym- pathetic nervous system indirectly inhibits gastro- intestinal function (i.e., by inhibiting the parasympathetic activity). The mechanism of action of these receptors involves the inhibition of adenylyl cyclase, described by the following steps: 1. The agonist (e.g., norepinephrine) binds to the α2 receptor, which is coupled to adenylyl cyclase by an inhibitory G protein, Gi. back to GDP, and the αq subunit returns to the inactive state (not shown). 4. Activated phospholipase C catalyzes the liberation of diacylglycerol and IP3 from phosphatidylinositol 4,5-diphosphate (Step 4). The IP3 that is generated causes the release of Ca2+ from intracellular stores in the endoplasmic or sarcoplasmic reticulum, result- ing in an increase in intracellular Ca2+ concentration (Step 5). Together, Ca2+ and diacylglycerol activate protein kinase C (Step 6), which phosphorylates proteins. These phosphorylated proteins execute the final physiologic actions (Step 7) such as contraction of smooth muscle. α2 Receptors α2 Receptors are inhibitory, are located both presynapti- cally and postsynaptically, and are less common than α1 receptors. They are found on presynaptic adrenergic and cholinergic nerve terminals and in the gastro- intestinal tract. α2 Receptors are found in two forms, autoreceptors and heteroreceptors. α2 Receptors present on sympathetic postganglionic nerve terminals are called autoreceptors. In this func- tion, activation of α2 receptors by norepinephrine released from presynaptic nerve terminals inhibits TABLE 2.4 Location and Mechanism of Action of Autonomic Receptors Receptor Target Tissue Mechanism of Action Adrenoreceptors α1 Vascular smooth muscle, skin, renal, and splanchnic Gastrointestinal tract, sphincters Bladder, sphincter Radial muscle, iris IP3, ↑ intracellular [Ca2+] α2 Gastrointestinal tract, wall Presynaptic adrenergic neurons Inhibition of adenylyl cyclase, ↓ cAMP β1 Heart Salivary glands Adipose tissue Kidney Stimulation of adenylyl cyclase, ↑ cAMP β2 Vascular smooth muscle of skeletal muscle Gastrointestinal tract, wall Bladder, wall Bronchioles Stimulation of adenylyl cyclase, ↑ cAMP Cholinoreceptors Nicotinic Skeletal muscle, motor end plate (N1) Postganglionic neurons, SNS and PNS (N2) Adrenal medulla (N2) Opening Na+ and K+ channels → depolarization Muscarinic All effector organs, PNS IP3, ↑ intracellular [Ca2+] (M1, M3, M5) Sweat glands, SNS ↓ adenylyl cyclase, ↓ cAMP (M2, M4) cAMP, Cyclic adenosine monophosphate; IP3, inositol 1,4,5-triphosphate; PNS, parasympathetic nervous system; SNS, sympathetic nervous system.Www.Medicalstudyzone.com
62 • Physiology respectively. β1 Receptors also are located in the salivary glands, in adipose tissue, and in the kidney (where they promote renin secretion). The mechanism of action of β1 receptors involves a Gs protein and activation of adenylyl cyclase. This action is illustrated in Figure 2.7 and involves the following steps, which correspond to the circled numbers in the figure: 1. Similar to other autonomic receptors, β1 receptors are embedded in the cell membrane. They are coupled, via a Gs protein, to adenylyl cyclase. In the inactive state, the αs subunit of the Gs protein is bound to GDP. 2. When an agonist such as norepinephrine binds to the β1 receptor (Step 1), a conformational change 2. When norepinephrine is bound, the Gi protein releases GDP and binds GTP, and the αi subunit dissociates from the G protein complex. 3. The αi subunit then migrates in the membrane and binds to and inhibits adenylyl cyclase. As a result, cAMP levels decrease, producing the final physiologic action. β1 Receptors β1 Receptors are prominent in the heart. They are present in the SA node, in the atrioventricular (AV) node, and in ventricular muscle. Activation of β1 recep- tors in these tissues produces increased heart rate in the SA node, increased conduction velocity in the AV node, and increased contractility in ventricular muscle, GDP GTP ˜ 1 2 3 7 6 5 4 Norepinephrine Inactive αq β γ˜ α1 Receptor Gq protein ˜ phospholipase C Norepinephrine Active αq β γ˜ α1 Receptor Gq protein Diacylglycerol protein kinase C PIP2 Ca2+ released from ER or SR phospholipase C α1 RECEPTORS IP3 Physiologic actions Fig. 2.6 Mechanism of action of α1 adrenoreceptors. In the inactive state, the αq subunit of the Gq protein is bound to GDP. In the active state, with norepinephrine bound to the α1 receptor, the αq subunit is bound to GTP. αq, β, and γ are subunits of the Gq protein. The circled numbers correspond to steps discussed in the text. ER, Endoplasmic reticulum; GDP, guanosine diphosphate; Gq, G protein; GTP, guanosine triphosphate; IP3, inositol 1,4,5-triphosphate; PIP2, phosphatidylinositol 4,5-diphosphate; SR, sarcoplasmic reticulum.Www.Medicalstudyzone.com
2—Autonomic Nervous System • 63 When β1 receptors are activated in the SA node, heart rate increases; when β1 receptors are activated in ventricular muscle, contractility increases; when β1 receptors are activated in the salivary gland, secre- tion increases; when β1 receptors are activated in the kidney, renin is secreted. β2 Receptors β2 Receptors are found in the vascular smooth muscle of skeletal muscle, in the walls of the gastrointestinal tract and bladder, and in the bronchioles. The activa- tion of β2 receptors in these tissues leads to relaxation or dilation. The β2 receptors have a mechanism of action similar to that of β1 receptors: activation of a Gs protein, release of the αs subunit, stimulation of adeny lyl cyclase, and generation of cAMP (see Fig. 2.7). occurs in the αs subunit. This change has two effects (Step 2): GDP is released from the αs subunit and replaced by GTP, and the activated αs subunit detaches from the G protein complex. 3. The αs-GTP complex migrates within the cell mem- brane and binds to and activates adenylyl cyclase (Step 3). GTPase activity converts GTP back to GDP, and the αs subunit is returned to its inactive state (not shown). 4. Activated adenylyl cyclase catalyzes the conversion of ATP to cAMP, which serves as the second messen- ger (Step 4). cAMP, via steps involving activation of protein kinases, initiates the final physiologic actions (Step 5). As mentioned previously, these physiologic actions are tissue specific and cell type specific. GDP GTP Inactive 1 2 3 5 4 β1 AND β2 RECEPTORS Norepinephrine αs β γ β Receptor Gs protein adenylyl cyclase Norepinephrine Active αs β γ β Receptor Gs protein cAMPATP adenylyl cyclase Physiologic actions ˜ ˜ ˜ ˜ Fig. 2.7 Mechanism of action of β adrenoreceptors. In the inactive state, the αs subunit of the Gs protein is bound to GDP. In the active state, with norepinephrine bound to the β receptor, the αs subunit is bound to GTP. β1 and β2 receptors have the same mechanism of action. The circled numbers correspond to steps discussed in the text. ATP, Adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate.Www.Medicalstudyzone.com
64 • Physiology can be answered by examining the actions of drugs that serve as agonists or antagonists to the nicotinic recep- tor. The nicotinic receptors at the two loci are certainly similar: Both are activated by the agonists ACh, nico- tine, and carbachol, and both are antagonized by the drug curare (see Table 2.2). However, another antago- nist to the nicotinic receptor, hexamethonium, blocks the nicotinic receptor in the ganglia but not the nicotinic receptor on the motor end plate. Thus it can be con- cluded that the receptors at the two loci are similar but not identical, where the nicotinic receptor on the skeletal muscle end plate is designated N1 and the nico- tinic receptor in the autonomic ganglia is designated N2. This pharmacologic distinction predicts that drugs such as hexamethonium will be ganglionic-blocking agents but not neuromuscular-blocking agents. A second conclusion can be drawn about ganglionic blocking agents such as hexamethonium. These agents should inhibit nicotinic receptors in both sympathetic and parasympathetic ganglia, and thus they should produce widespread effects on autonomic function. However, to predict the actions of ganglionic-blocking agents on a particular organ system, it is necessary to know whether sympathetic or parasympathetic control is dominant in that organ. For example, vascular smooth muscle has only sympathetic innervation, which causes vasoconstriction; thus ganglionic-blocking agents produce relaxation of vascular smooth muscle and vasodilation. (Because of this property, ganglionic- blocking agents can be used to treat hypertension.) On the other hand, male sexual function is dramatically impaired by ganglionic-blocking agents because the male sexual response has both sympathetic (ejacula- tion) and parasympathetic (erection) components. The mechanism of action of nicotinic receptors, whether at the motor end plate or in the ganglia, is based on the fact that this ACh receptor is also an ion channel for Na+ and K+. When the nicotinic receptor is activated by ACh, the channel opens and both Na+ and K+ flow through the channel, down their respective electrochemical gradients. Figure 2.8 illustrates the function of the nicotinic receptor/channel in two states: closed and open. The nicotinic receptor is an integral cell membrane protein consisting of five subunits: two α, one β, one delta (δ), and one gamma (γ). These five subunits form a funnel around the mouth of a central core. When no ACh is bound, the mouth of the channel is closed. When ACh is bound to each of the two α subunits, a conformational change occurs in all of the subunits, resulting in opening of the central core of the channel. When the core of the channel opens, Na+ and K+ flow down their respective electrochemical gradients (Na+ into the cell, and K+ out of the cell), with each ion attempting to drive the membrane potential to its Responses of Adrenoreceptors to Norepinephrine and Epinephrine There are significant differences in the responses of α1, β1, and β2 adrenoreceptors to the catecholamines epi- nephrine and norepinephrine. These differences are explained as follows, recalling that norepinephrine is the catecholamine released from postganglionic sympa- thetic adrenergic nerve fibers, while epinephrine is the primary catecholamine released from the adrenal medulla: (1) Norepinephrine and epinephrine have almost the same potency at α1 receptors, with epineph- rine being slightly more potent. However, compared with β receptors, α1 receptors are relatively insensitive to catecholamines. Higher concentrations of catechol- amines are necessary to activate α1 receptors than to activate β receptors. Physiologically, such high concen- trations are reached locally when norepinephrine is released from postganglionic sympathetic nerve fibers but not when catecholamines are released from the adrenal medulla. For example, the amount of epineph- rine (and norepinephrine) released from the adrenal medulla in the fight or flight response is insufficient to activate α1 receptors. (2) Norepinephrine and epineph- rine are equipotent at β1 receptors. As noted previously, much lower concentrations of catecholamines will activate β1 receptors than will activate α1 receptors. Thus norepinephrine released from sympathetic nerve fibers or epinephrine released from the adrenal medulla will activate β1 receptors. (3) β2 receptors are preferen- tially activated by epinephrine. Thus epinephrine released from the adrenal medulla is expected to acti- vate β2 receptors, whereas norepinephrine released from sympathetic nerve endings is not. Cholinoreceptors There are two types of cholinoreceptors: nicotinic and muscarinic. Nicotinic receptors are found on the motor end plate, in all autonomic ganglia, and on chromaffin cells of the adrenal medulla. Muscarinic receptors are found in all effector organs of the parasympathetic division and in a few effector organs of the sympathetic division. Nicotinic Receptor
2—Autonomic Nervous System • 65 intracellular Ca2+ with diacylglycerol produces the tissue-specific physiologic actions. Other muscarinic receptors (e.g., M4) act by inhibit- ing adenylyl cyclase and decreasing intracellular cAMP levels. Still other muscarinic receptors (M2) alter physiologic processes via a direct action of the G protein. In these cases, no other second messenger is involved. For example, muscarinic receptors in the cardiac SA node, when activated by ACh, produce activation of a Gi protein and release of the αi subunit, which binds directly to K+ channels of the SA node. When the αi subunits bind to K+ channels, the channels open, slowing the rate of depolarization of the SA node and decreasing the heart rate. In this mechanism, there is no stimulation or inhibition of either adenylyl cyclase or phospholipase C and no involvement of any second messenger; rather, the Gi protein acts directly on the ion channel (Box 2.4). equilibrium potential. The resulting membrane potential is midway between the Na+ and K+ equilibrium poten- tials, approximately 0 millivolts, which is a depolarized state. Muscarinic Receptors Muscarinic receptors are located in all of the effector organs of the parasympathetic nervous system: in the heart, gastrointestinal tract, bronchioles, bladder, and male sex organs. These receptors also are found in certain effector organs of the sympathetic nervous system, specifically, in sweat glands. Some muscarinic receptors (e.g., M1, M3, and M5) have the same mechanism of action as the α1 adreno- receptors (see Fig. 2.6). In these cases, binding of the agonist (ACh) to the muscarinic receptor causes dis- sociation of the α subunit of the G protein, activation of phospholipase C, and generation of IP3 and diacyl- glycerol. IP3 releases stored Ca2+, and the increased Extracellular fluid ACh ACh α αγ β δ γ α α Channel open K+ Na+ Channel closedIntracellular fluid ACh ACh NICOTINIC RECEPTOR Fig. 2.8 Mechanism of action of nicotinic cholinoreceptors. The nicotinic receptor for acetylcholine (ACh) is an ion channel for Na+ and K+. The receptor has five subunits: two α, one β, one δ, and one γ.Www.Medicalstudyzone.com
66 • Physiology ■ Often, the sympathetic and parasympathetic inner- vations of organs or organ systems have reciprocal effects. These effects are coordinated by autonomic centers in the brain stem. For example, autonomic centers in the brain stem control the heart rate by modulating sympathetic and parasympathetic activ- ity to the SA node. ■ Receptors for neurotransmitters in the autonomic nervous system are either adrenergic (adreno- receptors) or cholinergic (cholinoreceptors). Adrenoreceptors are activated by the catecholamines norepinephrine and epinephrine. Cholinoreceptors are activated by ACh. ■ Autonomic receptors are coupled to G proteins, which may be stimulatory (Gs) or inhibitory (Gi). The G proteins in turn activate or inhibit enzymes that are responsible for the final physiologic actions. ■ The mechanism of action of the adrenoreceptors can be explained as follows: α1 Receptors act through activation of phospholipase C and generation of IP3; β1 and β2 receptors act through activation of adenylyl cyclase and generation of cAMP; α2 receptors act through inhibition of adenylyl cyclase. ■ The mechanism of action of cholinoreceptors can be explained as follows: Nicotinic receptors act as ion channels for Na+ and K+. Many muscarinic receptors have the same mechanism of action as α1 receptors; some muscarinic receptors act by inhibiting adenylyl cyclase; a few muscarinic receptors involve direct action of a G protein on the physiologic mechanism. SUMMARY ■ The autonomic nervous system is composed of two major divisions, the sympathetic and the parasym- pathetic, which operate in a coordinated fashion to regulate involuntary functions. The sympathetic division is thoracolumbar, referring to its origin in the spinal cord. The parasympathetic division is craniosacral, referring to its origin in the brain stem and sacral spinal cord. ■ Efferent pathways in the autonomic nervous system consist of a preganglionic and a postganglionic neuron, which synapse in autonomic ganglia. The axons of postganglionic neurons then travel to the periphery to innervate the effector organs. The adrenal medulla is a specialized ganglion of the sympathetic division; when stimulated, it secretes catecholamines into the circulation. BOX 2.4 Clinical Physiology: Treatment of Motion Sickness With a Muscarinic Receptor Antagonist DESCRIPTION OF CASE. A woman planning a 10-day cruise asks her physician for medication to prevent motion sickness. The physician prescribes scopolamine, a drug related to atropine, and recom- mends that she take it for the entire duration of the cruise. While taking the drug, the woman experi- ences no nausea or vomiting, as hoped. However, she does experience dry mouth, dilation of the pupils (mydriasis), increased heart rate (tachycar- dia), and difficulty voiding urine. EXPLANATION OF CASE. Scopolamine, like atro- pine, blocks cholinergic muscarinic receptors in target tissues. Indeed, it can be used effectively to treat motion sickness, whose etiology involves muscarinic receptors in the vestibular system. The adverse effects that the woman experienced while taking scopolamine can be explained by understand- ing the physiology of muscarinic receptors in target tissues. Activation of muscarinic receptors causes increased salivation, constriction of the pupils, decreased heart rate (bradycardia), and contraction of the bladder wall during voiding (see Table 2.2). Therefore inhibi tion of the muscarinic receptors with scopolamine would be expected to cause symptoms of decreased salivation (dry mouth), dilation of the pupils (due to the unopposed influence of the sympathetic nervous system on the radial muscles), increased heart rate, and slowed voiding of urine (caused by the loss of contractile tone of the bladder wall). TREATMENT. Scopolamine is discontinued. Challenge Yourself Answer each question with a word, phrase, sentence, or numerical solution. When a list of possible answers is supplied with the question, one, more than one, or none of the choices may be correct. The correct answers are provided at the end of the book. 1 Which of the following actions is/are mediated by β2 receptors: increased heart rate, contraction of gastrointestinal sphincters, contraction of vascular smooth muscle, dilation of airways, relaxation of bladder wall? 2 A woman who is taking atropine for a gastrointestinal disorder notices that her pupils are dilated. This has occurred because atropine blocks ___________ receptors on the __________ muscle of the iris. 3 Which of the following is/are characteristic of the parasympathetic nervous system but notWww.Medicalstudyzone.com
2—Autonomic Nervous System • 67 of the sympathetic nervous system: ganglia in or near target tissues, nicotinic receptors on postganglionic neurons, muscarinic receptors on some target tissues, β1 receptors on some target tissues, cholinergic preganglionic neurons? 4 Propranolol causes a decrease in heart rate because it _______________ the _____________ receptors in the sinoatrial node of the heart. 5 Which of the following actions is/are mediated by the adenylyl cyclase mechanism: effect of parasympathetic nervous system to increase gastric acid secretion, effect of epinephrine to increase cardiac contractility, effect of epinephrine to increase heart rate, effect of acetylcholine to decrease heart rate, effect of acetylcholine to constrict airways, constriction of vascular smooth muscle in splanchnic blood vessels? 6 What enzyme is responsible for the fact that the adrenal medulla synthesizes more epinephrine than norepinephrine? 7 A man had a pheochromocytoma that caused severe elevation of his blood pressure. Prior to surgery to remove the tumor, he received the wrong drug, which caused a further elevation in blood pressure. Name two classes of drugs that may have been given in error to cause this further elevation. 8 A man’s bladder is full. When he voids (micturition), __________ receptors cause __________ of the detrusor muscle and __________ receptors cause __________ of the internal sphincter. 9 In the action of α1 receptors, what is the correct order of steps: αq binds to GDP, αq binds to GTP, generation of IP3, release of Ca2+ from intracellular stores, activation of protein kinase, activation of phospholipase C? 10 Which of the following actions are mediated by muscarinic receptors: slowing of conduction velocity in AV node, gastric acid secretion, mydriasis, contraction of gastrointestinal sphincters, erection, renin secretion, sweating on a hot day?Www.Medicalstudyzone.com
69 CHAPTER 3 Neurophysiology Organization of the Nervous System, 69 Cells of the Nervous System, 72 General Features of Sensory and Motor Systems, 73 Sensory Systems, 75 Somatosensory System and Pain, 80 Vision, 85 Audition, 91 Vestibular System, 95 Olfaction, 98 Taste, 100 Motor Systems, 103 Higher Functions of the Nervous System, 112 Cerebrospinal Fluid, 113 Summary, 115 Challenge Yourself, 115 The nervous system is a complex network that allows an organism to communicate with its environment. The network includes sensory components, which detect changes in environmental stimuli, and motor compo- nents, which generate movement, contraction of cardiac and smooth muscle, and glandular secretions. Integra- tive components of the nervous system receive, store, and process sensory information and then orchestrate the appropriate motor responses. ORGANIZATION OF THE NERVOUS SYSTEM To understand neurophysiology, it is necessary to appreciate the organization of the nervous system and the gross anatomic arrangement of structures. A com- prehensive presentation of neuroanatomy would be the subject of an entire text. Thus in this chapter the anatomy will be described briefly, as is appropriate for the physiologic context. The nervous system is composed of two divisions: the central nervous system (CNS), which includes the brain and the spinal cord, and the peripheral nervous system (PNS), which includes sensory receptors, sensory nerves, and ganglia outside the CNS. The CNS and PNS communicate extensively with each other. Further distinction can be made between the sensory and motor divisions of the nervous system. The sensory or afferent division brings information into the nervous system, usually beginning with events in sensory receptors in the periphery. These receptors include, but are not limited to, visual receptors, auditory receptors, chemore- ceptors, and somatosensory (touch) receptors. This afferent information is then transmit- ted to progressively higher levels of the nervous system and finally to the cerebral cortex. The motor or efferent division carries information out of the nervous system to the periphery. This efferent information results in contraction of skeletal muscle, smooth muscle, and cardiac muscle or secretion by endocrine and exocrine glands. To illustrate and compare the functions of the sensory and motor divisions of the nervous system, consider an example introduced in Chapter 2: regulation of arterial blood pressure. Arterial blood pressure is sensed by baroreceptors located in the walls of the carotid sinus. This information is transmitted, via the glossopharyngeal nerveWww.Medicalstudyzone.com
70 • Physiology Spinal Cord The spinal cord is the most caudal portion of the CNS, extending from the base of the skull to the first lumbar vertebra. The spinal cord is segmented, with 31 pairs of spinal nerves that contain both sensory (afferent) nerves and motor (efferent) nerves. Sensory nerves carry information to the spinal cord from the skin, joints, muscles, and visceral organs in the periphery via dorsal root and cranial nerve ganglia. Motor nerves carry information from the spinal cord to the periph- ery and include both somatic motor nerves, which innervate skeletal muscle, and motor nerves of the autonomic nervous system, which innervate cardiac muscle, smooth muscle, glands, and secretory cells (see Chapter 2). Information also travels up and down within the spinal cord. Ascending pathways in the spinal cord carry sensory information from the periphery to higher levels of the CNS. Descending pathways in (cranial nerve [CN] IX), to the vasomotor center in the medulla of the brain stem—this is the sensory or affer- ent limb of blood pressure regulation. In the medulla, the sensed blood pressure is compared with a set point, and the medullary vasomotor center directs changes in sympathetic and parasympathetic outflow to the heart and blood vessels, which produce appropriate adjust- ments in arterial pressure—this is the motor or efferent limb of blood pressure regulation. The CNS includes the brain and spinal cord. The organization of major structures of the CNS is shown in Figures 3.1 and 3.2. Figure 3.1 shows the structures in their correct anatomic positions. These same struc- tures are illustrated schematically in Figure 3.2, which may prove more useful as a reference. The major divisions of the CNS are the spinal cord; brain stem (medulla, pons, and midbrain); cerebellum; diencephalon (thalamus and hypothalamus); and cere- bral hemispheres (cerebral cortex, white matter, basal ganglia, hippocampal formation, and amygdala). Midbrain Medulla Pons Pituitary gland Thalamus Frontal lobe Hypothalamus Spinal cord Occipital lobe Cerebellum Parietal lobe Fig. 3.1 Midsagittal section of the brain. Relationships are shown between the lobes of the cerebral cortex, the cerebellum, the thalamus and hypothalamus, the brain stem, and the spinal cord.Www.Medicalstudyzone.com
3—Neurophysiology • 71 ♦ The midbrain is rostral to the pons and participates in control of eye movements. It also contains relay nuclei of the auditory and visual systems. Cerebellum The cerebellum is a foliated (“leafy”) structure that is attached to the brain stem and lies dorsal to the pons and medulla. The functions of the cerebellum are coordination of movement, planning and execution of movement, maintenance of posture, and coordination of head and eye movements. Thus the cerebellum, conveniently positioned between the cerebral cortex and the spinal cord, integrates sensory information about position from the spinal cord, motor information from the cerebral cortex, and information about balance from the vestibular organs of the inner ear. Thalamus and Hypothalamus Together, the thalamus and hypothalamus form the diencephalon, which means “between brain.” The term refers to the location of the thalamus and the spinal cord carry motor information from higher levels of the CNS to the motor nerves that innervate the periphery. Brain Stem The medulla, pons, and midbrain are collectively called the brain stem. Ten of the 12 cranial nerves (CNs III–XII) arise in the brain stem. They carry sensory information to the brain stem and motor information away from it. The components of the brain stem are as follows: ♦ The medulla is the rostral extension of the spinal cord. It contains autonomic centers that regulate breathing and blood pressure, as well as the centers that coordinate swallowing, coughing, and vomiting reflexes (see Chapter 2, Fig. 2.5). ♦ The pons is rostral to the medulla and, together with centers in the medulla, participates in balance and maintenance of posture and in regulation of breath- ing. In addition, the pons relays information from the cerebral hemispheres to the cerebellum. Brain stem Spinal cord Cerebellum HypothalamusPituitary Thalamus Cerebral cortex Midline CENTRAL NERVOUS SYSTEM Midbrain Pons Medulla Fig. 3.2 Schematic diagram of the central nervous system.Www.Medicalstudyzone.com
72 • Physiology ♦ Basal ganglia, hippocampus, and amygdala. There are three deep nuclei of the cerebral hemispheres. The basal ganglia consist of the caudate nucleus, the putamen, and the globus pallidus. The basal ganglia receive input from all lobes of the cerebral cortex and have projections, via the thalamus, to the frontal cortex to assist in regulating movement. The hippocampus and amygdala are part of the limbic system. The hippocampus is involved in memory; the amygdala is involved with the emotions and communicates with the autonomic nervous system via the hypothalamus (e.g., effect of the emotions on heart rate, pupil size, and hypothalamic hormone secretion). CELLS OF THE NERVOUS SYSTEM Neurons, or nerve cells, are specialized for receiving and sending signals. The structure of neurons includes the cell body, or soma; the dendrites; the axon; and the presynaptic terminals (Fig. 3.3). Glial cells, which greatly outnumber neurons, include astrocytes, oligo- dendrocytes, and microglial cells; their function, broadly, is to provide support for the neurons. Structure of the Neuron Cell Body The cell body, or soma, surrounds the nucleus of the neuron and contains the endoplasmic reticulum and Golgi apparatus. It is responsible for the neuron’s synthesis and processing of proteins. Dendrites Dendrites are tapering processes that arise from the cell body. They receive information and thus contain recep- tors for neurotransmitters that are released from adja- cent neurons. Axon The axon is a projection arising from a specialized region of the cell body called the axon hillock, which adjoins the spike initiation zone (or initial segment) where action potentials are generated to send informa- tion. Whereas dendrites are numerous and short, each neuron has a single axon, which can be quite long (up to 1 meter in length). The cytoplasm of the axon con- tains dense, parallel arrays of microtubules and micro- filament that rapidly move materials between the cell body and the axon terminus. Axons carry action potentials between the neuron cell body and the targets of that neuron, either other neurons or muscle. Axons may be insulated with myelin (see Chapter 1), which increases conduction velocity; breaks in the myelin sheath occur at the nodes of Ranvier. hypothalamus between the cerebral hemispheres and the brain stem. The thalamus processes almost all sensory informa- tion going to the cerebral cortex and almost all motor information coming from the cerebral cortex to the brain stem and spinal cord. The hypothalamus lies ventral to the thalamus and contains centers that regulate body temperature, food intake, and water balance. The hypothalamus is also an endocrine gland that controls the hormone secretions of the pituitary gland. The hypothalamus secretes releasing hormones and release-inhibiting hormones into hypophysial portal blood that cause release (or inhibition of release) of the anterior pituitary hormones. The hypothalamus also contains the cell bodies of neurons of the posterior pituitary gland that secrete antidiuretic hormone (ADH) and oxytocin. Cerebral Hemispheres The cerebral hemispheres consist of the cerebral cortex, an underlying white matter, and three deep nuclei (basal ganglia, hippocampus, and amygdala). The functions of the cerebral hemispheres are perception, higher motor functions, cognition, memory, and emotion. ♦ Cerebral cortex. The cerebral cortex is the convo- luted surface of the cerebral hemispheres and con- sists of four lobes: frontal, parietal, temporal, and occipital. These lobes are separated by sulci or grooves. The cerebral cortex receives and processes sensory information and integrates motor functions. These sensory and motor areas of the cortex are further designated as “primary,” “secondary,” and “tertiary,” depending on how directly they deal with sensory or motor processing. The primary areas are the most direct and involve the fewest synapses; the tertiary areas require the most complex processing and involve the greatest number of synapses. Asso ciation areas integrate diverse information for pur- poseful actions. For example, the limbic association area is involved in motivation, memory, and emo- tions. The following examples illustrate the nomen- clature: (1) The primary motor cortex contains the upper motoneurons, which project directly to the spinal cord and activate lower motoneurons that innervate skeletal muscle. (2) The primary sensory cortices consist of the primary visual cortex, primary auditory cortex, and primary somatosensory cortex and receive information from sensory receptors in the periphery, with only a few intervening synapses. (3) Secondary and tertiary sensory and motor areas surround the primary areas and are involved with more complex processing by connecting to associa- tion areas.Www.Medicalstudyzone.com
3—Neurophysiology • 73 GENERAL FEATURES OF SENSORY AND MOTOR SYSTEMS Before proceeding to specific discussions about the major sensory and motor systems, some common organizational features will be considered. Although the details of each system will vary, these features can be appreciated as a set of recurring themes throughout neurophysiology. Synaptic Relays The simplest synapses are one-to-one connections consisting of a presynaptic element (e.g., motoneuron) and a postsynaptic element (e.g., skeletal muscle fiber). In the nervous system, however, many synapses are more complicated and use synapses in relay nuclei to integrate converging information. Relay nuclei are found throughout the CNS, but they are especially prominent in the thalamus. Relay nuclei contain several different types of neurons including local interneurons and projection neurons. The projection neurons extend long axons out of the nuclei to synapse in other relay nuclei or in the cerebral cortex. Almost all information going to and coming from the cerebral cortex is processed in thal- amic relay nuclei. Presynaptic Terminals The axon terminates on its target cells (e.g., other neurons) in multiple endings, called presynaptic termi- nals. When the action potential transmitted down the axon reaches the presynaptic terminal, neurotransmitter is released into the synapse. The transmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic membrane (e.g., of dendrites of other neurons). In this way, information is transmitted rapidly from neuron to neuron (or, in the case of the neuro- muscular junction, from neuron to skeletal muscle). Glial Cells Glial cells occupy over half of the brain’s volume and function as support cells for neurons. Some glial cells of the adult brain have the properties of stem cells and thus can give rise to new glial cells or even new neurons. Astrocytes supply metabolic fuel, as lactic acid, to the neurons; they also synthesize neurotrans- mitters, secrete trophic factors that promote neuronal survival, modulate cerebral blood flow, and help maintain the brain’s extracellular K+ concentration. Oligodendrocytes synthesize myelin in the CNS; Schwann cells synthesize myelin in the PNS. Microglial cells proliferate following neuronal injury and serve as scavengers to remove cellular debris. Axon hillock Spike initiation zone Node of Ranvier Myelin Axon Presynaptic terminal Cell body Dendrites Presynaptic terminal Synaptic cleft Fig. 3.3 Structure of the neuron.Www.Medicalstudyzone.com
74 • Physiology commissures; for example, the corpus callosum is the commissure connecting the two cerebral hemispheres. Some systems are mixed, having both crossed and uncrossed pathways. For example, in the visual system, half of the axons from each retina cross to the contra- lateral side and half remain ipsilateral. Visual fibers that cross do so in the optic chiasm. Types of Nerve Fibers Nerve fibers are classified according to their conduction velocity, which depends on the size of the fibers and the presence or absence of myelination. The effects of fiber diameter and myelination on conduction velocity are explained in Chapter 1. Briefly, the larger the fiber, the higher the conduction velocity. Conduction velocity also is increased by the presence of a myelin sheath around the nerve fiber. Thus large myelinated nerve fibers have the fastest conduction velocities, and small unmyelinated nerve fibers have the slowest conduction velocities. Two classification systems, which are based on dif- ferences in conduction velocity, are used. The first system, described by Erlanger and Gasser, applies to both sensory (afferent) and motor (efferent) nerve fibers and uses a lettered nomenclature of A, B, and C. The second system, described by Lloyd and Hunt, applies only to sensory nerve fibers and uses a Roman numeral nomenclature of I, II, III, and IV. Table 3.1 provides a summary of nerve fiber types within each classification, examples of each type, information about Topographic Organization One of the striking features of sensory and motor systems is that information is encoded in neural maps. For example, in the somatosensory system, a somato topic map is formed by an array of neurons that receive information from and send information to specific locations on the body. The topographic coding is pre- served at each level of the nervous system, even as high as the cerebral cortex. Thus in the somatosensory system, the topographic information is represented as a sensory homunculus in the cerebral cortex (see Fig. 3.12). In the visual system, the topographic repre- sentation is called retinotopic, in the auditory system it is called tonotopic, and so forth. Decussations Almost all sensory and motor pathways are bilater- ally symmetric, and information crosses from one side (ipsilateral) to the other (contralateral) side of the brain or spinal cord. Thus sensory activity on one side of the body is relayed to the contralateral cerebral hemisphere; likewise, motor activity on one side of the body is controlled by the contralateral cerebral hemisphere. All pathways do not cross at the same level of the CNS, however. Some pathways cross in the spinal cord (e.g., pain), and many cross in the brain stem. These crossings are called decussations. Areas of the brain that contain only decussating axons are called TABLE 3.1 Classification of Nerve Fibers Classification Type of Nerve Fiber Example Relative Diameter Relative Conduction Velocity Myelination Sensory and Motor A alpha (Aα) α Motoneurons Largest Fastest Yes A beta (Aβ) Touch, pressure Medium Medium Yes A gamma (Aγ) γ Motoneurons to muscle spindles (intrafusal fibers) Medium Medium Yes A delta (Aδ) Touch, pressure, temperature, fast pain Small Medium Yes B Preganglionic autonomic nerves Small Medium Yes C Slow pain; postganglionic autonomic nerves; olfaction Smallest Slowest No Sensory Only Ia Muscle spindle afferents Largest Fastest Yes Ib Golgi tendon organ afferents Largest Fastest Yes II Secondary afferents of muscle spindles; touch, pressure Medium Medium Yes III Touch, pressure, fast pain, temperature Small Medium Yes IV Pain, temperature; olfaction Smallest Slowest NoWww.Medicalstudyzone.com
3—Neurophysiology • 75 are first-order, or primary afferent, neurons. Regard- less of these differences, the basic function of the receptors is the same: to convert a stimulus (e.g., sound waves, electromagnetic waves, or pressure) into electrochemical energy. The conversion process, called sensory transduction, is mediated through opening or closing specific ion channels. Opening or closing ion channels leads to a change in membrane potential, either depolarization or hyperpolarization, of the sensory receptor. Such a change in membrane potential of the sensory receptor is called the recep tor potential. After transduction and generation of the receptor potential, the information is transmitted to the CNS along a series of sensory afferent neurons, which are designated as first-order, second-order, third-order, and fourth-order neurons (see Fig. 3.4). First-order refers to those neurons closest to the sensory recep- tor, and the higher-order neurons are those closer to the CNS. fiber diameter and conduction velocity, and whether the fibers are myelinated or unmyelinated. SENSORY SYSTEMS Sensory Pathways Sensory systems receive information from the environ- ment via specialized receptors in the periphery and transmit this information through a series of neurons and synaptic relays to the CNS. The following steps are involved in transmitting sensory information (Fig. 3.4): 1. Sensory receptors. Sensory receptors are activated by stimuli in the environment. The nature of the receptors varies from one sensory modality to the next. In the visual, taste, and auditory systems, the receptors are specialized epithelial cells. In the somatosensory and olfactory systems, the receptors Brain stem Spinal cord Thalamus Cerebral cortex Fourth-order neuron Third-order neuron Second-order neuron Relay nucleus First-order neuron Midline Receptor Fig. 3.4 Schematic diagram of sensory pathways in the nervous system. Information is transmitted, via a series of neurons, from receptors in the periphery to the cerebral cortex. Synapses are made in relay nuclei between first- and second-order neurons, between second- and third-order neurons, and between third- and fourth-order neurons. Second-order neurons cross the midline either in the spinal cord (shown) or in the brain stem (not shown) so that information from one side of the body is transmitted to the contralateral thalamus and cerebral cortex.Www.Medicalstudyzone.com
76 • Physiology pathway, fourth-order neurons are found in the primary auditory cortex; in the visual pathway, they reside in the primary visual cortex; and so forth. As noted, there are secondary and tertiary areas, as well as association areas in the cortex, all of which integrate complex sensory information. Sensory Receptors Consider again the first step in the sensory pathway in which an environmental stimulus is transduced into an electrical signal in the sensory receptor. This section discusses the various types of sensory receptors, mechanisms of sensory transduction, receptive fields of sensory neurons, sensory coding, and adaptation of sensory receptors. Types of Receptors Receptors are classified by the type of stimulus that activates them. The five types of receptors are mecha- noreceptors, photoreceptors, chemoreceptors, thermo- receptors, and nociceptors. Table 3.2 summarizes the receptors and gives examples and locations of each type. Mechanoreceptors are activated by pressure or changes in pressure. Mechanoreceptors include, but are not limited to, the pacinian corpuscles in subcutaneous tissue, Meissner corpuscles in nonhairy skin (touch), baroreceptors in the carotid sinus (blood pressure), and hair cells on the organ of Corti (audition) and in the semicircular canals (vestibular system). Photorecep tors are activated by light and are involved in vision. Chemoreceptors are activated by chemicals and are involved in olfaction, taste, and detection of oxygen and carbon dioxide in the control of breathing. Thermo receptors are activated by temperature or changes in 2. First order sensory afferent neurons. The first- order neuron is the primary sensory afferent neuron; in some cases (somatosensory, olfaction), it also is the receptor cell. When the sensory receptor is a specialized epithelial cell, it synapses on a first-order neuron. When the receptor is also the primary affer- ent neuron, there is no need for this synapse. The primary afferent neuron usually has its cell body in a dorsal root or spinal cord ganglion. (Exceptions are the auditory, olfactory, and visual systems.) 3. Second order sensory afferent neurons. First-order neurons synapse on second-order neurons in relay nuclei, which are located in the spinal cord or in the brain stem. Usually, many first-order neurons synapse on a single second-order neuron within the relay nucleus. Interneurons, also located in the relay nuclei, may be excitatory or inhibitory. These inter- neurons process and modify the sensory information received from the first-order neurons. Axons of the second-order neurons leave the relay nucleus and ascend to the next relay, located in the thalamus, where they synapse on third-order neurons. En route to the thalamus, the axons of these second-order neurons cross at the midline. The decussation, or crossing, may occur in the spinal cord (illustrated in Fig. 3.4) or in the brain stem (not illustrated). 4. Third order sensory afferent neurons. Third-order neurons typically reside in relay nuclei in the thala mus. Again, many second-order neurons synapse on a single third-order neuron. The relay nuclei process the information they receive via local interneurons, which may be excitatory or inhibitory. 5. Fourth order sensory afferent neurons. Fourth- order neurons reside in the appropriate sensory area of the cerebral cortex. For example, in the auditory TABLE 3.2 Types and Examples of Sensory Receptors Type of Receptor Modality Receptor Location Mechanoreceptors Touch Pacinian corpuscle Skin Audition Hair cell Organ of Corti Vestibular Hair cell Macula, semicircular canal Photoreceptors Vision Rods and cones Retina Chemoreceptors Olfaction Olfactory receptors Olfactory mucosa Taste Taste buds Tongue Arterial PO2 Carotid and aortic bodies pH of CSF Ventrolateral medulla Thermoreceptors Temperature Cold receptors Skin Warm receptors Skin Nociceptors Extremes of pain and temperature Thermal nociceptors Skin Polymodal nociceptors Skin CSF, Cerebrospinal fluid; PO2, partial pressure of oxygen.Www.Medicalstudyzone.com
3—Neurophysiology • 77 the cell), then hyperpolarization occurs. The result- ing change in membrane potential, either depolar- ization or hyperpolarization, is called the receptor potential or generator potential. The receptor potential is not an action potential. Rather, the recep- tor potential increases or decreases the likelihood that an action potential will occur, depending on whether it is depolarizing or hyperpolarizing (i.e., whether it brings the membrane potential toward or away from threshold). Receptor potentials are graded electronic potentials, whose amplitude correlates with the size of the stimulus. 3. If the receptor potential is depolarizing, it moves the membrane potential toward the threshold poten- tial and increases the likelihood that an action potential will occur (Fig. 3.5). Because receptor potentials are graded in amplitude, a small depolar- izing receptor potential still may be subthreshold and therefore insufficient to produce an action potential. However, a larger stimulus will produce a larger depolarizing receptor potential, and if it reaches or exceeds threshold, action potentials will occur. If the receptor potential is hyperpolarizing (not illustrated), it moves the membrane potential away from the threshold potential, always decreas- ing the likelihood that action potentials will occur. Receptive Fields A receptive field defines an area of the body that when stimulated results in a change in firing rate of a sensory neuron. The change in firing rate can be an increase or a decrease; therefore receptive fields are described as temperature. Nociceptors are activated by extremes of pressure, temperature, or noxious chemicals. Sensory Transduction and Receptor Potentials Sensory transduction is the process by which an environmental stimulus (e.g., pressure, light, chemi- cals) activates a receptor and is converted into electrical energy. The conversion typically involves opening or closing of ion channels in the receptor membrane, which leads to a flow of ions (current flow) across the membrane. Current flow then leads to a change in membrane potential, called a receptor potential, which increases or decreases the likelihood that action poten- tials will occur. The following series of steps occurs when a stimulus activates a sensory receptor: 1. The environmental stimulus interacts with the sensory receptor and causes a change in its proper- ties. A mechanical stimulus causes movement of the mechanoreceptor (e.g., sound waves move the hair cells in the organ of Corti). Photons of light are absorbed by pigments in photoreceptors on the retina, causing photoisomerization of rhodopsin (a chemical in the photoreceptor membrane). Chemical stimulants react with chemoreceptors, which activate Gs proteins and adenylyl cyclase. In each case, a change occurs in the sensory receptor. 2. These changes cause ion channels in the sensory receptor membrane to open or close, which results in a change in current flow. If net ionic current flow is inward (i.e., positive charges move into the recep- tor cell), then depolarization occurs. If net current flow is outward (i.e., positive charges move out of Threshold Subthreshold depolarizing receptor potential Action potential occurs RECEPTOR POTENTIALS No action potential occurs BA Threshold level depolarizing receptor potential Fig. 3.5 Receptor potentials in sensory receptor cells. Receptor potentials may be either depolarizing (shown) or hyperpolarizing (not shown). A, If a depolarizing receptor potential does not bring the membrane potential to threshold, no action potential occurs. B, If a depolarizing receptor potential brings the membrane potential to threshold, then an action potential occurs in the sensory receptor.Www.Medicalstudyzone.com
78 • Physiology is transduced by sensory receptors and continues as the information is transmitted to progressively higher levels of the CNS. One or more aspects of the stimulus are encoded and interpreted. For example, in seeing a red ball, its size, location, color, and depth all are encoded. The features that can be encoded include sensory modality, spatial location, frequency, intensity, thresh- old, and duration of stimulus. ♦ Stimulus modality is often encoded by labeled lines, which consist of pathways of sensory neurons dedicated to that modality. Thus the pathway of neurons dedicated to vision begins with photorecep- tors in the retina. This pathway is not activated by somatosensory, auditory, or olfactory stimuli. Those modalities have their own labeled lines. ♦ Stimulus location is encoded by the receptive field of sensory neurons and may be enhanced by lateral inhibition as previously described. ♦ Threshold is the minimum stimulus that can be detected. Threshold is best appreciated in the context of the receptor potential. If a stimulus is large enough to produce a depolarizing receptor potential that reaches threshold, it will be detected. Smaller sub- threshold stimuli will not be detected. ♦ Stimulus intensity is encoded in three ways. (1) Intensity can be encoded by the number of receptors that are activated. Thus large stimuli will activate more receptors and produce larger responses than will small stimuli. (2) Intensity can be encoded by differences in firing rates of sensory neurons in the pathway. (3) Intensity even may be encoded by excitatory (producing an increase in the firing rate of a sensory neuron) or inhibitory (producing a decrease in the firing rate of a sensory neuron). There are receptive fields for first-, second-, third-, and fourth-order sensory neurons. For example, the receptive field of a second-order neuron is the area of receptors in the periphery that causes a change in the firing rate of that second-order neuron. Receptive fields vary in size (Fig. 3.6). The smaller the receptive field, the more precisely the sensation can be localized or identified. Typically, the higher the order of the CNS neuron, the more complex the recep- tive field, since more neurons converge in relay nuclei at each level. Thus first-order sensory neurons have the simplest receptive fields, and fourth-order sensory neurons have the most complex receptive fields. As noted, receptive fields can be excitatory or inhibi- tory, with the pattern of excitatory or inhibitory recep- tive fields conveying additional information to the CNS. Figure 3.7 illustrates one such pattern for a second-order neuron. The receptive field on the skin for this particu- lar neuron has a central region of excitation, bounded on either side by regions of inhibition. All of the incom- ing information is processed in relay nuclei of the spinal cord or brain stem. The areas of inhibition contribute to a phenomenon called lateral inhibition and aid in the precise localization of the stimulus by defining its boundaries and providing a contrasting border. Sensory Coding Sensory neurons are responsible for encoding stimuli in the environment. Coding begins when the stimulus + + + + Small receptive field Large receptive field Second-order neurons First-order neurons Receptive field Relay nucleus Fig. 3.6 Size of receptive fields of sensory neurons. Inhibitory receptive field Inhibitory receptive field Excitatory receptive field Second-order neuron Inhibitory interneuron First-order neurons ++ + – – Fig. 3.7 Excitatory and inhibitory receptive fields of sensory neurons.Www.Medicalstudyzone.com
3—Neurophysiology • 79 longed stimulus, receptors “adapt” to the stimulus and change their firing rates. Sensory neurons may be rapidly adapting or slowly adapting. Adaptation of Sensory Receptors Sensory receptors “adapt” to stimuli. Adaptation is observed when a constant stimulus is applied for a period of time. Initially, the frequency of action poten- tials is high, but as time passes, this frequency declines even though the stimulus continues (Fig. 3.8). The pattern of adaptation differs among different types of receptors. Some receptors are phasic, meaning they adapt rapidly to the stimulus (e.g., pacinian corpuscles), and others are tonic, meaning they adapt slowly to the stimulus (e.g., Merkel cells). The physiologic basis for adaptation also is illus- trated in Figure 3.8. Two types of receptors are shown: a phasic receptor and a tonic receptor. A stimulus (e.g., pressure) is applied (on), and then the stimulus is removed (off). While the stimulus is on, the receptor potential and the frequency of action potentials are measured. (In the figure, action potentials appear as “spikes.”) activating different types of receptors. Thus a light touch of the skin may activate only mechanorecep- tors, whereas an intense damaging stimulus to the skin may activate mechanoreceptors and nocicep- tors. The intense stimulus would be detected not only as stronger but also as a different modality. ♦ Stimulus information also is encoded in neural maps formed by arrays of neurons receiving infor- mation from different locations on the body (i.e., somatotopic maps), from different locations on the retina (i.e., retinotopic maps), or from different sound frequencies (i.e., tonotopic maps). ♦ Other stimulus information is encoded in the pattern of nerve impulses. Some of these codes are based on mean discharge frequency, others are based on the duration of firing, while others are based on a temporal firing pattern. The frequency of the stimu- lus may be encoded directly in the intervals between discharges of sensory neurons (called interspike intervals). ♦ Stimulus duration is encoded by the duration of firing of sensory neurons. However, during a pro- Action potentials Phasic receptor (rapidly adapting) Tonic receptor (slowly adapting) Receptor potentials Stimulus On Off On Off Fig. 3.8 Response of phasic and tonic mechanoreceptors.Www.Medicalstudyzone.com
80 • Physiology SOMATOSENSORY SYSTEM AND PAIN The somatosensory system processes information about touch, position, pain, and temperature. The receptors involved in transducing these sensations are mechano- receptors, thermoreceptors, and nociceptors. There are two pathways for transmission of somatosensory information to the CNS: the dorsal column system and the anterolateral system. The dorsal column system processes the sensations of fine touch, pressure, two- point discrimination, vibration, and proprioception (limb position). The anterolateral system processes the sensations of pain, temperature, and light touch. Types of Somatosensory Receptors Somatosensory receptors are categorized according to the specific sensation they encode. The major groups of receptors are mechanoreceptors (for touch and proprioception), thermoreceptors (for temperature), and nociceptors (for pain or noxious stimuli). Mechanoreceptors Mechanoreceptors are subdivided into different types of receptors, depending on which kind of pressure or proprioceptive quality they encode. Some types of mechanoreceptors are found in nonhairy skin and other types in hairy skin. Mechanoreceptors are described in Table 3.3 according to their location in the skin or muscle, the type of adaptation they exhibit, and the sensation they encode, and they are illustrated in Figure 3.9. An important characteristic of each receptor is the type of adaptation that it exhibits. Among the various mechanoreceptors, adaptation varies from “very rapidly adapting” (e.g., pacinian corpuscle), to “rapidly adapt- ing” (e.g., Meissner corpuscle and hair follicles), to “slowly adapting” (e.g., Ruffini corpuscle, Merkel ♦ Phasic receptors are illustrated by the pacinian corpuscles, which detect rapid changes in the stimu- lus or vibrations. These receptors adapt rapidly to a constant stimulus and primarily detect onset and offset of a stimulus and a changing stimulus. The phasic receptor responds promptly at the onset of the stimulus with a depolarizing receptor potential that brings the membrane potential above threshold. A short burst of action potential follows. After this burst, the receptor potential decreases below the threshold level, and although the stimulus continues, there are no action potentials (i.e., there is silence). When the stimulus is turned off, the receptor is once again activated, as the receptor potential depolarizes to threshold, causing a second short burst of action potentials. ♦ Tonic receptors are illustrated by mechanoreceptors (e.g., Merkel receptors) in the skin, which detect steady pressure. When compared with the pacinian corpuscles (which detect vibration with their fast on-off response), tonic mechanoreceptors are designed to encode duration and intensity of stimu- lus. The tonic receptor responds to the onset of the stimulus with a depolarizing receptor potential that brings the membrane to threshold, resulting in a long series of action potentials. Unlike the pacinian corpuscle, whose receptor potential returns quickly to baseline, here the receptor potential remains depolarized for a longer portion of the stimulus period, and the action potentials continue. Once the receptor potential begins to repolarize, the rate of action potentials declines and eventually there is silence. Tonic receptors encode stimulus intensity: The greater the intensity, the larger the depolarizing receptor potential, and the more likely action poten- tials are to occur. Thus tonic receptors also encode stimulus duration: The longer the stimulus, the longer the period in which the receptor potential exceeds threshold. TABLE 3.3 Types of Mechanoreceptors Type of Mechanoreceptor Location Adaptation Sensation Encoded Pacinian corpuscle Subcutaneous; intramuscular Very rapidly Vibration, tapping Meissner corpuscle Nonhairy skin Rapidly Point discrimination, tapping, flutter Hair follicles Hairy skin Rapidly Velocity, direction of movement Ruffini corpuscle Hairy skin Slowly Stretch, joint rotation Merkel receptors Nonhairy skin Slowly Vertical indentation of skin Tactile discs Hairy skin Slowly Vertical indentation of skinWww.Medicalstudyzone.com
3—Neurophysiology • 81 ♦ Hair follicle. Hair-follicle receptors are arrays of nerve fibers surrounding hair follicles in hairy skin. When the hair is displaced, it excites the hair-follicle receptors. These receptors are also rapidly adapting and detect velocity and direction of movement across the skin. ♦ Ruffini corpuscle. Ruffini corpuscles are located in the dermis of nonhairy and hairy skin and in joint capsules. These receptors have large receptive fields and are stimulated when the skin is stretched. The stimulus may be located some distance from the receptors it activates. Ruffini corpuscles are slowly adapting receptors. When the skin is stretched, the receptors fire rapidly, then slowly adapt to a new level of firing that corresponds to stimulus intensity. Ruffini corpuscles detect stretch and joint rotation. ♦ Merkel receptors and tactile discs. Merkel recep- tors are slowly adapting receptors found in nonhairy skin and have very small receptive fields. These receptors detect vertical indentations of the skin, and their response is proportional to stimulus receptors, and tactile discs). Very rapidly and rapidly adapting receptors detect changes in the stimulus and therefore detect changes in velocity. Slowly adapting receptors respond to intensity and duration of the stimulus. ♦ Pacinian corpuscle. Pacinian corpuscles are encap- sulated receptors found deep in the dermis, in the subcutaneous layers of nonhairy and hairy skin, and in muscle. They are the most rapidly adapting of all mechanoreceptors. Because of their very rapid on-off response, they can detect changes in stimulus veloc- ity and encode the sensation of vibration. ♦ Meissner corpuscle. Meissner corpuscles are also encapsulated receptors found in the dermis of non- hairy skin, most prominently on the fingertips, lips, and other locations where tactile discrimination is especially good. They have small receptive fields and can be used for two point discrimination. Meissner corpuscles are rapidly adapting receptors that encode point discrimination, precise location, tapping, and flutter. MECHANORECEPTORS Nonhairy skin Very rapidly adapting Pacinian corpuscle Rapidly adapting Meissner corpuscle Hair-follicle receptor Slowly adapting Merkel cell Ruffini corpuscle Tactile Epidermis Dermis Subcutaneous tissue Hairy skin Fig. 3.9 Types of mechanoreceptors found in nonhairy skin and hairy skin.Www.Medicalstudyzone.com
82 • Physiology mechanical stimuli such as sharp, pricking pain. Poly modal nociceptors are supplied by unmyelinated C fibers and respond to high-intensity mechanical or chemical stimuli and hot and cold stimuli. Damaged skin releases a variety of chemicals includ- ing bradykinin, prostaglandins, substance P, K+, and H+, which initiate the inflammatory response. The blood vessels become permeable, and, as a result, there is local edema and redness of the skin. Mast cells near the site of injury release histamine, which directly activates nociceptors. In addition, axons of the nocicep- tors release substances that sensitize the nociceptors to stimuli that were not previously noxious or painful. This sensitization process, called hyperalgesia, is the basis for various phenomena including reduced thresh- old for pain. Somatosensory Pathways There are two pathways for transmission of somato- sensory information to the CNS: the dorsal column system and the anterolateral or spinothalamic system (Fig. 3.11). Each pathway follows the general pattern already described for sensory systems. 1. The first order neuron in the somatosensory pathway is the primary afferent neuron. Primary afferent neurons have their cell bodies in dorsal root or cranial ganglia, and their axons synapse on somatosensory receptor cells (i.e., mechanorecep- tors). The signal is transduced by the receptor and transmitted to the CNS by the primary afferent neuron. 2. The second order neuron is located in the spinal cord (anterolateral system) or in the brain stem (dorsal column system). The second-order neurons receive information from first-order neurons and transmit that information to the thalamus. Axons of the second-order neurons cross the midline, either in the spinal cord or in the brain stem, and ascend to the thalamus. This decussation means that somatosensory information from one side of the body is received in the contralateral thalamus. 3. The third order neuron is located in one of the somatosensory nuclei of the thalamus. The thalamus has a somatotopic arrangement of somatosensory information. 4. The fourth order neuron is located in the somato- sensory cortex, called S1 and S2. Higher-order neurons in the somatosensory cortex and other associative cortical areas integrate complex informa- tion. The S1 somatosensory cortex has a somatotopic representation, or “map,” similar to that in the thalamus. This map of the body is called the somato sensory homunculus (Fig. 3.12). The largest areas intensity. Tactile discs are similar to Merkel receptors but are found in hairy, rather than nonhairy, skin. Thermoreceptors Thermoreceptors are slowly adapting receptors that detect changes in skin temperature. The two classes of thermoreceptors are cold receptors and warm receptors (Fig. 3.10). Each type of receptor functions over a broad range of temperatures, with some overlap in the moderate temperature range (e.g., at 36°C, both receptors are active). When the skin is warmed above 36°C, the cold receptors become quiescent, and when the skin is cooled below 36°C, the warm receptors become quiescent. If skin temperature rises to damaging levels (above 45°C), warm receptors become inactive; thus warm receptors do not signal pain from extreme heat. At temperatures above 45°C, polymodal nociceptors will be activated. Likewise, extremely cold (freezing) tem- peratures also activate nociceptors. Transduction of warm temperatures involves tran sient receptor potential (TRP) channels in the family of vanilloid receptors (i.e., TRPV). These channels are activated by compounds in the vanilloid class, which includes capsaicin, an ingredient in spicy foods. (This phenomenon explains why people describe the taste of chili peppers as “hot.”) Transduction of cold temperatures involves a dif- ferent TRP channel, TRPM8, which is also opened by compounds like menthol (which gives a cold sensation). Nociceptors Nociceptors respond to noxious stimuli that can produce tissue damage. There are two major classes of nocicep- tors: thermal or mechanical nociceptors and polymodal nociceptors. Thermal or mechanical nociceptors (TRPV or TRPM8 channels) are supplied by finely myelinated A-delta afferent nerve fibers and respond to Skin temperature (°C) Response 25 35 45 Cold receptors Warm receptors Fig. 3.10 The response profiles of skin temperature receptors.Www.Medicalstudyzone.com
3—Neurophysiology • 83 ganglion cells or in cranial nerve ganglion cells and ascend ipsilaterally to the nucleus gracilis (lower body) or nucleus cuneatus (upper body) in the medulla of the brain stem. In the medulla, first-order neurons synapse on second-order neurons, which cross the midline. The second-order neurons ascend to the contralateral thalamus, where they synapse on third- order neurons, which ascend to the somatosensory cortex and synapse on fourth-order neurons. Anterolateral System The anterolateral (spinothalamic) system transmits somatosensory information about pain, temperature, of representation of the body are the face, hands, and fingers, which are densely innervated by somatosensory nerves and where sensitivity is great- est. The sensory homunculus illustrates the “place” coding of somatosensory information. Dorsal Column System The dorsal column system is used for transmitting somatosensory information about discriminative touch, pressure, vibration, two point discrimination, and proprioception. The dorsal column system consists mainly of group I and II nerve fibers. The first-order neurons have their cell bodies in the dorsal root Receptor Brain stem Spinal cord Thalamus Somatosensory cortex Dorsal column system (fine touch, pressure, proprioception) SOMATOSENSORY PATHWAYS Anterolateral system (pain, temperature, light touch) A B Fourth-order neuron Fourth-order neuron Third-order neuron Second-order neuron Nucleus gracilis = lower body Nucleus cuneatus = upper body First-order neuron Receptor Third-order neuron Second-order neuron First-order neuron Fig. 3.11 Comparison of the dorsal column (A) and the anterolateral (B) somatosensory systems. The dorsal column system crosses the midline in the brain stem. The anterolateral system crosses the midline in the spinal cord.Www.Medicalstudyzone.com
84 • Physiology Fast pain (e.g., pin prick) is carried on A delta, group II, and group III fibers, has a rapid onset and offset, and is precisely localized. Slow pain (e.g., burn) is carried on C fibers and is characterized as aching, burning, or throbbing pain that is poorly localized. Referred pain is of visceral origin that is misper- ceived as pain arising from a somatic location. The pain is “referred” according to the dermatomal rule, which states that sites on the skin are innervated by nerves arising from the same spinal cord segments as those innervating the visceral organs. Thus according to the dermatomal rule, ischemic heart pain (angina) is referred to the chest and shoulder, gallbladder pain is and light touch. The anterolateral system consists mainly of group III and group IV fibers. (Recall that group IV fibers have the slowest conduction velocities of all the sensory nerves.) In the anterolateral system, first-order neurons have their cell bodies in the dorsal horn and synapse on thermoreceptors and nociceptors in the skin. The first-order neurons synapse on second- order neurons in the spinal cord. In the spinal cord, the second-order neurons cross the midline and ascend to the contralateral thalamus. In the thalamus, second- order neurons synapse on third-order neurons, which ascend to the somatosensory cortex and synapse on fourth-order neurons. Intraabdominal Pharynx Tongue Teeth, gums, jaw Lower lip Lips Upper lip Face Nose EyeThumb Index finger Middle finger Ring finger Little finger Hand Wrist Forearm Elbow Head Neck Arm Toes Foot Leg Hip Trunk Shoulder Genitals Fig. 3.12 The somatosensory homunculus. (From Penfield/Rasmussen. THE CEREBRAL CORTEX OF MAN. © 1950 Gale, a part of Cengage Learning, Inc. Reproduced by permission. www .cengage.com/permissions.)Www.Medicalstudyzone.com
3—Neurophysiology • 85 spot, which is the optic disc (head of the optic nerve). Visual acuity is highest at a central point of the retina, called the macula; light is focused at a depression in the macula, called the fovea. The eye also contains a lens, which focuses light; pigments, which absorb light and reduce scatter; and two fluids, aqueous and vitre- ous humors. Aqueous humor fills the anterior chamber of the eye, and vitreous humor fills the posterior chamber of the eye. The sensory receptors for vision are photoreceptors, which are located on the retina. There are two types of photoreceptors, rods and cones (Table 3.4). Rods have low thresholds, are sensitive to low-intensity light, and function well in darkness. The rods have low acuity and do not participate in color vision. Cones have a higher threshold for light than the rods, operate best in daylight, provide higher visual acuity, and participate in color vision. The cones are not sensitive to low- intensity light. Information is received and transduced by photore- ceptors on the retina and then is carried to the CNS via axons of retinal ganglion cells. Some optic nerves cross at the optic chiasm, and others continue ipsilaterally. referred to the abdomen, kidney pain is referred to the lower back, and so forth. VISION The visual system detects and interprets light stimuli, which are electromagnetic waves. The eye can distin- guish two qualities of light: its brightness and its wavelength. For humans, the wavelengths between 400 and 750 nanometers are called visible light. Structures of the Eye The major structures of the eye are illustrated in Figure 3.13. The wall of the eye consists of three concentric layers: an outer layer, a middle layer, and an inner layer. The outer layer, which is fibrous, includes the cornea, corneal epithelium, conjunctiva, and sclera. The middle layer, which is vascular, includes the iris and the choroid. The inner layer, which is neural, contains the retina. The functional portions of the retina cover the entire posterior eye, with the exception of the blind Ciliary body Posterior chamber Iris Retina Optic nerve Choroid Sclera Conjunctiva Limbus Anterior chamber Cornea Aqueous humor Optic axisVisual axis Lens Fovea Optic disc Vitreous humor Fig. 3.13 Structures of the eye.Www.Medicalstudyzone.com
86 • Physiology (bipolar cells, horizontal cells, and amacrine cells), and ganglion cells. Synapses are made between cells in two plexiform layers, an outer plexiform layer and an inner plexiform layer. The layers of the retina are described as follows and correspond with the circled numbers in Figure 3.14: 1. Pigment cell layer. The retina begins just inside the choroid with a layer of pigment epithelium (see Fig. 3.13). The pigment epithelial cells absorb stray The main visual pathway is through the dorsal lateral geniculate nucleus of the thalamus, which projects to the visual cortex. Photoreception Layers of the Retina The retina is a specialized sensory epithelium that con- tains photoreceptors and other cell types arranged in layers. Retinal cells include photoreceptors, interneurons LAYERS OF THE RETINA Pigment cell layer Photoreceptor layer Outer nuclear layer Outer plexiform layer Inner nuclear layer Inner plexiform layer Ganglion cell layer Optic nerve layer 1 2 3 4 5 6 7 8 Light R B H A B G GG A R Fig. 3.14 Layers of the retina. The output cells of the retina are the retinal ganglion cells, whose axons form the optic nerves. Circled numbers correspond to layers of the retina described in the text. A, Amacrine cells; B, bipolar cells; G, ganglion cells; H, horizontal cells; R, photoreceptors. TABLE 3.4 Properties of Rods and Cones Photoreceptor Sensitivity to Light Acuity Dark Adaptation Color Vision Rods Low threshold Sensitive to low-intensity light Night vision Low acuity Not present on fovea Adapt late No Cones High threshold Sensitive to high-intensity light Day vision High acuity Present on fovea Adapt early YesWww.Medicalstudyzone.com
3—Neurophysiology • 87 7. Ganglion cell layer. The ganglion cell layer contains cell bodies of ganglion cells (G), which are the output cells of the retina. 8. Optic nerve layer. Axons of retinal ganglion cells form the optic nerve layer. These axons pass through the retina (avoiding the macula), enter the optic disc, and leave the eye in the optic nerve. As mentioned, there are differences in acuity between rods and cones, which can be explained by differences in their retinal circuitry (see Table 3.4). Only a few cones synapse on a single bipolar cell, which synapses on a single ganglion cell. This arrangement accounts for the higher acuity and lower sensitivity of the cones. Acuity is highest in the fovea, where one cone synapses on one bipolar cell, which synapses on one ganglion cell. In contrast, many rods synapse on a single bipolar cell. This arrangement accounts for the lower acuity but the higher sensitivity of the rods—light striking any one of the rods will activate the bipolar cell. Structure of the Photoreceptors Photoreceptors, the rods and cones, span several layers of the retina, as previously described. The outer and inner segments of photoreceptors are located in the photoreceptor layer, the nuclei are located in the outer nuclear layer, and the synaptic terminals (on bipolar and horizontal cells) are located in the outer plexiform layer. The structures of the rods and cones are shown in Figure 3.15. light and have tentacle-like processes that extend into the photoreceptor layer to prevent scatter of light between photoreceptors. The pigment cells also convert all-trans-retinal to 11-cis retinal and deliver the 11-cis form to the photoreceptors (refer to the steps in photoreception). 2. Photoreceptor layer. The photoreceptors are rods and cones, which consist of a cell body, an outer segment, and an inner segment. Only rods are shown in this figure. 3. Outer nuclear layer. The nuclei of photoreceptors (R) are contained in the outer nuclear layer. 4. Outer plexiform layer. The outer plexiform layer is a synaptic layer containing presynaptic and postsyn- aptic elements of photoreceptors and interneurons of the retina. (The cell bodies of retinal interneurons are contained in the inner nuclear layer.) Synapses are made between photoreceptors and interneurons and also between the interneurons themselves. 5. Inner nuclear layer. The inner nuclear layer con- tains cell bodies of retinal interneurons including bipolar cells (B), horizontal cells (H), and amacrine cells (A). 6. Inner plexiform layer. The inner plexiform layer is the second synaptic layer. It contains presynaptic and postsynaptic elements of retinal interneurons. Synapses are made between retinal interneurons and ganglion cells. STRUCTURE OF PHOTORECEPTORS Outer segments Double-membrane discs Membrane infoldings Inner segments Synaptic terminals Rod Cone Fig. 3.15 Structure of photoreceptors. The enlargements show a magnified view of the outer segments.Www.Medicalstudyzone.com
88 • Physiology The outer segments of both rods and cones contain rhodopsin, a light-sensitive pigment (a photopigment). In rods, the outer segments are long and consist of stacks of free-floating double-membrane discs contain- ing large amounts of rhodopsin. The cones have short, cone-shaped outer segments, which consist of infold- ings of surface membrane. This infolded membrane also contains rhodopsin, but a smaller amount than is present in the rods. The greater the amount of photo- pigment, the greater the sensitivity to light, which accounts in part for the greater light sensitivity of the rods. A single photon of light can activate a rod, whereas several hundred photons are required to activate a cone. The inner segments of the rods and cones are con- nected to the outer segments by a single cilium. The inner segments contain mitochondria and other organ- elles. Rhodopsin is synthesized in the inner segments and then incorporated in the membranes of the outer segments as follows: In the rods, rhodopsin is inserted in new membrane discs, which are displaced toward the outer segment; eventually they are shed and phago- cytosed by the pigment cell epithelium, giving the outer segments their rodlike shape. In the cones, rhodopsin is incorporated randomly into membrane folds, with no shedding process. Steps in Photoreception Photoreception is the transduction process in rods and cones that converts light energy into electrical energy. Rhodopsin, the photosensitive pigment, is composed of opsin (a protein belonging to the superfamily of G protein–coupled receptors) and retinal (an aldehyde of vitamin A). When light strikes the photoreceptors, retinal is chemically transformed in a process called photoisomerization, which begins the transduction process. The steps in photoreception, discussed as follows, correspond to the circled numbers shown in Figure 3.16: 1. Light strikes the retina, which initiates photo isomerization of retinal. 11-cis Retinal is converted to all-trans retinal. From there, a series of conforma- tional changes occur in the opsin that culminate in the production of metarhodopsin II. (Regeneration of 11-cis retinal involves reconversion of all-trans- retinal to retinol [vitamin A].) 2. Metarhodopsin II activates a G protein that is called transducin, or Gt. (There is enormous amplification at this step, whereby one photon of light activates one metarhodopsin II molecule, which activates almost 800 molecules of transducin!) When acti- vated, transducin stimulates a phosphodiesterase that catalyzes the conversion of cyclic guanosine monophosphate (cGMP) to 5′-GMP. Consequently, there is increased breakdown of cGMP, causing cGMP levels to decrease. Metarhodopsin II 1 all-trans retinal 2 Hyperpolarization of photoreceptor membrane Activation of transducin (G protein) 11-cis retinal Decreased cyclic GMP Closure of Na+ channels Decreased release of glutamate Decreased release of glutamate + Decreased excitatory glutamate response (ionotropic receptor) Decreased inhibitory glutamate response (metabotropic receptor) Hyperpolarization of bipolar and horizontal cells (inhibition) Depolarization of bipolar and horizontal cells (excitation) 3 4 cyclic GMP 5' GMP Activation of phosphodiesterase 5 6 6 STEPS IN PHOTORECEPTION Light Fig. 3.16 Steps in photoreception. When light impinges on the retina, the photoreceptors are hyperpolarized. In turn, the photoreceptors decrease their release of glutamate, leading to either hyperpolarization or depolarization of bipolar or horizontal cells. Circled numbers correlate with steps described in the text. Cyclic GMP, Cyclic guanosine monophosphate; GMP, guanosine monophosphate.Www.Medicalstudyzone.com
3—Neurophysiology • 89 3 and 4. In the photoreceptor membrane, Na+ channels that carry inward current are regulated by cGMP. In the dark, there is an increase in cGMP levels, which produces an Na+ inward current (or “dark current”) and depolarization of the photorecep- tor membrane. In the light, there is a decrease in cGMP levels, as already described, which closes Na+ channels in the photoreceptor membrane, reduces inward Na+ current, and produces hyperpolariza tion. (Terminating the light-activated state involves decreased intracellular Ca2+, which replenishes cGMP levels.) 5. Hyperpolarization of the photoreceptor membrane decreases the release of glutamate, an excitatory neurotransmitter, from the synaptic terminals of the photoreceptor. (Recall from Figure 3.14 that photo- receptors synapse on bipolar cells and horizontal cells in the outer plexiform layer.) 6. There are two types of glutamate receptors on bipolar and horizontal cells: ionotropic receptors, which are depolarizing (excitatory), and metabo- tropic receptors, which are hyperpolarizing (inhib- itory). The type of receptor on the bipolar or horizontal cell determines whether the response will be depolarization (excitation) or hyperpolarization (inhibition). Thus decreased release of glutamate that interacts with ionotropic receptors will result in hyperpolarization and inhibition of the bipolar or horizontal cell (i.e., decreased excitation). And decreased release of glutamate that interacts with metabotropic receptors will result in depolarization and excitation of the bipolar or horizontal cell (i.e., decreased inhibition causes excitation). This process will establish the on off patterns for visual fields. Visual Receptive Fields Each level of the visual pathway can be described by its receptive fields. Thus there are receptive fields for photoreceptors, bipolar and horizontal cells, ganglion cells, cells of the lateral geniculate body in the thala- mus, and cells in the visual cortex. At each higher level, the receptive fields become increasingly complex. PHOTORECEPTORS, HORIZONTAL CELLS, AND BIPOLAR CELLS One simple arrangement of visual receptive fields is illustrated in Figure 3.17. The figure shows the recep- tive fields for three photoreceptors, for two bipolar cells, and for one horizontal cell positioned between the bipolar cells. When light hits the photoreceptors, they are always hyperpolarized and release decreased amounts of glutamate (recall the steps in photorecep- tion), as indicated by the minus signs on the photore- ceptors. Photoreceptors synapse directly on bipolar cells in the outer plexiform layer of the retina. The receptive field of the bipolar cell is shown as two concentric circles: The inner circle is called the “center,” and the outer circle is called the “surround.” The center of the bipolar cell’s receptive field represents direct connections from photoreceptors and can be either excited (on) or inhibited (off), depending on the type of glutamate receptor on the bipolar cell, as described earlier. If the center of the receptive field has metabo- tropic glutamate receptors, then the bipolar cell will be excited (+); if the center of the receptive field has ionotropic glutamate receptors, then the bipolar cell will be inhibited (−). The surround of the bipolar cell’s receptive field receives input from adjacent photorecep- tors via horizontal cells. The surround of the receptive field shows the opposite response of the center because the horizontal cells are inhibitory (i.e., they reverse the direct response of the photoreceptor on its bipolar cell). Two patterns for receptive fields of bipolar cells are illustrated in Figure 3.17 and explained as follows: ♦ On center, off surround (or “on-center”). This pattern is illustrated in the bipolar cell shown on the left of the figure. The center of its receptive field is excited (on) by light, and the surround of its receptive field is inhibited (off) by light. How is this pattern achieved? As always, light impinging on photoreceptors produces hyperpolarization and decreased release of glutamate. This photoreceptor is connected to the center of the bipolar cell’s recep- tive field and glutamate binds to a metabotropic receptor. Thus the center of the receptive field is excited (i.e., decreased inhibition produces excita- tion); this arrangement is also called sign-inverting. Light also inhibits the adjacent photoreceptor, which binds to an ionotropic receptor in the horizontal cell, thus inhibiting the horizontal cell. The horizontal cell is connected to the surround of the bipolar cell’s receptive field. Because the horizontal cell is inhib- ited, it reverses the direct action of the photorecep- tors on the bipolar cell and produces inhibition in the surround. ♦ Off center, on surround (or “off-center”). This pattern is illustrated in the bipolar cell shown on the right of the figure. The center of its receptive field is inhibited (off) by light, and the surround i
90 • Physiology VISUAL CORTEX Neurons of the visual cortex detect shape and orienta- tion of figures. Three cell types are involved in this type of visual discrimination: simple cells, complex cells, and hypercomplex cells. Simple cells have receptive fields similar to those of the ganglion cells and lateral geniculate cells (i.e., on-center or off-center), although the patterns are elongated rods rather than concentric circles. Simple cells respond best to bars of light that have the “correct” position and orientation. Complex cells respond best to moving bars of light or edges of light with the correct orientation. Hypercomplex cells respond best to lines of particular length and to curves and angles. Optic Pathways The optic pathways from the retina to the CNS are shown in Figure 3.18. Axons from retinal ganglion cells form the optic nerves and optic tracts, synapse in the AMACRINE CELLS The amacrine cells receive input from different combi- nations of on-center and off-center bipolar cells. Thus the receptive fields of the amacrine cells are mixtures of on-center and off-center patterns. GANGLION CELLS Ganglion cells receive input from both bipolar cells and amacrine cells (see Fig. 3.14). When input to the ganglion cells is primarily from bipolar cells, the gan- glion cells retain the on-center and off-center patterns established at the level of the bipolar cells. When the input to a ganglion cell is primarily from amacrine cells, the receptive fields tend to be diffuse because there has been mixing of input at the amacrine cell level. LATERAL GENICULATE CELLS OF THE THALAMUS Cells of the lateral geniculate body of the thalamus retain the on-center or off-center patterns transmitted from the ganglion cells. – Reverses response of center Reverses response of center On-center, off-surround Off-center, on-surround Glutamate Glutamate Glutamate Photoreceptors Horizontal cell Bipolar cells VISUAL RECEPTIVE FIELDS LightLight Light – – – – – – ++ ++ ++ + ++ ++ – – –+ + + + –– –– –– – –– –– + + + – – – – – – – – – – – Depolarization (metabotropic receptors) Hyperpolarization (ionotropic receptors) Hyperpolarization (ionotropic receptors) Fig. 3.17 Visual receptive fields of bipolar cells in the retina. Two patterns are shown: on-center and off-center.Www.Medicalstudyzone.com
3—Neurophysiology • 91 Lesions at various points in the optic pathway cause deficits in vision, which can be predicted by tracing the pathway, as shown in Figure 3.19. Hemianopia is the loss of vision in half the visual field of one or both eyes. If the loss occurs on the same side of the body as the lesion, it is called ipsilateral; if the loss occurs on the opposite side of the body as the lesion, it is called contralateral. The following lesions cor- respond to the shaded bars and circled numbers on the figure: 1. Optic nerve. Cutting the optic nerve causes blind- ness in the ipsilateral (same side) eye. Thus cutting the left optic nerve causes blindness in the left eye. All sensory information coming from that eye is lost because the cut occurs before any fibers cross at the optic chiasm. 2. Optic chiasm. Cutting the optic chiasm causes het- eronymous (both eyes) bitemporal (both temporal visual fields) hemianopia. In other words, all infor- mation is lost from fibers that cross. Thus information from the temporal visual fields from both eyes is lost because these fibers cross at the optic chiasm. 3. Optic tract. Cutting the optic tract causes homony- mous contralateral hemianopia. As shown in the figure, cutting the left optic tract results in loss of the temporal visual field from the right eye (crossed) and loss of the nasal visual field from the left eye (uncrossed). 4. Geniculocalcarine tract. Cutting the geniculocalca- rine tract causes homonymous contralateral hemi- anopia with macular sparing (the visual field from the macula is intact). Macular sparing occurs because lesions of the visual cortex do not destroy all neurons that represent the macula. AUDITION Audition, the sense of hearing, involves the transduc- tion of sound waves into electrical energy, which then can be transmitted in the nervous system. Sound is produced by waves of compression and decompres- sion, which are transmitted in elastic media such as air or water. These waves are associated with increases (compression) and decreases (decompression) in pres- sure. The units for expressing sound pressure are decibels (dB), which is a relative measure on a log scale. Sound frequency is measured in cycles per second or hertz (Hz). A pure tone results from sinusoidal waves of a single frequency. Most sounds are mixtures of pure tones. The human ear is sensitive to tones with frequencies between 20 and 20,000 Hz and is most sensitive between 2000 and 5000 Hz. A reference, 0 dB, is the average threshold for lateral geniculate body of the thalamus, and ascend to the visual cortex in the geniculocalcarine tract. Notice that the temporal visual fields project onto the nasal retina, and the nasal fields project onto the temporal retina. Nerve fibers from each nasal hemiret ina cross at the optic chiasm and ascend contralater- ally. Nerve fibers from each temporal hemiretina remain uncrossed and ascend ipsilaterally. Thus fibers from the left nasal hemiretina and fibers from the right temporal hemiretina form the right optic tract and synapse on the right lateral geniculate body. Conversely, fibers from the right nasal hemiretina and fibers from the left temporal hemiretina form the left optic tract and synapse on the left lateral geniculate body. Fibers from the lateral geniculate body form the geniculocalcarine tract, which ascends to the visual cortex (area 17 of the occipital lobe). Fibers from the right lateral genicu- late body form the right geniculocalcarine tract; fibers from the left lateral geniculate body form the left geniculocalcarine tract. Optic nerve Temporal field Temporal field Optic chiasm Optic tract Ganglion cell Lateral geniculate body Left eye Right eye Nasal fields OPTIC PATHWAYS Pretectal region Occipital cortex Geniculocalcarine tract Fig. 3.18 Optic pathways. Fibers from the temporal visual fields cross at the optic chiasm, but fibers from the nasal visual fields remain uncrossed. (Adapted from Barrett, et al. Ganong’s Review of Medical Physiology, 23rd ed., McGraw-Hill 2010.)Www.Medicalstudyzone.com
92 • Physiology Structures of the Ear Structures of the external, middle, and inner ear are shown in Figure 3.20 and are described as follows: ♦ The external ear consists of the pinna and the external auditory meatus (auditory canal). The func- tion of the external ear is to direct sound waves into the auditory canal. The external ear is air filled. ♦ The middle ear consists of the tympanic membrane and a chain of auditory ossicles called the malleus, incus, and stapes. The tympanic membrane sepa- rates the external ear from the middle ear. An oval window and a round window lie between the middle ear and the inner ear. The stapes has a footplate, which inserts into the oval window and provides the interface between the middle ear and the inner ear. The middle ear is air filled. ♦ The inner ear consists of a bony labyrinth and a membranous labyrinth. The bony labyrinth consists hearing at 1000 Hz. Sound pressure, in dB, is calculated as follows: dB P P= 20 0log where dB Decibel= P Sound pressure being measured= P Reference pressure measured at the threshold frequency 0 = Therefore if a sound pressure is 10 times the refer- ence pressure, it is 20 dB (20 × log 10 = 20 × 1 = 20 dB). If a sound pressure is 100 times the reference pressure, it is 40 dB (20 × log 100 = 20 × 2 = 40 dB). The usual range of frequencies in human speech is between 300 and 3500 Hz, and the sound intensity is about 65 dB. Sound intensities greater than 100 dB can damage the auditory apparatus, and those greater than 120 dB can cause pain. Optic nerve Temporal field Temporal field Optic chiasm Optic tract Ganglion cell Lateral geniculate body Nasal fields Geniculocalcarine tract Left eye Right eye Occipital cortex Pretectal region 2 1 3 4 1 2 4 3 Left Right LESIONS OF OPTIC PATHWAYS Fig. 3.19 Visual field defects produced by lesions at various levels of the visual pathway. Circled numbers refer to deficits and are explained in the text. (Adapted from Barrett, et al. Ganong’s Review of Medical Physiology, 23rd ed., McGraw-Hill 2010.)Www.Medicalstudyzone.com
3—Neurophysiology • 93 the ossicles serves as an impedance-matching device that makes this conversion. Impedance matching is accomplished by the ratio of the large surface area of the tympanic membrane to the small surface area of the oval window and the mechanical advantage offered by the lever system of the ossicles. The external ear directs sound waves into the audi- tory canal, which transmits the sound waves onto the tympanic membrane. When sound waves move the tympanic membrane, the chain of ossicles also moves, pushing the footplate of the stapes into the oval window and displacing the fluid in the inner ear. Cochlea and Organ of Corti The cochlea contains the sensory transduction appara- tus, the organ of Corti. The structures of the cochlea and the organ of Corti are shown in Figure 3.21. The cross section of the cochlea shows its three chambers: scala vestibuli, scala media, and scala tympani. Each chamber is fluid filled, the scala vestibuli and scala tympani with perilymph and the scala media with endolymph. The scala vestibuli is separated from the scala media by Reissner membrane. The basilar membrane separates the scala media from the scala tympani. The organ of Corti lies on the basilar membrane of the cochlea and is bathed in the endolymph contained in the scala media. Auditory hair cells in the organ of Corti are the sites of auditory transduction. The organ of Corti contains two types of receptor cells: inner hair cells and outer hair cells. There are fewer inner hair cells, which are arranged in single rows. Outer hair cells are arranged in parallel rows and are more of three semicircular canals (lateral, posterior, and superior). The membranous labyrinth consists of a series of ducts called the scala vestibuli, scala tympani, and scala media. The cochlea and the vestibule are formed from the bony and membranous labyrinths. The cochlea, which is a spiral-shaped structure composed of three tubular canals or ducts, contains the organ of Corti. The organ of Corti contains the receptor cells and is the site of auditory transduction. The inner ear is fluid filled, and the fluid in each duct has a different composition. The fluid in the scala vestibuli and scala tympani is called perilymph, which is similar to extracellular fluid. The fluid in the scala media is called endolymph, which has a high potas sium (K+) concentration and a low sodium (Na+) concentration. Thus endolymph is unusual in that its composition is similar to that of intracellular fluid, even though, technically, it is extracellular fluid. Auditory Transduction Auditory transduction is the transformation of sound pressure into electrical energy. Many of the structures of the ear participate, directly or indirectly, in this transduction process. Recall that the external and middle ears are air filled, and the inner ear, which contains the organ of Corti, is fluid filled. Thus before transduction can occur, sound waves traveling through air must be converted into pressure waves in fluid. The acoustic impedance of fluid is much greater than that of air. The combination of the tympanic membrane and Semicircular canals Auditory nerve Facial nerve Cochlea Tympanic membrane Malleus Vestibule Vestibular nerve Incus Stapes Oval window Fig. 3.20 Structures of the external, middle, and inner ear. The cochlea has been turned slightly for visualization.Www.Medicalstudyzone.com
94 • Physiology numerous than inner hair cells. Cilia, protruding from the hair cells, are embedded in the tectorial membrane. Thus the bodies of the hair cells are in contact with the basilar membrane, and the cilia of the hair cells are in contact with the tectorial membrane. The nerves that serve the organ of Corti are con- tained in the vestibulocochlear nerve (CN VIII). The cell bodies of these nerves are located in spiral ganglia, and their axons synapse at the base of the hair cells. These nerves will transmit information from the audi- tory hair cells to the CNS. Steps in Auditory Transduction Several important steps precede transduction of sound waves by the auditory hair cells on the organ of Corti. Sound waves are directed toward the tympanic mem- brane, and, as the tympanic membrane vibrates, it causes the ossicles to vibrate and the stapes to be pushed into the oval window. This movement displaces fluid in the cochlea. The sound energy is amplified by two effects: the lever action of the ossicles and the concentration of sound waves from the large tympanic membrane onto the small oval window. Thus sound waves are transmitted and amplified from the air-filled external and middle ears to the fluid-filled inner ear, which contains the receptors. Auditory transduction by hair cells on the organ of Corti then occurs in the following steps (Fig. 3.22): 1. Sound waves are transmitted to the inner ear and cause vibration of the organ of Corti. 2. The auditory hair cells are mechanoreceptors, which are located on the organ of Corti (see Fig. 3.21). The base of the hair cells sits on the Organ of CortiCross-section of cochlea Scala tympani Scala media Stria vascularis Scala vestibuli Reissner membrane Auditory nerve fibers Auditory nerve fibers Tectorial membrane Scala media Scala tympani Basilar membrane Inner hair cell Outer hair cells Fig. 3.21 Structure of the cochlea and the organ of Corti. 1 Sound waves 2 Vibration of organ of Corti 3 Bending of cilia on hair cells 4 Change in K+ conductance of hair cell membrane 5 Oscillating receptor potential (cochlear microphonic) 6 Intermittent glutamate release Intermittent action potentials in afferent cochlear nerves MECHANISM OF AUDITORY TRANSDUCTION Fig. 3.22 Steps in auditory transduction in hair cells. Circled numbers correspond to steps described in the text.Www.Medicalstudyzone.com
3—Neurophysiology • 95 Auditory Pathways Information is transmitted from the hair cells of the organ of Corti to the afferent cochlear nerves. The cochlear nerves synapse on neurons of the dorsal and ventral cochlear nuclei of the medulla, which send out axons that ascend in the CNS. Some of these axons cross to the contralateral side and ascend in the lateral lemniscus (the primary auditory tract) to the inferior colliculus. Other axons remain ipsilateral. The two inferior colliculi are connected via the commissure of the inferior colliculus. Fibers from nuclei of the inferior colliculus ascend to the medial geniculate nucleus of the thalamus. Fibers from the thalamus ascend to the auditory cortex. The tonotopic map, generated at the level of the organ of Corti, is preserved at all levels of the CNS. Complex feature discrimination (e.g., the ability to recognize a patterned sequence) is the prop- erty of the auditory cortex. Because some auditory fibers are crossed and some are uncrossed, a mixture of ascending nerve fibers represents both ears at all levels of the CNS. Thus lesions of the cochlea of one ear will cause ipsilateral deafness. However, more central unilateral lesions do not cause deafness because some of the fibers transmit- ting information from that ear have already crossed to the undamaged side. VESTIBULAR SYSTEM The vestibular system is used to maintain equilibrium or balance by detecting angular and linear accelera- tions of the head. Sensory information from the basilar membrane, and the cilia of the hair cells are embedded in the tectorial membrane. The basilar membrane is more elastic than the tectorial mem- brane. Thus vibration of the organ of Corti causes bending of cilia on the hair cells by a shearing force as the cilia push against the tectorial membrane. 3. Bending of the cilia produces a change in K+ con ductance of the hair cell membrane. Bending in one direction produces an increase in K+ conductance and depolarization; bending in the other direction produces a decrease in K+ conductance and hyper- polarization. (These changes in membrane potential are the opposite of what one might predict. Recall, however, that hair cell cilia are bathed in endolymph, with its high K+ concentration; thus K+ concentration gradients are opposite those across other cell mem- branes. Consequently, changes in the K+ conductance of cilia will have the opposite effect on membrane potential.) 4. These changes in membrane potential are the receptor potentials of the auditory hair cells. The oscillating receptor potential is called the cochlear microphonic potential. 5. When hair cells are depolarized, the depolarization opens voltage-gated Ca2+ channels in the presynaptic terminals of the hair cells. As a result, Ca2+ enters the presynaptic terminals and causes release of glutamate, which functions here as an excitatory neurotransmitter, causing action potentials in the afferent cochlear nerves that will transmit this infor- mation to the CNS. When the hair cells are hyper- polarized, the opposite events occur, and there is decreased release of glutamate. 6. Thus oscillating depolarizing and hyperpolarizing receptor potentials in the hair cells cause intermit- tent release of glutamate, which produces intermit- tent firing of afferent cochlear nerves. Encoding of Sound Encoding of sound frequencies occurs because different auditory hair cells are activated by different frequen- cies. The frequency that activates a particular hair cell depends on the position of that hair cell along the basilar membrane, as illustrated in Figure 3.23. The base of the basilar membrane is nearest the stapes and is narrow and stiff. Hair cells located at the base respond best to high frequencies. The apex of the basilar membrane is wide and compliant. Hair cells located at the apex respond best to low frequencies. Thus the basilar membrane acts as a sound frequency analyzer, with hair cells positioned along the basilar membrane responding to different frequencies. This spatial mapping of frequencies generates a tonotopic map, which then is transmitted to higher levels of the auditory system. Stiff Compliant High frequencies Low frequencies Base 100 μm Apex 500 μm Basilar membrane Fig. 3.23 Frequency responses of the basilar membrane.Www.Medicalstudyzone.com
96 • Physiology composed of mucopolysaccharides and calcium car- bonate crystals overlies the vestibular hair cells (like a pillow). When the head is tilted, gravitational forces act on the otolith mass, moving it across the vestibular hair cells. The hair cells are either activated or inhib- ited, alerting the person to a change in the position of the head. Vestibular Transduction Semicircular Canals The function of the horizontal semicircular canals is to detect angular acceleration of the head, as illustrated in Figure 3.25. In this figure, the left and right horizon- tal canals are shown with their attached ampullae. The ampulla contains the vestibular hair cells, which are embedded in the gelatinous mass of the cupula. The vestibular hair cells differ from auditory hair cells in that the vestibular hair cells have a large kinocilium and a cluster of stereocilia. Afferent nerve fibers from the hair cells carry vestibular information to the CNS. For example, when the head is rotated counter clockwise (to the left), the following events occur in the horizontal semicircular canals: 1. When the head is rotated to the left, the horizontal semicircular canals and their attached ampullae also rotate left. Initially, the cupula (anchored to the ampulla) moves before the endolymph begins to flow. Thus the cupula is displaced or dragged through the endolymph, causing bending of the cilia on the hair cells. Eventually, as rotation continues, the endolymph begins to move. vestibular system is then used to provide a stable visual image for the retina (while the head moves) and to make the adjustments in posture that are necessary to maintain balance. Vestibular Organ The vestibular organ is located within the temporal bone, adjacent to the auditory apparatus (the cochlea). The vestibular organ consists of a membranous laby- rinth within the bony labyrinth (Fig. 3.24). The mem- branous labyrinth consists of three perpendicular semicircular canals (horizontal, superior, and posterior) and two otolith organs (utricle and saccule). The semi- circular canals and otolith organs are filled with endo- lymph and are surrounded by perilymph, much like the auditory organ. The semicircular canals, which are arranged per- pendicular to each other, are used to detect angular or rotational acceleration of the head. (The perpendicular arrangement of canals ensures that they cover the three principal axes of head rotation.) Each canal, filled with endolymph, contains an enlargement at one end called an ampulla. Each ampulla contains vestibular hair cells, which are covered with a gelatinous mass called a cupula (Fig. 3.25). The cupula, which spans the cross-sectional area of the ampulla, has the same spe- cific gravity as the endolymph in the canal. During angular acceleration of the head, the cupula is dis- placed, causing excitation or inhibition of the hair cells. The otolith organs, the utricle and saccule, are used to detect linear acceleration (e.g., gravitational forces). Within the utricle and saccule, an otolith mass Superior Horizontal Ampulla Semicircular canals Posterior Saccule Utricle Fig. 3.24 Structures of the vestibular organ, showing the three perpendicular semicir- cular canals and two otolith organs (utricle and saccule).Www.Medicalstudyzone.com
3—Neurophysiology • 97 now return to their original positions, and the hair cells are neither depolarized nor hyperpolarized. 4. When the head stops rotating, the events occur in reverse. For a brief period, the endolymph continues to move, pushing the cupula and kinocilia on the hair cells in the opposite direction. Thus if the hair cell was depolarized in the initial rotation, it now will be hyperpolarized, with inhibition of afferent nerve output. If the hair cell was hyperpolarized in the initial rotation, it now will be depolarized, with excitation of afferent nerve output. Thus when the head stops moving left, the left horizontal 2. If the stereocilia are bent toward the kinocilium, the hair cell depolarizes and there is an increased firing rate in the afferent vestibular nerves. If the stereocilia are bent away from the kinocilium, the hair cell hyperpolarizes and there is a decreased firing rate in the afferent vestibular nerves. Therefore, during the initial leftward rotation of the head, the left horizon- tal canal is excited and the right horizontal canal is inhibited. 3. While the head is still rotating to the left, the endo- lymph eventually “catches up” with the movement of the head, the ampulla, and the cupula. The cilia Cupula Kinocilium Stereocilia Vestibular hair cell Left horizontal semicircular canal Right horizontal semicircular canal Right ampulla Depolarized Hyperpolarized Excitation Afferent vestibular nerve fiber Inhibition C o u n t e r c l o c k w i s e r o t a ti o n o f h e a d Left ampulla Initial direction of fluid movement Fig. 3.25 Structure of a vestibular hair cell, showing the function of the hair cells in the horizontal semicircular canal. Counterclockwise (left) rotation of the head causes excitation of the left semicircular canals and inhibition of the right semicircular canals.Www.Medicalstudyzone.com
98 • Physiology Vestibulo-Ocular Reflexes Several vestibular reflexes are produced in response to movement of the head. One reflex, called nystagmus, occurs in response to angular or rotational accelera- tion of the head. When the head is rotated, the eyes initially move in the opposite direction of the rota- tion, attempting to maintain a constant direction of gaze. This initial movement is the slow component of nystagmus. Once the eyes approach the limit of their lateral movement, there is a rapid eye movement in the same direction as the head’s rotation. This movement is the rapid component of nystagmus, in which the eyes “jump ahead” to fix on a new position in space. Nystagmus is defined by the direction of the rapid com- ponent: The nystagmus is in the direction of the head’s rotation. If the rotation is stopped abruptly, the eyes will move in the direction opposite that of the original rotation. This eye movement is called postrotatory nystagmus. During the postrotatory period, the person tends to fall in the direction of the original rotation (due to stimula- tion of contralateral extensor muscles) because the person thinks he or she is spinning in the opposite direction. Testing Vestibulo-Ocular Reflexes Vestibular function can be tested using the phenomena of nystagmus and postrotatory nystagmus. The Bárány test involves rotating a person on a special chair for about 10 revolutions. In a person with normal vestibular function, rotation to the right causes a right rotatory nystagmus, a left postrotatory nystag- mus, and the person falls to the right during the postrotatory period. Likewise, rotation to the left causes a left rotatory nystagmus, a right postrotatory nystag- mus, and the person falls to the left during the postrota- tory period. The caloric test involves thermal stimulation of the inner ears, in which the right and left horizontal semi- circular canals can be stimulated separately. In this test, the head is tilted back 60 degrees so that the horizontal canals have a vertical orientation. Rinsing the ear with warm or cold water causes endolymph to flow, which deflects the cupula as if the head were rotated. A nystagmus occurs, lasting approximately 2 minutes. Warm water produces a nystagmus toward the treated side; cold water produces a nystagmus toward the untreated side. OLFACTION The chemical senses involve detection of chemical stimuli and transduction of those stimuli into electrical energy that can be transmitted in the nervous system. canal will be inhibited and the right canal will be excited. In summary, rotation of the head to the left stimu- lates the left semicircular canals, and rotation to the right stimulates the right semicircular canals. Otolith Organs The maculae are sensitive to linear acceleration (e.g., acceleration due to gravitational forces). Recall that the hair cells of the maculae are embedded in the otolith mass. When the head is tilted, gravitational forces cause the otolith mass to slide across the vestibular hair cells, bending the stereocilia toward or away from the kinocilium. Movement of the stereocilia toward the kinocilium causes depolarization of the hair cell and excitation. Movement of the stereocilia away from the kinocilium causes hyperpolarization of the hair cell and inhibition. When the head is upright, the macula of the utricle is oriented horizontally and the saccule is oriented vertically. In the utricle, tilting the head forward or laterally causes excitation of the ipsilateral utricle; tilting the head backward or medially causes inhibition of the ipsilateral utricle. The saccule responds to head movements in all directions. Hair cells of the saccule are excited with both forward and backward move- ments (called “pitch”) and lateral and medial move- ments (called “roll”). The saccule also responds to up and down movements of the head. Because of the bilateral arrangement of the otolith organs, every possible orientation of the head can be encoded by excitation or inhibition of the vestibular hair cells. For each position of the head, there is a unique pattern of activity from the afferent nerves innervating the otolith organs that provides detailed information to the CNS about the position of the head in space. Vestibular Pathways Afferent nerves from vestibular hair cells terminate in vestibular nuclei of the medulla: the superior, medial, lateral (Deiters nucleus), and inferior nuclei. Medial and superior nuclei receive their input from the semicircular canals and project to nerves innervat- ing extraocular muscles via the medial longitudinal fasciculus. The lateral vestibular nucleus receives input from the utricles and projects to spinal cord motoneurons via the lateral vestibulospinal tract. Pro- jections of the lateral vestibular nucleus play a role in maintaining postural reflexes. The inferior vestibular nucleus receives its input from the utricles, saccules, and semicircular canals. It projects to the brain stem and the cerebel
3—Neurophysiology • 99 Olfaction, the sense of smell, is one of the chemical senses. In humans, olfaction is not necessary for sur- vival, yet it improves the quality of life and even protects against hazards. Anosmia is the absence of the sense of smell, hyposmia is impaired sense of smell, and dysosmia is a distorted sense of smell. Head injury, upper respira- tory infections, tumors of the anterior fossa, and exposure to toxic chemicals (which destroy the olfac- tory epithelium) all can cause olfactory impairment. Olfactory Epithelium and Receptors Odorant molecules, which are present in the gas phase, reach the olfactory receptors via the nasal cavity: Air enters the nostril, crosses the nasal cavity, and exits into the nasopharynx. The nasal cavity contains struc- tures called turbinates, some of which are lined with olfactory epithelium containing the olfactory receptor cells. (The remainder of the nasal cavity is lined by respiratory epithelium.) The turbinates act as baffles, causing air flow to become turbulent and thereby to reach the upper regions of the nasal cavity. The olfactory epithelium consists of three cell types: supporting cells, basal cells, and olfactory recep- tor cells (Fig. 3.26). ♦ Supporting cells are columnar epithelial cells lined with microvilli at their mucosal border and filled with secretory granules. ♦ Basal cells are located at the base of the olfactory epithelium and are undifferentiated stem cells that give rise to the olfactory receptor cells. These stem cells undergo mitosis, producing a continuous turn- over of receptor cells. ♦ Olfactory receptor cells, which are also primary afferent neurons, are the site of odorant binding, detection, and transduction. Odorant molecules bind to receptors on the cilia, which extend into the nasal mucosa. Axons from olfactory receptor cells leave the olfactory epithelium and travel cen- trally to the olfactory bulb. These axons must pass through the cribriform plate at the base of the skull to reach the olfactory bulb. Thus fractures of the cribriform plate can sever olfactory neurons, leading to olfactory disorders (e.g., anosmia). Olfac- tory nerve axons are unmyelinated and are among the smallest and slowest fibers in the nervous system (recall the relationships between fiber diameter, myelination, and conduction velocity discussed in Chapter 1). Because the olfactory receptor cells are also primary afferent neurons, the continuous replace- ment of receptor cells from basal cells means that there is continuous neurogenesis. Supporting cell Odorant molecules Cilia Olfactory receptor cell Olfactory nerve axon Olfactory epithelium Mitral cell Glomerulus Cribriform plate To olfactory tract Olfactory bulb Basal cell Fig. 3.26 Olfactory pathways, showing the olfactory epi- thelium and olfactory bulb. Olfactory Transduction Transduction in the olfactory system involves the con- version of a chemical signal into an electrical signal that can be transmitted to the CNS. The steps in olfac- tory transduction are as follows (Fig. 3.27): 1. Odorant molecules bind to specific olfactory recep tor proteins located on the cilia of olfactory receptor cells. There are at least 1000 different olfactory receptor proteins (members of the superfamily of G protein–coupled receptors), each encoded by a dif- ferent gene and each found on a different olfactory receptor cell. 2. The olfactory receptor proteins are coupled to adeny- lyl cyclase via a G protein called Golf. When the odorant is bound, Golf is activated, which activates adenylyl cyclase. 3. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. Intracellular levels of cAMP increase, which opens cation channels in the cell membrane of the olfactory receptor that are permeable to Na+, K+, and Ca2+.Www.Medicalstudyzone.com
100 • Physiology across a population of receptors, which is projected onto targeted glomeruli in the olfactory bulb (“odor map”). The CNS then interprets these odor maps (e.g., a rose or a gardenia or a special person). Olfactory Pathways As noted, olfactory receptor cells are the primary affer- ent neurons in the olfactory system. Axons from the receptor cells leave the olfactory epithelium, pass through the cribriform plate, and synapse on apical dendrites of mitral cells (the second-order neurons) in the olfactory bulb. These synapses occur in clusters called glomeruli (see Fig. 3.26). In the glomeruli, approximately 1000 olfactory receptor axons converge onto 1 mitral cell. The mitral cells are arranged in a single layer in the olfactory bulb and have lateral dendrites in addition to the apical dendrites. The olfac- tory bulb also contains granule cells and periglomerular cells (not shown). The granule and periglomerular cells are inhibitory interneurons that make dendrodendritic synapses on neighboring mitral cells. The inhibitory inputs serve a function similar to that of the horizontal cells of the retina and may provide lateral inhibition that “sharpens” the information projected to the CNS. Mitral cells of the olfactory bulb project to higher centers in the CNS. As the olfactory tract approaches the base of the brain, it divides into two major tracts, a lateral tract and a medial tract. The lateral olfactory tract synapses in the primary olfactory cortex, which includes the prepiriform cortex. The medial olfactory tract projects to the anterior commissure and the contralateral olfactory bulb. TASTE The second chemical sense is gustation, or taste. For the sense of taste, chemicals called tastants are detected and transduced by chemoreceptors located in taste buds. Tastes are mixtures of five elementary taste quali- ties: salty, sweet, sour, bitter, and umami (savory, including monosodium glutamate). Disorders associated with the sense of taste are not life-threatening, but they can impair the quality of life, impair nutritional status, and increase the possibility of accidental poisoning. Taste disorders include ageusia (absence of taste), hypogeusia (decreased taste sensi- tivity), hypergeusia (increased taste sensitivity), and dysgeusia (distortion of taste, including taste sensation in the absence of taste stimuli). Taste Buds and Receptors Taste receptor cells are located within taste buds on the tongue, palate, pharynx, and larynx. The taste buds on 4. The receptor cell membrane depolarizes (i.e., the membrane potential is driven toward a value between the equilibrium potentials for the three cations, which is depolarization). This depolarizing receptor potential brings the membrane potential closer to threshold and depolarizes the initial segment of the olfactory nerve axon. 5. Action potentials are then generated and propagated along the olfactory nerve axons toward the olfactory bulb. Encoding Olfactory Stimuli It is not known exactly how olfactory stimuli are encoded; that is, how do we recognize the scent of a rose or a gardenia or a special person, and how do we distinguish a rose from a gardenia? The following information is known: (1) Olfactory receptor proteins are not dedicated to a single odorant, and each protein can respond to a variety of odorants. (2) Still, olfactory receptor proteins are selective, responding to some odorants more than others, and to some not at all. (3) Different olfactory receptor proteins have different responses to the same odorant. For example, receptor protein “A” has a much stronger response to “apple” than does receptor protein “B.” (4) If the response to a given odorant is examined across many receptors, different patterns emerge for different odorants. This is called an across fiber pattern code. Each odorant produces a unique pattern of activity 1 Odorant molecules Opens cation channels 2 Bind olfactory receptor proteins 3 Golf 4 cAMP 5 Depolarization of olfactory cilia Action potentials in olfactory nerve axons Fig. 3.27 Steps in olfactory transduction. Circled numbers correspond to steps described in the text. cAMP, Cyclic adenosine monophosphate.Www.Medicalstudyzone.com
3—Neurophysiology • 101 base of the tongue. Each circumvallate papilla is surrounded by a trench, with taste buds located along the sides of the trenches. Because of their large size, approximately half the total number of taste buds are found in circumvallate papillae. The taste cells in circumvallate papillae are innervated by CNs VII and IX. ♦ Foliate papillae are located on the lateral borders of the tongue. Taste buds are located in folds on the sides of the papillae. ♦ Fungiform papillae are scattered on the dorsal surface of the tongue and are most numerous near the anterior tip. They are mushroom shaped (“fungi- form”), with each papilla containing anywhere from three to five taste buds. The fungiform papillae are translucent with a dense blood supply, making them appear as red spots on the surface of the tongue. The taste cells in fungiform papillae are innervated exclusively by the chorda tympani branch of CN VII. the tongue are found in taste papillae, which include as many as several hundred taste buds. The taste buds are anatomically similar to the olfactory epithelium and consist of three cell types: supporting cells, basal cells, and receptor cells (Fig. 3.28). ♦ Supporting cells are found among the taste receptor cells. These cells do not respond to taste stimuli, and their function is not known. ♦ Basal cells are undifferentiated stem cells that serve as precursors to taste receptor cells (just as basal cells serve as precursors to olfactory receptor cells). Basal cells undergo continuous replacement. New cells, which are generated approximately every 10 days, migrate toward the center of the taste bud and differentiate into new receptor cells. New receptor cells are needed to replace those cells that are sloughed from the tongue. ♦ Taste receptor cells are the chemoreceptors of the taste system. They line the taste buds and extend microvilli into the taste pores. These microvilli provide a large surface area for detection of chemical stimuli. In contrast to the olfactory system (in which the receptor cells are the primary afferent neurons), in the gustatory system the receptor cells are not neurons. They are specialized epithelial cells that function as chemoreceptors, transducing chemical stimuli into electrical signals. Afferent fibers inner- vate the taste receptor cells and transmit this infor- mation to the CNS. Taste buds on the tongue are organized in spe- cialized papillae (Fig. 3.29). Three types of papil- lae contain taste buds: circumvallate, foliate, and fungiform. ♦ Circumvallate papillae are the largest in size but fewest in number. They are arranged in rows at the Epithelial cell Taste stimuliTaste pore Supporting cell Basal cell Taste receptor cell Afferent taste nerves STRUCTURE OF A TASTE BUD Fig. 3.28 Structure of a taste bud. STRUCTURE OF THE TASTE PAPILLAE Foliate Fungiform Circumvallate Fig. 3.29 Structure of taste papillae lined with taste buds.Www.Medicalstudyzone.com
102 • Physiology Taste Transduction Detection of the five basic taste qualities involves dif- ferential sensitivity of areas of the tongue (Fig. 3.30). Although all five taste qualities can be detected over the full surface of the tongue, different regions of the tongue do have different thresholds. The tip of the tongue is most responsive to sweet, salty, and umami, whereas the posterior tongue is most responsive to bitter, and the sides of the tongue are most responsive to sour. The chemical signals for the five taste qualities are transduced by the mechanisms shown in Figure 3.31. In most cases, transduction ultimately results in depolarization of the taste receptor membrane (i.e., a depolarizing generator potential). This depolarization leads to action potentials in afferent nerves innervating that portion of the tongue. For bitter sensation, the tastant molecules bind to G protein–coupled receptors on the taste receptor membrane and, mediated by an inositol 1,4,5-triphosphate (IP3)/Ca2+ mechanism, open so-called TRP channels and result in depolarization. For sweet and umami sensations, molecules bind to a different class of G protein–coupled receptors on the taste receptor cell membrane and, mediated by IP3/Ca2+, open TRP channels and cause depolarization. For sour sensation (mediated by H+), H+ enters the taste receptor through epithelial Na+ channels (ENaCs), leading to depolarization. For salty sensation (mediated by Na+), Na+ enters the taste receptor through the same ENaCs, leading directly to depolarization. Bitter Circumvallate papillae Foliate papillae Fungiform papillae Sour Salty Sweet, umami Fig. 3.30 Organization of taste papillae on the tongue. The circumvallate, foliate, and fungiform papillae and the chemicals they detect are shown. Bitter Sweet, umami MECHANISMS OF TASTE TRANSDUCTION Sour Salty IP3, Ca2+ IP3, Ca2+ Binds G protein–coupled membrane receptor Binds G protein–coupled membrane receptor Opens TRP channels Opens TRP channels Enters through membrane Na+ channels (ENaC) Enters through membrane Na+ channels (ENaC) DepolarizationDepolarization Depolarization Depolarization Na+ Na+ Na+ Na+ Na+H+ H+ H+ H+H+ Fig. 3.31 Mechanisms of transduction in taste receptor cells. ENaC, Epithelial Na+ channel; IP3, inositol 1,4,5-triphosphate; TRP, transient receptor potential. Encoding Taste Stimuli How taste qualities are encoded in the CNS is not precisely known. One theory states there is an across fiber pattern code in which each taste fiber responds best to one stimulus but also responds to a lesser extent to other stimuli. Thus an afferent taste fiber might respond best to salt but also responds to acid. AnotherWww.Medicalstudyzone.com
3—Neurophysiology • 103 fibers. For postural muscles involved in large move- ments, motoneurons innervate thousands of muscle fibers. A motoneuron pool is the set of motoneurons innervating fibers within the same muscle. The force of contraction of a muscle is graded by recruitment of motor units (size principle). For example, small motoneurons innervate a few muscle fibers, and, because they have the lowest thresholds, they fire first. Small motoneurons also generate the smallest amounts of force. On the other hand, large motoneurons innervate many muscle fibers. They have the highest thresholds to fire action potentials; thus they fire last. Because large motoneurons innervate many muscle fibers, they also generate the greatest amounts of force. The size principle states that as more motor units are recruited, progressively larger motoneurons are involved and greater tension will be generated. Types of Motoneurons There are two types of motoneurons: α motoneu- rons and γ motoneurons. α Motoneurons innervate extrafusal skeletal muscle fibers. Action potentials in α motoneurons lead to action potentials in the extrafusal muscle fibers they innervate, which results in contraction (see Chapter 1). γ Motoneurons inner- vate specialized intrafusal muscle fibers, a component of the muscle spindles. The overall function of the muscle spindle is to sense muscle length; the function of the γ motoneurons innervating them is to adjust the sensitivity of the muscle spindles (so that they respond appropriately as the extrafusal fibers contract and shorten). α Motoneurons and γ motoneurons are coactivated (activated simultaneously) so that muscle spindles remain sensitive to changes in muscle length even as the muscle contracts and shortens. Types of Muscle Fibers As already noted, there are two types of muscle fibers: extrafusal fibers and intrafusal fibers. Extrafusal fibers constitute the majority of skeletal muscle, are inner- vated by α motoneurons, and are used to generate force. Intrafusal fibers are specialized fibers that are innervated by γ motoneurons and are too small to generate significant force. Intrafusal fibers are encapsu- lated in sheaths, forming muscle spindles that run parallel to the extrafusal fibers. Muscle Spindles Muscle spindles are distributed among the extrafusal muscle fibers, and they are especially abundant in muscles utilized for fine movements (e.g., muscles of the eye). Muscle spindles are spindle-shaped organs composed of intrafusal muscle fibers and innervated by sensory and motor nerve fibers, as illustrated in taste fiber might respond best to acid but also responds to bitter. Thus each afferent taste fiber receives input from a population of taste receptors with a distinctive pattern of responses. The response pattern across many fibers then encodes for a particular taste sensation. Taste Pathways As noted, taste begins with transduction of chemical signals in the taste receptor cells, which are located in taste buds. Transduction leads to depolarizing receptor potentials, which lead to action potentials in primary afferent neurons innervating specific regions of the tongue. Different regions of the tongue are innervated by branches of three cranial nerves. The posterior one- third of the tongue (where bitter and sour sensations are most sensitive) is innervated by the glossopharyn- geal nerve (CN IX). The anterior two-thirds of the tongue (where sweet, umami, and salty sensations are most sensitive) is innervated by the facial nerve (CN VII). The back of the throat and epiglottis are inner- vated by the vagus nerve (CN X). These three cranial nerves (CNs VII, IX, and X) enter the brain stem, ascend in the solitary tract, and terminate on second- order neurons in the solitary nucleus of the medulla. The second-order neurons project ipsilaterally to the ventral posteromedial nucleus of the thalamus. Third- order neurons leave the thalamus and terminate in the taste cortex. MOTOR SYSTEMS Posture and movement depend on a combination of involuntary reflexes coordinated by the spinal cord and voluntary actions controlled by higher brain centers. Organization of Motor Function by the Spinal Cord Posture and movement ultimately depend on contrac- tion of some skeletal muscles while, simultaneously, other muscles remain relaxed. Recall that activation and contraction of skeletal muscles are under the control of the motoneurons that innervate them. The motor system is designed to execute this coordinated response largely through reflexes integrated in the spinal cord. Motor Units A motor unit is defined as a single motoneuron and the muscle fibers that it innervates. The number of muscle fibers innervated can vary from a few fibers to thousands of fibers, depending on the nature of the motor activity. Thus for eye movements requiring fine control, motoneurons innervate only a few muscleWww.Medicalstudyzone.com
104 • Physiology the nuclear chain fibers, and group II afferent nerves, which primarily innervate the nuclear chain fibers. Recall that group Ia fibers are among the largest nerves in the body; thus they have among the fastest conduction velocities. These fibers form primary endings in a spiral-shaped terminal around the central region of the nuclear bag and nuclear chain fibers. Group II fibers have intermediate diam- eters and intermediate conduction velocities. Group II fibers form secondary endings primarily on the nuclear chain fibers. ♦ Motor innervation of the muscle spindle consists of two types of γ motoneurons: dynamic and static. Dynamic γ motoneurons synapse on nuclear bag fibers in “plate endings.” Static γ motoneurons synapse on nuclear chain fibers in “trail endings,” which spread out over longer distances. γ Motoneu- rons are smaller and slower than the α motoneurons that innervate the extrafusal fibers. Again, the func- tion of the γ motoneurons (either static or dynamic) is to regulate the sensitivity of the intrafusal muscle fibers they innervate. Figure 3.32. Muscle spindles are attached to connective tissue and arranged in parallel with the extrafusal muscle fibers. Intrafusal Muscle Fibers of Muscle Spindles There are two types of intrafusal fibers present in muscle spindles: nuclear bag fibers and nuclear chain fibers (see Fig. 3.32). Generally, both types of fibers are present in every muscle spindle, but nuclear chain fibers are more plentiful than nuclear bag fibers. (There are five or six nuclear chain fibers per muscle spindle, compared with two nuclear bag fibers.) Nuclear bag fibers are larger, and their nuclei are accumulated in a central (“bag”) region. Nuclear chain fibers are smaller, and their nuclei are arranged in rows (“chains”). Innervation of Muscle Spindles Muscle spindles are innervated by both sensory (affer- ent) and motor (efferent) nerves. ♦ Sensory innervation of the muscle spindle consists of a single group Ia afferent nerve, which innervates the central region of both the nuclear bag fibers and Nuclear chain fiber Static γ motoneuron α Motoneuron Dynamic γ motoneuron Group II afferent Group Ia afferent Intrafusal muscle fiber (muscle spindle) Extrafusal muscle fiber Nuclear bag fiber STRUCTURE OF MUSCLE SPINDLE Fig. 3.32 Structure of the muscle spindle. An intrafusal muscle fiber is shown in relation to an extrafusal muscle fiber.Www.Medicalstudyzone.com
3—Neurophysiology • 105 response is called the reflex arc. The reflex arc includes the sensory receptors; the sensory afferent nerves, which carry information to the spinal cord; the inter- neurons in the spinal cord; and the motoneurons, which direct the muscle to contract or relax. The stretch reflex is the simplest of all spinal cord reflexes, having only one synapse between sensory afferent nerves and motor efferent nerves. The Golgi tendon reflex is of intermediate complexity and has two synapses. The most complex of the spinal cord reflexes is the flexor-withdrawal reflex, which has multiple synapses. Characteristics of the three types of spinal cord reflexes are summarized in Table 3.5. Stretch Reflex The stretch (myotatic) reflex is exemplified by the knee-jerk reflex (Fig. 3.33). The following steps occur in the stretch reflex, which has only one synapse between the sensory afferent nerves (group Ia afferents) and the motor efferent nerves (α motoneurons): 1. When the muscle is stretched, group Ia afferent fibers in the muscle spindle are activated and their firing rate increases. These group Ia afferents enter the spinal cord and synapse directly on and activate α motoneurons. This pool of α motoneurons inner- vates the homonymous muscle. 2. When these α motoneurons are activated, they cause contraction of the muscle that was originally stretched (the homonymous muscle). When the muscle contracts, it shortens, thereby decreasing stretch on the muscle spindle. The muscle spindle returns to its original length, and the firing rate of the group Ia afferents returns to baseline. 3. Simultaneously, information is sent from the spinal cord to cause contraction of synergistic muscles and relaxation of antagonistic muscles. The stretch reflex is illustrated by the knee jerk reflex, which is initiated by tapping the patellar tendon, causing the quadriceps muscle to stretch. When the Function of Muscle Spindles Muscle spindles are stretch receptors whose function is to correct for changes in muscle length when extra- fusal muscle fibers are either shortened (by contraction) or lengthened (by stretch). Thus muscle spindle reflexes operate to return muscle to its resting length after it has been shortened or lengthened. To illustrate the function of the muscle spindle reflex, consider the events that occur when a muscle is stretched. 1. When a muscle is stretched, the extrafusal muscle fibers are lengthened. Because of their parallel arrangement in the muscle, the intrafusal muscle fibers also are lengthened. 2. The increase in length of the intrafusal fibers is detected by the sensory afferent fibers innervating them. The group Ia afferent fibers (innervating the central region of nuclear bag and nuclear chain fibers) detect the velocity of length change, and the group II afferent fibers (innervating the nuclear chain fibers) detect the length of the muscle fiber. Thus when the muscle is stretched, the increase in the length of the intrafusal fibers activates both group Ia and group II sensory afferent fibers. 3. Activation of the group Ia afferent fibers stimulates α motoneurons in the spinal cord. These α moto- neurons innervate extrafusal fibers in the homony- mous (same) muscle and, when activated, cause the muscle to contract (i.e., to shorten). Thus the original stretch (lengthening) is opposed when the reflex causes the muscle to contract and shorten. γ Moto- neurons are coactivated with the α motoneurons, ensuring that the muscle spindle will remain sensi- tive to changes in muscle length even during the contraction. Spinal Cord Reflexes Spinal cord reflexes are stereotypical motor responses to specific kinds of stimuli, such as stretch of the muscle. The neuronal circuit that directs this motor TABLE 3.5 Muscle Reflexes Type of Reflex (Example) Number of Synapses Stimulus for Reflex Sensory Afferent Fibers Responses Stretch reflex (knee jerk) One Stretch (lengthening) of the muscle Ia Contraction of the muscle Golgi tendon reflex (clasp knife) Two Contraction (shortening) of the muscle Ib Relaxation of the muscle Flexor-withdrawal reflex (touching a hot stove) Many Pain; temperature II, III, and IV Flexion on ipsilateral side; extension on contralateral sideWww.Medicalstudyzone.com
106 • Physiology 3. As the homonymous muscle relaxes, the reflex also causes synergistic muscles to relax and antagonistic muscles to contract. An exaggerated form of the Golgi tendon reflex is illustrated by the clasp knife reflex. This reflex is abnormal and occurs when there is an increase in muscle tone (e.g., hypertonicity or spasticity of muscle). When a joint is passively flexed, the opposing muscles initially resist this passive movement. However, if the flexion continues, tension increases in the opposing muscle and activates the Golgi tendon reflex, which then causes the opposing muscles to relax and the joint to close rapidly. The initial resistance to flexion fol- lowed by a rapid flexion is similar to the way a pocket knife closes: At first the knife closes slowly against high resistance, and then it quickly snaps shut. Flexor-Withdrawal Reflex The flexor-withdrawal reflex is a polysynaptic reflex that occurs in response to a tactile, painful, or noxious stimulus. Somatosensory and pain afferent fibers initi- ate a flexion reflex that causes withdrawal of the affected part of the body from the painful or noxious stimulus (e.g., touching a hand to a hot stove and then rapidly withdrawing the hand). The reflex produces flexion on the ipsilateral side (i.e., side of the stimulus) and extension on the contralateral side (Fig. 3.35). The steps involved in the flexor-withdrawal reflex are explained as follows: 1. When a limb touches a painful stimulus (e.g., hand touches a hot stove), flexor reflex afferent fibers quadriceps and its muscle spindles are stretched, group Ia afferent fibers are stimulated. These group Ia afferent fibers synapse on and activate α motoneurons in the spinal cord. These α motoneurons innervate and cause contraction of the quadriceps (the muscle that originally was stretched). As the quadriceps muscle contracts and shortens, it forces the lower leg to extend in the char- acteristic knee-jerk reflex. Golgi Tendon Reflex The Golgi tendon reflex is a disynaptic spinal cord reflex, which is also called the inverse myotatic reflex (inverse or opposite of the stretch reflex). The Golgi tendon organ is a stretch receptor found in tendons, which senses contraction (shortening) of muscle and activates group Ib afferent nerves. Golgi tendon organs are arranged in series with the extrafusal muscle fibers (contrasting the parallel arrangement of muscle spindles in the stretch reflex). The steps in the Golgi tendon reflex are shown in Figure 3.34 and are described as follows: 1. When the muscle contracts, the extrafusal muscle fibers shorten, activating the Golgi tendon organs attached to them. In turn, the group Ib afferent fibers that synapse on inhibitory interneurons in the spinal cord are activated. These inhibitory interneurons synapse on the α motoneurons. 2. When the inhibitory interneurons are activated (i.e., activated to inhibit), they inhibit firing of the α motoneurons, producing relaxation of the homony- mous muscle (the muscle that originally was contracted). α Motoneuron Group Ia afferent Homonymous muscle Synergistic muscles Antagonistic muscles + + – + STRETCH REFLEX Fig. 3.33 Operation of the stretch reflex. Solid lines show excitatory pathways; dashed lines show inhibitory steps. Open neurons are excitatory; filled neurons are inhibitory.Www.Medicalstudyzone.com
3—Neurophysiology • 107 α Motoneuron Group Ib afferent Golgi tendon organ GOLGI TENDON REFLEX Synergistic muscles Antagonistic muscles Homonymous muscle – + + + + – Fig. 3.34 Operation of the Golgi tendon reflex. Solid lines show excitatory pathways; dashed lines show inhibitory steps. Open neurons are excitatory; filled neurons are inhibitory. Groups II, III, IV fibers Pain Flexor muscles Extensor muscles Flexor muscles Ipsilateral flexion Contralateral extension Extensor muscles FLEXOR-WITHDRAWAL REFLEX – + + – + + + + + Fig. 3.35 Operation of the flexor-withdrawal reflex. Solid lines show excitatory pathways; dashed lines show inhibitory steps. Open neurons are excitatory; filled neurons are inhibitory. (groups II, III, and IV) are activated. These afferent fibers synapse on multiple interneurons in the spinal cord (i.e., polysynaptic reflex). 2. On the ipsilateral side of the pain stimulus, reflexes are activated that cause flexor muscles to contract and extensor muscles to relax. This portion of the reflex produces flexion on the ipsilateral side (e.g., withdrawal of the hand from the hot stove). 3. On the contralateral side of the pain stimulus, reflexes are activated that cause extensor muscles to contract and flexor muscles to relax. This portion of the reflex produces extension on the contra- lateral side and is called the crossed extension reflex. Thus if the painful stimulus occurs on the left side, the left arm and leg will flex or withdraw and the right arm and leg will extend to maintain balance. 4. A persistent neural discharge, called an afterdis charge, occurs in the polysynaptic reflex circuits. As a result of the afterdischarge, the contracted musclesWww.Medicalstudyzone.com
108 • Physiology learning. The cerebellum helps control the rate, range, force, and direction of movements (collectively known as synergy). Damage to the cerebellum results in lack of coordination. The cerebellum is located in the posterior fossa just below the occipital lobe. It is connected to the brain stem by three cerebellar peduncles, which contain both afferent and efferent nerve fibers. There are three main divisions of the cerebellum: the vestibulocerebellum, the spinocerebellum, and the pontocerebellum. The vestibulocerebellum is domi- nated by vestibular input and controls balance and eye movements. The spinocerebellum is dominated by spinal cord input and controls synergy of movement. The pontocerebellum is dominated by cerebral input, via pontine nuclei, and controls the planning and initia- tion of movements. Layers of the Cerebellar Cortex The cerebellar cortex has three layers, which are described in relation to its output cells, the Purkinje cells (Fig. 3.36). The layers of the cerebellar cortex are as follows: ♦ The granular layer is the innermost layer. It contains granule cells, Golgi II cells, and glomeruli. In the glomeruli, axons of mossy fibers from the spinocer- ebellar and pontocerebellar tracts synapse on den- drites of granule and Golgi type II cells. ♦ The Purkinje cell layer is the middle layer. It con- tains Purkinje cells, and its output is always inhibitory. ♦ The molecular layer is the outermost layer. It con- tains outer stellate cells, basket cells, dendrites of Purkinje and Golgi II cells, and axons of granule cells. The axons of granule cells form parallel fibers, which synapse on the dendrites of Purkinje cells, basket cells, outer stellate cells, and Golgi type II cells. Input to the Cerebellar Cortex Two systems provide excitatory input to the cerebellar cortex: the climbing fiber system and the mossy fiber system. Each system also sends collateral branches directly to deep cerebellar nuclei, in addition to their projections to the cerebellar cortex. Excitatory projec- tions from the cerebellar cortex then activate secondary circuits, which modulate the output of the cerebellar nuclei via the Purkinje cells. ♦ Climbing fibers originate in the inferior olive of the medulla and project directly onto Purkinje cells. These fibers make multiple synaptic connections along the dendrites of Purkinje cells, although each Purkinje cell receives input from only one climbing remain contracted for a period of time after the reflex is activated. Control of Posture and Movement by the Brain Stem Descending motor pathways (i.e., those descending from the cerebral cortex and brain stem) are divided among the pyramidal tract and the extrapyramidal tract. Pyramidal tracts are corticospinal and corti- cobulbar tracts that pass through the medullary pyra- mids and descend directly onto lower motoneurons in the spinal cord. All others are extrapyramidal tracts. The extrapyramidal tracts originate in the following structures of the brain stem: ♦ The rubrospinal tract originates in the red nucleus and projects to motoneurons in the lateral spinal cord. Stimulation of the red nucleus produces activa- tion of flexor muscles and inhibition of extensor muscles. ♦ The pontine reticulospinal tract originates in nuclei of the pons and projects to the ventromedial spinal cord. Stimulation has a generalized activating effect on both flexor and extensor muscles, with its pre- dominant effect on extensors. ♦ The medullary reticulospinal tract originates in the medullary reticular formation and projects to motoneurons in the spinal cord. Stimulation has a generalized inhibitory effect on both flexor and extensor muscles, with the predominant effect on extensors. ♦ The lateral vestibulospinal tract originates in the lateral vestibular nucleus (Deiters nucleus) and projects to ipsilateral motoneurons in the spinal cord. Stimulation produces activation of extensors and inhibition of flexors. ♦ The tectospinal tract originates in the superior col- liculus (tectum or “roof” of the brain stem) and projects to the cervical spinal cord. It is involved in control of neck muscles. Both the pontine reticular formation and the lateral vestibular nucleus have powerful excitatory effects on extensor muscles. Therefore lesions of the brain stem above the pontine reticular formation and lateral ves- tibular nucleus, but below the midbrain, cause a dra- matic increase in extensor tone, called decerebrate rigidity. Lesions above the midbrain do not cause decerebrate rigidity. Cerebellum The cerebellum, or “little brain,” regulates movement and posture and plays a role in certain kinds of motorWww.Medicalstudyzone.com
3—Neurophysiology • 109 single action potentials called simple spikes. These parallel fibers also synapse on cerebellar interneu- rons (basket, stellate, and Golgi II). Interneurons of the Cerebellum The function of cerebellar interneurons is to modulate Purkinje cell output. With the exception of granule cells, all of the cerebellar interneurons are inhibitory. Granule cells have excitatory input to basket cells, stel- late cells, Golgi II cells, and Purkinje cells. Basket cells and stellate cells inhibit Purkinje cells (via parallel fibers). Golgi II cells inhibit granule cells, thereby reducing their excitatory effect on Purkinje cells. Output of the Cerebellar Cortex The only output of the cerebellar cortex is via axons of Purkinje cells. The output of the Purkinje cells is always inhibitory because the neurotrans- mitter released at these synapses is γ-aminobutyric acid (GABA) (see Chapter 1). Axons of Purkinje cells project topographically to deep cerebellar nuclei and to lateral vestibular nuclei. This inhibitory output of the fiber. These synaptic connections are powerful! A single action potential from a climbing fiber can elicit multiple excitatory bursts, called complex spikes, in the dendrites of the Purkinje cell. It is believed that climbing fibers “condition” the Pur- kinje cells and modulate their responses to mossy fiber input. Climbing fibers also may play a role in cerebellar learning. ♦ Mossy fibers constitute the majority of the cerebel- lar input. These fibers include vestibulocerebellar, spinocerebellar, and pontocerebellar afferents. Mossy fibers project to granule cells, which are excitatory interneurons located in collections of synapses called glomeruli. Axons from these granule cells then ascend to the molecular layer, where they bifurcate and give rise to parallel fibers. Parallel fibers from the granule cells contact the dendrites of many Purkinje cells, producing a “beam” of excitation along the row of Purkinje cells. The dendritic tree of each Purkinje cell may receive input from as many as 250,000 parallel fibers! In contrast to the climbing fiber input to the Purkinje dendrites (which produce complex spikes), the mossy fiber input produces Basket cell Purkinje cell Granule cell Glomerulus Mossy fiber Deep cerebellar nuclei Lateral vestibular nuclei Climbing fiber Parallel fibers Outer stellate cell Molecular layer Purkinje cell layer Granular layer Golgi II cells Fig. 3.36 Structures of the cerebellar cortex shown in cross-section.Www.Medicalstudyzone.com
110 • Physiology neurotransmitter is glutamate. The overall output of the indirect pathway is inhibitory, as illustrated in the summary diagram at the bottom of the figure. ♦ Direct pathway. In the direct pathway, the striatum sends inhibitory input to the internal segment of the globus pallidus and the pars reticulata of the sub- stantia nigra, which send inhibitory input to the thalamus. As in the indirect pathway, the thalamus sends excitatory input back to the motor cortex. Again, the inhibitory neurotransmitter is GABA, and the excitatory neurotransmitter is glutamate. The overall output of the direct pathway is excitatory, as shown in the summary diagram at the bottom of the figure. The outputs of the indirect and direct pathways from the basal ganglia to the motor cortex are opposite and carefully balanced: The indirect path is inhibitory, and the direct path is excitatory. A disturbance in one of the pathways will upset this balance of motor control, with either an increase or a decrease in motor activity. Such an imbalance is characteristic of diseases of the basal ganglia. In addition to the basic circuitry of the indirect and direct pathways, there is an additional connection, back and forth, between the striatum and the pars compacta of the substantia nigra. The neurotransmitter for the connection back to the striatum is dopamine. This additional connection between the substantia nigra and the striatum means that dopamine will be inhibitory (via D2 receptors) in the indirect pathway and excitatory (via D1 receptors) in the direct pathway. Diseases of the Basal Ganglia Diseases of the basal ganglia include Parkinson disease and Huntington disease. In Parkinson disease, cells of the pars compacta of the substantia nigra degenerate, reducing inhibition via the indirect pathway and reduc- ing excitation via the direct pathway. The characteristics of Parkinson disease are explainable by dysfunction of the basal ganglia: resting tremor, slowness and delay of movement, and shuffling gait. Treatment of Parkin- son disease includes replacement of dopamine by treatment with L dopa (the precursor to dopamine) or administration of dopamine agonists such as bromo- criptine. Huntington disease is a hereditary disorder caused by destruction of striatal and cortical cholinergic neurons and inhibitory GABAergic neurons. The neu- rologic symptoms of Huntington disease are choreic (writhing) movements and dementia. There is no cure. Motor Cortex Voluntary movements are directed by the motor cortex, via descending pathways. The motivation and ideas necessary to produce voluntary motor activity are cerebellar cortex regulates the rate, range, force, and direction of movement (synergy). Disorders of the Cerebellum Cerebellar lesions result in an abnormality of move- ment called ataxia. Cerebellar ataxia is a lack of coordination due to errors in rate, range, force, and direction of movement. Ataxia can be exhibited in one of several ways. There may be a delayed onset of movement or poor execution of the sequence of a movement, causing the movement to appear uncoordi- nated. A limb may overshoot its target or stop before reaching its target. Ataxia may be expressed as dysdi adochokinesia, in which a person is unable to perform rapid, alternating movements. Intention tremors may occur perpendicular to the direction of a voluntary movement, increasing near the end of the movement. (Intention tremors seen in cerebellar disease differ from the resting tremors seen in Parkinson disease.) The rebound phenomenon is the inability to stop a move- ment; for example, if a person with cerebellar disease flexes his forearm against a resistance, he may be unable to stop the flexion when the resistance is removed. Basal Ganglia The basal ganglia are the deep nuclei of the telencepha- lon: caudate nucleus, putamen, globus pallidus, and amygdala. There also are associated nuclei including the ventral anterior and ventral lateral nuclei of the thalamus, the subthalamic nucleus of the diencephalon, and the substantia nigra of the midbrain. The main function of the basal ganglia is to influence the motor cortex via pathways through the thalamus. The role of the basal ganglia is to aid in planning and execution of smooth movements. The basal ganglia also contribute to affective and cognitive functions. The pathways into and out of the basal ganglia are complex, as illustrated in Figure 3.37. Almost all areas of the cerebral cortex project topographically onto the striatum including a critical input from the motor cortex. The striatum then communicates with the thalamus and then back to the cortex via two different pathways. ♦ Indirect pathway. In the indirect pathway, the stria- tum has inhibitory input to the external segment of the globus pallidus, which has inhibitory input to the subthalamic nuclei. The subthalamic nuclei project excitatory input to the internal segment of the globus pallidus and the pars reticulata of the substantia
3—Neurophysiology • 111 The motor cortex consists of three areas: primary motor cortex, supplementary motor cortex, and premo- tor cortex. ♦ Premotor cortex and supplementary motor cortex (area 6) are the regions of the motor cortex respon- sible for generating a plan of movement, which then is transferred to the primary motor cortex for execution. The supplementary motor cortex pro- grams complex motor sequences and is active during “mental rehearsal” of a movement, even in the absence of movement. first organized in multiple associative areas of the cerebral cortex and then transmitted to the supplemen- tary motor and premotor cortices for the development of a motor plan. The motor plan will identify the specific muscles that need to contract, how much they need to contract, and in what sequence. The plan then is transmitted to upper motoneurons in the primary motor cortex, which send it through descending path- ways to lower motoneurons in the spinal cord. The planning and execution stages of the plan are also influenced by motor control systems in the cerebellum and basal ganglia. Cortex Thalamus – – + + Globus pallidus (external) Striatum – + Subthalamic nuclei Globus pallidus (internal) Substantia nigra (pars reticulata) Substantia nigra (pars compacta) + – – + Indirect pathway +, –, –, +, – = inhibitory + + – – Direct pathway +, –, – = excitatory + – –– BASAL GANGLIA PATHWAYS Fig. 3.37 Pathways in the basal ganglia. The relationships between the cerebral cortex, the basal ganglia, and the thalamus are shown. Solid blue lines show excitatory pathways; dashed brown lines show inhibitory pathways. The overall output of the indirect pathway is inhibition, and the overall output of the direct pathway is excitation. (Modified from Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science, 4th ed. New York, McGraw-Hill, 2000.)Www.Medicalstudyzone.com
112 • Physiology desynchronized, with low-voltage, high-frequency waves that resemble those in an awake person. REM sleep is sometimes called paradoxical sleep: Even though the EEG is most similar to that of the awake state, the person is (paradoxically) most difficult to awaken. REM sleep is characterized by loss of muscle tone, notably in the eye muscles resulting in rapid eye movements, loss of temperature regulation, pupillary constriction, penile erection, and fluctuations in heart rate, blood pressure, and respiration. Most dreams occur during REM sleep. The proportion of slow-wave sleep and REM sleep varies over the life span. New- borns spend half of their sleep in REM sleep; young adults spend about 25% of sleep in REM sleep; and the elderly have little REM sleep. Learning and Memory Learning and memory are higher-level functions of the nervous system. Learning is the neural mechanism by which a person changes his or her behavior as a result of experiences. Memory is the mechanism for storing what is learned. Learning is categorized as either nonassociative or associative. In nonassociative learning, exemplified by habituation, a repeated stimulus causes a response, but that response gradually diminishes as it is “learned” that the stimulus is not important. For example, a newcomer to New York City may be awakened at first by street noises, but eventually the noises will be ignored as it is learned they are not relevant. The opposite of habituation is sensitization, where a stimu- lus results in a greater probability of a subsequent response when it is learned that the stimulus is impor- tant. In associative learning, there is a consistent relationship in the timing of stimuli. In classic condi tioning, there is a temporal relationship between a conditioned stimulus and an unconditioned stimulus that elicits an unlearned response. When the combina- tion is repeated, provided the temporal relationship is maintained, the association is learned; once learned (e.g., by Pavlov’s dog), the stimulus alone (e.g., the bell) elicits the unlearned response (e.g., salivation). In operant conditioning, the response to a stimulus is reinforced, either positively or negatively, causing the probability of a response to change. Synaptic plasticity is the fundamental mechanism that underlies learning. That is, synaptic function and effectiveness are variable and depend on the prior level of activity or “traffic” through the synapse. The respon- siveness of postsynaptic neurons (called synaptic strength) is not fixed but rather depends on the previ- ous level of synaptic traffic. For example, in the phe- nomenon of potentiation, repeated activation of a neuronal pathway leads to increased responsiveness of ♦ Primary motor cortex (area 4) is the region of the motor cortex responsible for execution of a move- ment. Programmed patterns of motoneurons are activated from the primary motor cortex. As upper motoneurons in the motor cortex are excited, this activity is transmitted to the brain stem and spinal cord, where lower motoneurons are activated and produce coordinated contraction of the appropriate muscles (i.e., the voluntary movement). The primary motor cortex is topographically organized and is described as the motor homunculus. This topo- graphic organization is dramatically illustrated in jacksonian seizures, which are epileptic events originating in the primary motor cortex. The epileptic event usually begins in the fingers of one hand, progresses to the hand and arms, and eventually spreads over the entire body (i.e., the “jacksonian march”). HIGHER FUNCTIONS OF THE NERVOUS SYSTEM Electroencephalogram The electroencephalogram (EEG) records electrical activity of the cerebral cortex via electrodes placed on the skull. The EEG waves originate from alternating excitatory and inhibitory synaptic potentials that produce sufficient extracellular current flow across the cortex to be detected by surface electrodes. (EEG waves are not action potentials. Electrodes on the surface of the skull are not sufficiently sensitive to detect the small voltage changes of single action potentials.) The normal EEG (Fig. 3.38) comprises waves with various amplitudes and frequencies. In a normal, awake adult with eyes open, the dominant frequency recorded over the parietal and occipital lobes is the beta rhythm (13–30 Hz), which consists of desynchronous low-voltage, high-frequency waves. With eyes closed, the dominant frequency is the alpha rhythm (8–13 Hz), which has more synchronous waves of higher voltage and lower frequency. As a person falls asleep, he or she passes through four stages of slow wave sleep. In Stage 1, the alpha waves seen in an awake adult with eyes closed are interspersed with lower-frequency theta waves. In Stage 2, these low-frequency waves are interspersed with high-frequency bursts called sleep spindles and large, slow potentials called K complexes. In Stage 3 (not shown in the figure), there are very low-f
3—Neurophysiology • 113 CEREBROSPINAL FLUID The human brain is composed of 80% fluid, most of which is cerebrospinal fluid (CSF). CSF is formed at a rate of 500 milliliters (mL) per day by the epithelial cells of the choroid plexus (located in the lateral, third, and fourth ventricles). Once produced by the choroid plexus, CSF flows into the ventricles and the subarach- noid spaces, which surround the brain and spinal cord. Distended regions of the subarachnoid space are called subarachnoid cisterns. Fluid is transferred from CSF to venous blood by one-way bulk flow and is returned to the systemic circulation. In the steady state, the move- ment of fluid from CSF to venous blood should equal the rate of CSF formation (i.e., 500 mL/day). For diagnostic purposes, CSF can be sampled using a lumbar puncture in the lumbar cistern. The relationships between the arterial blood supply of the brain, the choroid plexus, and the blood-brain barrier are shown in Figure 3.39. Note that substances the postsynaptic neurons in that pathway. The period of enhanced responsiveness may be brief, lasting for only milliseconds, or it may last for days or weeks (i.e., long term potentiation). Conversely, in habituation, increased synaptic activity causes decreased respon- siveness of the postsynaptic neuron. The mechanism of long-term potentiation involves synaptic pathways that use the excitatory neurotrans- mitter glutamate and its N methyl D aspartate (NMDA) receptor. When the presynaptic neurons are activated, they release glutamate, which diffuses across the synapse and activates NMDA receptors on the postsyn- aptic membranes. The NMDA receptors are ligand-gated ion Ca2+ channels that, when open, allow Ca2+ to enter the postsynaptic cells. With high-frequency stimulation (increased activity of the pathway), more Ca2+ accumu- lates in the postsynaptic cells; the higher intracellular Ca2+ concentration leads to an increase in calcium- calmodulin-dependent protein kinase activity and, by mechanisms that are not fully understood, increased responsiveness of those synapses. Awake Stage 1 sleep Stage 2 sleep Stage 4 sleep REM sleep Alpha Beta Alpha Alpha Sleep spindle Delta Theta Alpha K complex Eyes closed Eyes open Eyes closed Fig. 3.38 Electroencephalogram of an awake subject and of subjects in Stages 1, 2, 4, and rapid eye movement (REM) sleep.Www.Medicalstudyzone.com
114 • Physiology large molecular size. On the other hand, lipid-soluble substances such as oxygen and carbon dioxide move freely and equilibrate between the two compartments. Thus depending on the transport mechanisms and the characteristics of the barrier, some substances are present in higher concentration in CSF than in blood, some are present at approximately the same concentra- tion, and some are present in lower concentration in CSF than in blood. Many substances readily exchange between brain interstitial fluid and CSF (see Fig. 3.38); thus the compositions of brain interstitial fluid and CSF are similar to each other but different from blood. Table 3.6 compares the composition of CSF and blood. Functions of Cerebrospinal Fluid The functions of CSF are to provide a constant, con- trolled environment for the brain cells and to protect the brain from endogenous or exogenous toxins. CSF can be exchanged between brain cells (which are bathed in interstitial fluid), the interstitial fluid, and CSF. The barrier between cerebral capillary blood and CSF is the choroid plexus. This barrier consists of three layers: capillary endothelial cells and basement mem- brane, neuroglial membrane, and epithelial cells of the choroid plexus. The choroid plexus epithelial cells are similar to those of the renal distal tubule and contain transport mechanisms that move solutes and fluid from capillary blood into CSF. The barrier between cerebral capillary blood and interstitial fluid of the brain is the blood brain barrier. Anatomically, the blood-brain barrier consists of capil- lary endothelial cells and basement membrane, neuro- glial membrane, and glial end feet (projections of astrocytes from the brain side of the barrier). Function- ally, the blood-brain barrier differs in two ways from the analogous barrier in other tissues. (1) The junctions between endothelial cells in the brain are so “tight” that few substances can cross between the cells. (2) Only a few substances can pass through the endothelial cells: Lipid-soluble substances (e.g., oxygen and carbon dioxide) can cross the blood-brain barrier, but water- soluble substances are excluded. Formation of Cerebrospinal Fluid CSF is formed by the epithelial cells of the choroid plexus. Transport mechanisms in these cells secrete some substances from blood into CSF (e.g., Na+, Cl−, HCO3−, and water) and absorb other substances from CSF into blood (K+). Molecules such as protein and cholesterol are excluded from CSF because of their Interstitial fluid CSFBrain cells Cerebral venous blood Cerebral arterial blood Blood-brain barrier Choroid plexus FORMATION OF CSF Fig. 3.39 Mechanism for the production of cerebrospinal fluid. CSF, Cerebrospinal fluid. TABLE 3.6 Composition of Cerebrospinal Fluid [CSF] ≈ [Blood] [CSF] < [Blood] [CSF] > [Blood] Na+ Cl− HCO3− Osmolarity K+ Ca2+ Glucose Amino acids pH Cholesterola Proteina Mg2+ Creatinine aNegligible in CSF. CSF, Cerebrospinal fluid.Www.Medicalstudyzone.com
3—Neurophysiology • 115 cells, which are also primary afferent neurons. Axons from these neurons pass through the cribriform plate and synapse in glomeruli of the olfactory bulb. Taste receptors are found on taste buds, which are orga- nized in papillae. ■ Muscle spindles are composed of intrafusal fibers and are arranged in parallel with extrafusal muscle fibers. Muscle spindles are stretch receptors, which detect changes in muscle length when extrafusal fibers contract or relax. ■ Spinal cord reflexes include the stretch reflex (mono- synaptic), the Golgi tendon reflex (disynaptic), and the flexor-withdrawal reflex (multisynaptic). ■ Descending motor pathways from the cerebral cortex and brain stem are divided among the pyramidal tract and extrapyramidal tract. Pyramidal tracts pass through the medulla and synapse on lower motoneu- rons in the spinal cord. Extrapyramidal tracts include rubrospinal, pontine reticulospinal, medullary reticu- lospinal, lateral vestibulospinal, and tectospinal tracts. ■ The cerebellum regulates movement by controlling synergy. The cerebellar cortex includes a granular layer, a Purkinje cell layer, and a molecular layer. The output of the cerebellar cortex is via axons of Purkinje cells and is always inhibitory. Disorders of the cerebellum cause ataxia. ■ Basal ganglia are deep nuclei of the telencephalon, which are involved in planning and execution of smooth movements. ■ The motor cortex includes premotor and supplemen- tary cortices, which are responsible for generating a motor plan. The primary motor cortex is responsible for execution of the motor plan. also may function to prevent escape of local neurotrans- mitters into the general circulation. Depending on their lipid solubility, drugs penetrate the blood-brain barrier in varying degrees. Thus non-ionized (lipid-soluble) drugs penetrate the brain readily, whereas ionized (non–lipid-soluble) drugs do not penetrate. Inflamma- tion, irradiation, and tumors may increase the perme- ability of the blood-brain barrier and allow substances normally excluded to enter the brain. These substances include cancer chemotherapeutic drugs, antibiotics, and radiolabeled markers. SUMMARY ■ Sensory systems transmit information from the environment to the CNS via specialized sensory receptors and a series of first-, second-, third-, and fourth-order neurons in the CNS. Sensory receptors include mechanoreceptors, photoreceptors, chemo- receptors, thermoreceptors, and nociceptors. A stimulus (e.g., light) is converted to electrical energy in the sensory receptors via transduction processes, which result in receptor potentials. ■ Somatosensory and pain systems process informa- tion about touch, position, pain, and temperature using the dorsal column and anterolateral systems. ■ The visual system detects and interprets light stimuli. Photoreceptors are rods and cones of the retina, which hyperpolarize in response to light. Photore- ceptors synapse on bipolar cells and horizontal cells of the retina, where they produce either excitation or inhibition, depending on the type of receptor on the bipolar and horizontal cells. The output cells of the retina are ganglion cells, whose axons form the optic nerves. The optic nerves synapse in the lateral geniculate nucleus of the thalamus. Fibers from each nasal hemiretina cross at the optic chiasm and ascend contralaterally; fibers from each temporal hemiretina ascend ipsilaterally. ■ The auditory system involves transduction of sound waves. The mechanoreceptors are auditory hair cells located in the organ of Corti of the inner ear. Bending of cilia on the hair cells produces an oscillating receptor potential. Location of the hair cells along the basilar membrane encodes frequency. ■ The vestibular system is used to maintain equilib- rium and balance. Vestibular hair cells are mecha- noreceptors located in ampullae of semicircular canals and in otolith organs. The semicircular canals detect angular acceleration of the head, and the otolith organs detect linear acceleration. ■ The chemical senses are olfaction and gustation. Olfactory epithelium contains olfactory receptor Challenge Yourself Answer each question with a word, phrase, sentence, or numerical solution. When a list of possible answers is supplied with the question, one, more than one, or none of the choices may be correct. Correct answers are provided at the end of the book. 1 Cutting which of the following leads to total blindness in the right eye: optic chiasm, left optic tract, right optic tract, right optic nerve, left optic nerve? 2 A ballerina spins to the right. When she suddenly stops spinning, which way will her eyes move?Www.Medicalstudyzone.com
116 • Physiology 3 How many motoneurons are in a motor unit? 4 Which of the following reflexes comprise(s) only one synapse: knee-jerk reflex, Golgi tendon reflex, stretch reflex, the reflex involved when one removes a hand from a hot stove? 5 In which type of receptor, phasic or tonic, does the receptor potential fall below threshold, even as the stimulus continues? 6 Put these photoreception events in their correct order: release of neurotransmitter, decreased cGMP, light, conversion of 11-cis rhodopsin to all-trans rhodopsin, transducin, hyperpolarization, closure of Na+ channels. 7 A hyperpolarizing receptor potential makes the membrane potential ______ (more or less) negative and ______ (increases or decreases) the likelihood of action potentials occurring. 8 Indicate whether each of the following is activated (increased), inhibited (decreased), or unchanged in the operation of the Golgi tendon reflex: Golgi tendon organs Ia afferent fibers Ib afferent fibers Inhibitory interneurons α motoneurons 9 Which of the following is/are found in higher concentration in blood than in CSF: protein, osmolarity, Mg2+, glucose, Na+, K+? 10 If the head is rotated to the right, which horizontal semicircular canal (right or left) is activated during the initial rotation? When the head stops rotating, which canal (right or left) is activated? 11 Compared with the base, the apex of the basilar membrane is ______ (wider/narrower), is ______ (more compliant/less compliant), and responds to ______ (higher/lower) frequencies.Www.Medicalstudyzone.com
117 CHAPTER 4 Cardiovascular Physiology Circuitry of the Cardiovascular System, 117 Hemodynamics, 119 Cardiac Electrophysiology, 131 Cardiac Muscle Contraction, 144 Cardiac Cycle, 154 Relationships Between Cardiac Output and Venous Return, 158 Regulation of Arterial Pressure, 163 Microcirculation, 170 Special Circulations, 173 Temperature Regulation, 177 Integrative Functions of the Cardiovascular System, 178 Summary, 186 Challenge Yourself, 187 The primary function of the cardiovascular system is to deliver blood to the tissues, which provides essential nutrients to the cells for metabolism and removes waste products from the cells. The heart serves as the pump, which, by contracting, generates the pressure to drive blood through a series of blood vessels. The vessels that carry blood from the heart to the tissues are the arteries, which are under high pressure and contain a relatively small percentage of the blood volume. The veins, which carry blood from the tissues back to the heart, are under low pressure and contain the largest percentage of the blood volume. Within the tissues, thin-walled blood vessels, called capillaries, are inter- posed between the arteries and veins. Exchange of nutrients, wastes, and fluid occurs across the capillary walls. The cardiovascular system also is involved in several homeostatic functions: It participates in the regulation of arterial blood pressure; it delivers regulatory hor- mones from the endocrine glands to their sites of action in target tissues; it participates in the regulation of body temperature; and it is involved in the homeostatic adjustments to altered physiologic states such as hem- orrhage, exercise, and changes in posture. CIRCUITRY OF THE CARDIOVASCULAR SYSTEM Left and Right Sides of the Heart Figure 4.1 is a schematic diagram of the circuitry of the cardiovascular system. The left and right sides of the heart and the blood vessels are shown in relation to each other. Each side of the heart has two chambers, an atrium and a ventricle, connected by one-way valves, called atrioventricular (AV) valves. The AV valves are designed so that blood can flow only in one direction, from the atrium to the ventricle. The left heart and right heart have different functions. The left heart and the systemic arteries, capillaries, and veins are collectively called the systemic circulation. The left ventricle pumps blood to all organs of the body except the lungs. The right heart and the pulmonary arteries, capillaries, and veins are collectively called the pulmonary circulation. The right ventricle pumps blood to the lungs. The left heart and right heart function in series so that blood is pumped sequentially from the left heart to the systemicWww.Medicalstudyzone.com
118 • Physiology Blood Vessels The blood vessels have several functions. They serve as a closed system of passive conduits, delivering blood to and from the tissues where nutrients and wastes are exchanged. The blood vessels also participate actively in the regulation of blood flow to the organs. When resistance of the blood vessels, particularly of the arterioles, is altered, blood flow to that organ is altered. Circuitry The steps in one complete circuit through the cardio- vascular system are shown in Figure 4.1. The circled circulation, to the right heart, to the pulmonary circula- tion, and then back to the left heart. The rate at which blood is pumped from either ventricle is called the cardiac output. Because the two sides of the heart operate in series, the cardiac output of the left ventricle equals the cardiac output of the right ventricle in the steady state. The rate at which blood is returned to the atria from the veins is called the venous return. Again, because the left heart and the right heart operate in series, venous return to the left heart equals venous return to the right heart in the steady state. Finally, in the steady state, cardiac output from the heart equals venous return to the heart. ARTERIESVEINS RIGHT HEART Pulmonary artery Lungs Cerebral Coronary Renal Gastrointestinal Skeletal muscle Skin Pulmonary vein Right atrium Right ventricle Tricuspid valve Pulmonic valve Aortic valve Vena cava Aorta LEFT HEART Left atrium Left ventricle Mitral valve 100% 100% 15% 5% 25% 25% 25% 5% 100% 8 7 4 3 2 5 6 1 Fig. 4.1 A schematic diagram showing the circuitry of the cardiovascular system. The arrows show the direction of blood flow. Percentages represent the percent (%) of cardiac output. See the text for an explanation of the circled numbers.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 119 percentage distribution to skeletal and cardiac muscle. 4. Blood flow from the organs is collected in the veins. The blood leaving the organs is venous blood and contains waste products from metabolism, such as carbon dioxide (CO2). This mixed venous blood is collected in veins of increasing size and finally in the largest vein, the vena cava. The vena cava carries blood to the right heart. 5. Venous return to the right atrium. Because the pressure in the vena cava is higher than in the right atrium, the right atrium fills with blood, called the venous return. In the steady state, venous return to the right atrium equals cardiac output from the left ventricle. 6. Mixed venous blood fills the right ventricle. Mixed venous blood flows from the right atrium to the right ventricle through the AV valve in the right heart, the tricuspid valve. 7. Blood is ejected from the right ventricle into the pulmonary artery. When the right ventricle con- tracts, blood is ejected through the pulmonic valve (the semilunar valve of the right side of the heart) into the pulmonary artery, which carries blood to the lungs. Note that the cardiac output ejected from the right ventricle is identical to the cardiac output that was ejected from the left ventricle. In the capil- lary beds of the lungs, oxygen (O2) is added to the blood from alveolar gas, and CO2 is removed from the blood and added to the alveolar gas. Thus the blood leaving the lungs has more O2 and less CO2 than the blood that entered the lungs. 8. Blood flow from the lungs is returned to the heart via the pulmonary vein. Oxygenated blood is returned to the left atrium via the pulmonary vein to begin a new cycle. HEMODYNAMICS The term hemodynamics refers to the principles that govern blood flow in the cardiovascular system. These basic principles of physics are the same as those applied to the movement of fluids in general. The concepts of flow, pressure, resistance, and capacitance are applied to blood flow to and from the heart and within the blood vessels. Types and Characteristics of Blood Vessels Blood vessels are the conduits through which blood is carried from the heart to the tissues and from the tissues back to the heart. In addition, some blood numbers in the figure correspond with the steps described here. 1. Oxygenated blood fills the left ventricle. Blood that has been oxygenated in the lungs returns to the left atrium via the pulmonary vein. This blood then flows from the left atrium to the left ventricle through the mitral valve (the AV valve of the left heart). 2. Blood is ejected from the left ventricle into the aorta. Blood leaves the left ventricle through the aortic valve (the semilunar valve of the left side of the heart), which is located between the left ventricle and the aorta. When the left ventricle contracts, the pressure in the ventricle increases, causing the aortic valve to open and blood to be ejected forcefully into the aorta. (As noted previously, the volume of blood ejected from the left ventricle per unit time is called the cardiac output.) Blood then flows through the arterial system, driven by the pressure created by contraction of the left ventricle. 3. Cardiac output is distributed among various organs. The total cardiac output of the left heart is distributed among the organ systems via sets of parallel arteries. Thus simultaneously, approximately 15% of the cardiac output is delivered to the brain via the cerebral arteries, 5% is delivered to the heart via the coronary arteries, 25% is delivered to the kidneys via the renal arteries, and so forth. Given this parallel arrangement of the organ systems, it follows that the total systemic blood flow must equal the cardiac output. The percentage distribution of cardiac output among the various organ systems is not fixed, however. For example, during strenuous exercise, the percentage of the cardiac output going to skeletal and cardiac muscle increases, compared with the percentages at rest. There are three major mecha- nisms for achieving such changes in blood flow to an organ system. In the first mechanism, the cardiac output remains constant, but the blood flow is redistributed among the organ systems by the selective alteration of arteriolar resistance. In this scenario, blood flow to one organ can be increased at the expense of blood flow to other organs. In the second mechanism, the cardiac output increases or decreases, but the percentage distribution of blood flow among the organ systems is kept constant. Finally, in a third mechanism, a combination of the first two mechanisms occurs in which both cardiac output and the percentage distribution of blood flow are altered. This third mechanism is used, for example, in the response to strenuous exercise: Blood flow to skeletal and cardiac muscle increases to meet the increased metabolic demand by a com- bination of increased cardiac output and increasedWww.Medicalstudyzone.com
120 • Physiology the total cross-sectional area, the number of blood vessels at each level of the vasculature, and the per- centage of the blood volume contained in each type of vessel. ♦ Arteries. The aorta is the largest artery of the sys- temic circulation. Medium- and small-sized arteries branch off the aorta. The function of the arteries is to deliver oxygenated blood to the organs. The arteries are thick-walled structures with extensive vessels (capillaries) are so thin walled that substances can exchange across them. The size of the various types of blood vessels and the histologic charac- teristics of their walls vary. These variations have profound effects on their resistance and capacitance properties. Figure 4.2 is a schematic drawing of a vascular bed. The direction of blood flow through the vascular bed is from artery to arteriole, to capillaries, to venule, to vein. Figure 4.3, a companion figure, is a graph showing From aorta Artery To vena cava Vein Venule Capillaries Arteriole Fig. 4.2 Arrangement of blood vessels in the cardiovascular system. Cross-sectional area (cm2) Blood volume (%) Area Blood volume 2500 300 200 100 Number 20 0 40 60 80 100 Aorta 1 Arteries 105 Arterioles 107 Capillaries 1010 Veins* 107 Vena cava 1 Fig. 4.3 Area and volume contained in systemic blood vessels. The blood vessels are described by the number of each type, total cross-sectional area, and percentage (%) of blood volume contained. (Pulmonary blood vessels are not included in this figure.) *Total number includes veins and venules.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 121 and by vasoactive metabolites produced in the tissues. ♦ Venules and veins. Like the capillaries, the venules are thin-walled structures. The walls of the veins are composed of the usual endothelial cell layer and a modest amount of elastic tissue, smooth muscle, and connective tissue. Because the walls of the veins contain much less elastic tissue than the arteries, the veins have a large capacitance (capacity to hold blood). In fact, the veins contain the largest percent- age of blood in the cardiovascular system. The volume of blood contained in the veins is called the unstressed volume (meaning the blood volume under low pressure). The smooth muscle in the walls of the veins is, like that in the walls of the arterioles, innervated by sympathetic nerve fibers. Increases in sympathetic nerve activity, via α1-adrenergic recep- tors, cause contraction of the veins, which reduces their capacitance and therefore reduces the unstressed volume. Velocity of Blood Flow The velocity of blood flow is the rate of displacement of blood per unit time. The blood vessels of the cardio- vascular system vary in terms of diameter and cross- sectional area. These differences in diameter and area, in turn, have profound effects on velocity of flow. The relationship between velocity, flow, and cross-sectional area (which depends on vessel radius or diameter) is as follows: v Q A= where v Velocity of blood flow (cm/s Q Flow mL/s A Cross-sectiona = = = ) ( ) ll area cm( )2 Velocity of blood flow (v) is linear velocity and refers to the rate of displacement of blood per unit time. Thus velocity is expressed in units of distance per unit time (e.g., cm/s). Flow (Q) is volume flow per unit time and is expressed in units of volume per unit time (e.g., mL/s). Area (A) is the cross-sectional area of a blood vessel (e.g., aorta) or a group of blood vessels (e.g., all of the capillaries). Area is calculated as A = πr2, where r is the radius of a single blood vessel (e.g., aorta) or the total radius of a group of blood vessels (e.g., all of the capillaries). Figure 4.4 illustrates how changes in diameter alter the velocity of flow through a vessel. In this figure, development of elastic tissue, smooth muscle, and connective tissue. The thickness of the arterial wall is a significant feature: The arteries receive blood directly from the heart and are under the highest pressure in the vasculature. The volume of blood contained in the arteries is called the stressed volume (meaning the blood volume under high pressure). ♦ Arterioles. The arterioles are the smallest branches of the arteries. Their walls have an extensive devel- opment of smooth muscle, and they are the site of highest resistance to blood flow. The smooth muscle in the walls of the arterioles is tonically active (i.e., always contracted). It is extensively innervated by sympathetic adrenergic nerve fibers. α1-Adrenergic receptors are found on the arterioles of several vascular beds (e.g., skin and splanchnic vasculature). When activated, these receptors cause contraction, or constriction, of the vascular smooth muscle. Constriction produces a decrease in the diameter of the arteriole, which increases its resistance to blood flow. Less common, β2-adrenergic receptors are found in arterioles of skeletal muscle. When activated, these receptors cause dilation, or relaxation, of the vascular smooth muscle, which increases the diameter and decreases the resistance of these arterioles to blood flow. Thus arterioles are not only the site of highest resistance in the vasculature, but they also are the site where resistance can be changed by alterations in sympathetic nerve activity, by circulating catechol- amines, and by other vasoactive substances. ♦ Capillaries. The capillaries are thin-walled structures lined with a single layer of endothelial cells, which is surrounded by a basal lamina. Capillaries are the site where nutrients, gases, water, and solutes are exchanged between the blood and the tissues and, in the lungs, between the blood and the alveolar gas. Lipid-soluble substances (e.g., O2 and CO2) cross the capillary wall by dissolving in and diffusing across the endothelial cell membranes. In contrast, water-soluble substances (e.g., ions) cross the capillary wall either through water-filled clefts (spaces) between the endothelial cells or through large pores in the walls of some capillaries (e.g., fenestrated capillaries). Not all capillaries are perfused with blood at all times. Rather, there is selective perfusion of capillary beds, depending on the metabolic needs of the tissues. This selective perfusion is determined by the degree of dilation or constriction of the arterioles and precapillary sphincters (smooth muscle bands that lie “before” the capillaries). The degree of dila- tion or constriction is, in turn, controlled by the sympathetic innervation of vascular smooth muscleWww.Medicalstudyzone.com
122 • Physiology Velocity (v) 10 cm/s 1 cm/s 0.1 cm/s Area (A) 1 cm2 10 cm2 100 cm2 Flow (Q) 10 mL/s 10 mL/s 10 mL/s 10 mL/s v = Q/A Fig. 4.4 Effect of the diameter of the blood vessel on the velocity of blood flow. SAMPLE PROBLEM. A man has a cardiac output of 5.5 L/min. The diameter of his aorta is estimated to be 20 mm, and the total cross-sectional area of his systemic capillaries is estimated to be 2500 cm2. What is the velocity of blood flow in the aorta relative to the velocity of blood flow in the capillaries? SOLUTION. To compare the velocity of blood flow in the aorta with the velocity in the capillaries, two values are needed for each type of blood vessel: the total blood flow (Q) and the total cross-sectional area (cm2). The total flow at each level is the same and is equal to the cardiac output. The total cross- sectional area of the capillaries is given in the problem, and the cross-sectional area of the aorta must be calculated from its radius, which is 10 mm. Area = πr2 = 3.14 × (10 mm)2 = 3.14 × (1 cm)2 = 3.14 cm2. Thus three blood vessels are shown in order of increasing diameter and cross-sectional area. The flow through each blood vessel is identical, at 10 mL/s. However, because of the inverse relationship between velocity and cross-sectional area, as vessel diameter increases, the velocity of flow through the vessel decreases. This example can be extrapolated to the cardiovas- cular system. Imagine that the smallest vessel represents the aorta, the medium-sized vessel represents all of the arteries, and the largest vessel represents all of the capillaries. The total blood flow at each level of blood vessels is the same and is equal to the cardiac output. Because of the inverse relationship between velocity and total cross-sectional area, the velocity of blood flow will be highest in the aorta and lowest in the capillaries. From the standpoint of capillary function (i.e., exchange of nutrients, solutes, and water), the low velocity of blood flow is advantageous, as it maximizes the time for exchange across the capillary walls. V Q A L/min cm mL/min cm cm / capillaries = = = = 5 5 2500 5500 2500 5500 2 2 3 . mmin cm cm/min 2500 2 2 2 = . V Q A cm /min cm cm/min aorta = = = 5500 3 14 1752 3 2 . Hence, velocity in the aorta is 800-fold that in the capillaries (1752 cm/min in the aorta compared with 2.2 cm/min in the capillaries). These calcula- tions confirm the previous discussion concerning velocity of blood flow. The velocity of flow should be lowest in vessels with the largest total cross- sectional area (the capillaries) and highest in the vessels with the smallest total cross-sectional area (the aorta). Relationships Between Blood Flow, Pressure, and Resistance Blood flow through a blood vessel or a series of blood vessels is determined by two factors: the pressure dif- ference between the two ends of the vessel (the inlet and the outlet) and the resistance of the vessel to blood flow. The pressure difference is the driving force for blood flow, and the resistance is an impediment to flow. The relationship of flow, pressure, and resistance is analogous to the relationship of current (I), voltage (ΔV), and resistance (R) in electrical circuits, as expressed by Ohm’s law (Ohm’s law states that ΔV =Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 123 and the difference in pressure between the renal artery and the renal vein for ΔP. I × R or I = ΔV/R). Blood flow is analogous to current flow, the pressure difference or driving force is analo- gous to the voltage difference, and hydrodynamic resistance is analogous to electrical resistance. The equation for blood flow is expressed as follows: Q P R= ∆ where Q Flow mL/min P Pressure difference mm Hg R Resistance mm = = = ( ) ( ) ( ∆ Hg/mL per min) The magnitude of blood flow (Q) is directly propor- tional to the size of the pressure difference (ΔP) or pressure gradient. The direction of blood flow is deter- mined by the direction of the pressure gradient and always is from high to low pressure. For example, during ventricular ejection, blood flows from the left ventricle into the aorta and not in the other direction, because pressure in the ventricle is higher than pressure in the aorta. For another example, blood flows from the vena cava to the right atrium because pressure in the vena cava is slightly higher than in the right atrium. Furthermore, blood flow is inversely proportional to resistance (R). Increasing resistance (e.g., by arteriolar vasoconstriction) decreases flow, and decreasing resis- tance (e.g., by arteriolar vasodilation) increases flow. The major mechanism for changing blood flow in the cardiovascular system is by changing the resistance of blood vessels, particularly the arterioles. The flow, pressure, and resistance relationship also can be rearranged to determine resistance. If the blood flow and the pressure gradient are known, the resis- tance is calculated as R = ΔP/Q. This relationship can be applied to measure the resistance of the entire sys- temic vasculature (i.e., total peripheral resistance), or it can be used to measure resistance in a single organ or single blood vessel. ♦ Total peripheral resistance. The resistance of the entire systemic vasculature is called the total periph- eral resistance (TPR) or the systemic vascular resistance (SVR). TPR can be measured with the flow, pressure, and resistance relationship by substi- tuting cardiac output for flow (Q) and the difference in pressure between the aorta and the vena cava for ΔP. ♦ Resistance in a single organ. The flow, pressure, and resistance relationship also can be applied on a smaller scale to determine the resistance of a single organ. As illustrated in the following sample problem, the resistance of the renal vasculature can be deter- mined by substituting renal blood flow for flow (Q) SAMPLE PROBLEM. Renal blood flow is measured by placing a flow meter on a woman’s left renal artery. Simultaneously, pressure probes are inserted in her left renal artery and left renal vein to measure pressure. Renal blood flow measured by the flow meter is 500 mL/min. The pressure probes measure renal arterial pressure as 100 mm Hg and renal venous pressure as 10 mm Hg. What is the vascular resistance of the left kidney in this woman? SOLUTION. Blood flow to the left kidney, as mea- sured by the flow meter, is Q. The difference in pressure between the renal artery and renal vein is ΔP. The resistance to flow in the renal vascu- lature is calculated by rearranging the blood flow equation: Q P R= ∆ Rearranging and solving for R, R P Q Pressure in renal artery Pressure in renal vein / Re = = − ∆ ( ) nnal blood flow R mm Hg mm Hg mL per min mm Hg/ = − = ( )/100 10 500 90 5500 0 18 mL per min mm Hg/mL per min= . Resistance to Blood Flow The blood vessels and the blood itself constitute resis- tance to blood flow. The relationship between resis- tance, blood vessel diameter (or radius), and blood viscosity is described by the Poiseuille equation. The total resistance offered by a set of blood vessels also depends on whether the vessels are arranged in series (i.e., blood flows sequentially from one vessel to the next) or in parallel (i.e., the total blood flow is distrib- uted simultaneously among parallel vessels). Poiseuille Equation The factors that determine the resistance of a blood vessel to blood flow are expressed by the Poiseuille equation: R l r = 8 4 η π where R Resistance Viscosity of blood l Length of blood vessel r = = = η 4 == Radius of blood vessel raised to the fourth powerWww.Medicalstudyzone.com
124 • Physiology ♦ Series resistance is illustrated by the arrangement of blood vessels within a given organ. Each organ is supplied with blood by a major artery and drained by a major vein. Within the organ, blood flows from the major artery to smaller arteries, to arterioles, to capillaries, to venules, to veins. The total resistance of the system arranged in series is equal to the sum of the individual resistances, as shown in the following equation and in Figure 4.5. Of the various resistances in series, arteriolar resistance is by far the greatest. The total resistance of a vascular bed is determined, therefore, in large part by the arterio- lar resistance. Series resistance is expressed as follows: R R R R R Rtotal artery venules veinarterioles capillaries= + + + + When resistances are arranged in series, the total flow at each level of the system is the same. For example, blood flow through the aorta equals blood flow through all the large systemic arteries, equals blood flow through all the systemic arterioles, equals blood flow through all the systemic capillaries. For another example, blood flow through the renal artery equals blood flow through all the renal capillaries, equals blood flow through the renal vein (less a small volume lost in urine). Although total flow is constant at each level in the series, the pressure decreases progressively as blood flows through each sequential component (remember Q = ΔP/R or ΔP = Q × R). The greatest decrease in pressure occurs in the arterioles because they contribute the largest portion of the resistance. ♦ Parallel resistance is illustrated by the distribution of blood flow among the various major arteries branching off the aorta (see Figs. 4.1 and 4.5). Recall that the cardiac output flows through the aorta and then is distributed simultaneously, on a percentage basis, among the various organ systems. Thus there is parallel, simultaneous blood flow through each of the circulations (e.g., renal, cerebral, and coronary). The venous effluent from the organs then collects in the vena cava and returns to the heart. As shown in the following equation and in Figure 4.5, the total resistance in a parallel arrangement is less than any of the individual resistances. The subscripts 1, 2, 3, and so forth refer to the resistances of cerebral, coronary, renal, gastrointestinal, skeletal muscle, and skin circulations. Parallel resistance is expressed as follows: 1 1 1 1 1 1 1 1 2 3 4 5 6R R R R R R Rtotal = + + + + + When blood flow is distributed through a set of parallel resistances, the flow through each organ is The most important concepts expressed in the Poiseuille equation are as follows: First, resistance to flow is directly proportional to viscosity (η) of the blood; for example, as viscosity increases (e.g., if the hema- tocrit increases), the resistance to flow also increases. Second, resistance to flow is directly proportional to the length (l) of the blood vessel. Third, and most important, resistance to flow is inversely proportional to the fourth power of the radius (r4) of the blood vessel. This is a powerful relationship, indeed! When the radius of a blood vessel decreases, its resistance increases, not in a linear fashion but magnified by the fourth-power relationship. For example, if the radius of a blood vessel decreases by one-half, resistance does not simply increase twofold—it increases by 16-fold (24)! SAMPLE PROBLEM. A man suffers a stroke caused by partial occlusion of his left internal carotid artery. An evaluation of the carotid artery using magnetic resonance imaging (MRI) shows a 75% reduction in its radius. Assuming that blood flow through the left internal carotid artery was 400 mL/min prior to the occlusion, what is blood flow through the artery after the occlusion? SOLUTION. The variable in this example is the diameter (or radius) of the left internal carotid artery. Blood flow is inversely proportional to the resistance of the artery (Q = ΔP/R), and resistance is inversely proportional to the radius raised to the fourth power (Poiseuille equation). The internal carotid artery is occluded, and its radius is decreased by 75%. Another way of expressing this reduction is to say that the radius is decreased to one-fourth its original size. The first question is How much would resistance increase with 75% occlusion of the artery? The answer is found in the Poiseuille equation. After the occlusion, the radius of the artery is one-fourth its original radius; thus resistance has increased by 1/(1/4)4, or 256-fold. The second question is What would the flow be if resistance were to increase by 256-fold? The answer is found in the flow, pressure, resistance relationship (Q = ΔP/R). Because resistance increased by 256-fold, flow decreased to 1/256, or 0.0039, or 0.39% of the original value. The flow is 0.39% of 400 mL/min, or 1.56 mL/min. Clearly, this is a dramatic decrease in blood flow to the brain, all based on the fourth-power relationship b
4—Cardiovascular Physiology • 125 resistance becomes infinite. The total resistance of the parallel arrangement then increases to 3.333 (1/Rtotal = 1/10 + 1/10 + 1/10 + 1/∞). Laminar Flow and Reynolds Number Ideally, blood flow in the cardiovascular system is laminar, or streamlined. In laminar flow, there is a smooth parabolic profile of velocity within a blood vessel, with the velocity of blood flow highest in the center of the vessel and lowest toward the vessel walls (Fig. 4.6). The parabolic profile develops because the layer of blood next to the vessel wall adheres to the wall and, essentially, does not move. The next layer of blood (toward the center) slips past the motionless layer and moves a bit faster. Each successive layer of blood toward the center moves faster yet, with less adherence to adjacent layers. Thus the velocity of flow at the vessel wall is zero, and the velocity at the center of the stream is maximal. Laminar blood flow conforms to this orderly parabolic profile. When an irregularity occurs in a blood vessel (e.g., at the valves or at the site of a blood clot), a fraction of the total blood flow. The effects of this arrangement are that there is no loss of pressure in the major arteries and that mean pressure in each major artery will be the same and be approximately the same as mean pressure in the aorta. Another predictable consequence of a parallel arrangement is that adding a resistance to the circuit causes total resistance to decrease, not to increase. Mathematically, this can be demonstrated as follows: Four resistances, each with a numerical value of 10, are arranged in parallel. According to the equation, the total resistance is 2.5 (1/Rtotal = 1/10 + 1/10 + 1/10 + 1/10 = 4/10). If a fifth resistance with a value of 10 is added to the parallel arrangement, the total resistance decreases to 2 (1/Rtotal = 1/10 + 1/10 + 1/10 + 1/10 + 1/10 = 5/10). On the other hand, if the resistance of one of the individual vessels in a parallel arrangement increases, then total resistance increases. This can be shown by returning to the parallel arrangement of four blood vessels where each individual resistance is 10 and the total resistance is 2.5. If one of the four blood vessels is completely occluded, its individual Artery R1 Arteriole R2 Rtotal = R1 + R2 + R3 + R4 + R5 Capillary R3 Venule R4 Vein R5 SERIES RESISTANCES PARALLEL RESISTANCES Cerebral (R1) Coronary (R2) Renal (R3) Gastrointestinal (R4) Skeletal muscle (R5) Skin (R6) Aorta Vena cava Rtotal = R1 + R2 + R3 + R4 + R5 + R6 11 1 1 1 1 1 Fig. 4.5 Arrangements of blood vessels in series and in parallel. The arrows show the direction of blood flow. R, Resistance (subscripts refer to individual resistances).Www.Medicalstudyzone.com
126 • Physiology If Reynolds number (NR) is less than 2000, blood flow will be laminar. If Reynolds number is greater than 2000, there is increasing likelihood that blood flow will be turbulent. Values greater than 3000 always predict turbulent flow. The major influences on Reynolds number in the cardiovascular system are changes in blood viscosity and changes in the velocity of blood flow. Inspection of the equation shows that decreases in viscosity (e.g., decreased hematocrit) cause an increase in Reynolds number. Likewise, narrowing of a blood vessel, which produces an increase in velocity of blood flow, causes an increase in Reynolds number. The effect of narrowing a blood vessel (i.e., decreased diameter and radius) on Reynolds number is initially puzzling because, according to the equation, decreases in vessel diameter should decrease Reynolds number (diameter is in the numerator). Recall, however, that the velocity of blood flow also depends on diameter (radius), according to the earlier equation, v = Q/A or v = Q/πr2. Thus velocity (also in the numerator of the equation for Reynolds number) increases as radius decreases, raised to the second power. Hence, the dependence of Reynolds number on velocity is more powerful than the dependence on diameter. Two common clinical situations, anemia and thrombi, illustrate the application of Reynolds number in predicting turbulence. ♦ Anemia is associated with a decreased hematocrit (decreased mass of red blood cells) and, because of turbulent blood flow, causes functional murmurs. Reynolds number, the predictor of turbulence, is increased in anemia due to decreased blood viscos- ity. A second cause of increased Reynolds number in patients with anemia is a high cardiac output, which causes an increase in the velocity of blood flow (v = Q/A). ♦ Thrombi are blood clots in the lumen of a vessel. Thrombi narrow the diameter of the blood vessel, which causes an increase in blood velocity at the site of the thrombus, thereby increasing Reynolds number and producing turbulence. Shear Shear is a consequence of the fact that blood travels at different velocities within a blood vessel (see Fig. 4.6). Shear occurs if adjacent layers of blood travel at different velocities; when adjacent layers travel at the same velocity, there is no shear. Thus shear is highest at the blood vessel wall, according to the fol- lowing reasoning. Right at the wall, there is a motion- less layer of blood (i.e., velocity is zero); the adjacent layer of blood is moving and therefore has a velocity. The greatest relative difference in velocity of blood is the laminar stream is disrupted and blood flow may become turbulent. In turbulent flow (see Fig. 4.6), the fluid streams do not remain in the parabolic profile; instead, the streams mix radially and axially. Because kinetic energy is wasted in propelling blood radially and axially, more energy (pressure) is required to drive turbulent blood flow than laminar blood flow. Laminar flow is silent, while turbulent flow is audible. For example, the Korotkoff sounds used in the ausculta- tory measurement of blood pressure are caused by turbulent flow. Blood vessel stenosis (narrowing) and cardiac valve disease can cause turbulent flow and often are accompanied by audible vibrations called murmurs. The Reynolds number is a dimensionless number that is used to predict whether blood flow will be laminar or turbulent. It considers a number of factors including diameter of the blood vessel, mean velocity of flow, and viscosity of the blood. Thus N dv R = ρ η where N Reynolds number Density of blood d Diameter of blood ve R = = = ρ sssel v Velocity of blood flow Viscosity of blood = =η Zero velocity Highest velocityLaminar flow Turbulent flow Fig. 4.6 Comparison of laminar flow to turbulent blood flow. The length of the arrows shows the approximate velocity of blood flow. Laminar blood flow has a parabolic profile, with velocity lowest at the vessel wall and highest in the center of the stream. Turbulent blood flow exhibits axial and radial flow.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 127 For each type of blood vessel, volume is plotted as a function of pressure. The slope of each curve is the compliance. Compliance of the veins is high; in other words, the veins hold large volumes of blood at low pressure. Compliance of the arteries is much lower than that of the veins; the arteries hold much less blood than the veins, and they do so at high pressure. The difference in the compliance of the veins and the arteries underlies the concepts of unstressed volume and stressed volume. The veins are most compliant and contain the unstressed volume (large volume under low pressure). The arteries are much less compliant and contain the stressed volume (low volume under high pressure). The total volume of blood in the cardiovas- cular system is the sum of the unstressed volume plus the stressed volume (plus whatever volume is contained in the heart). Changes in compliance of the veins cause redistri- bution of blood between the veins and the arteries (i.e., the blood shifts between the unstressed and stressed volumes). For example, if the compliance or capaci- tance of the veins decreases (e.g., due to venoconstric- tion), there is a decrease in the volume the veins can hold and, consequently, a shift of blood from the veins to the arteries: unstressed volume decreases and stressed volume increases. If the compliance or capaci- tance of the veins increases, there is an increase in the volume the veins can hold and, consequently, a shift of blood from the arteries to the veins: unstressed volume increases and stressed volume decreases. Such redistributions of blood between the veins and arteries have consequences for arterial pressure, as discussed later in this chapter. Figure 4.7 also illustrates the effect of aging on compliance of the arteries. The characteristics of the arterial walls change with increasing age: The walls become stiffer, less distensible, and less compliant. At a given arterial pressure, the arteries can hold less blood. Another way to think of the decrease in compli- ance associated with aging is that in order for an “old artery” to hold the same volume as a “young artery,” the pressure in the “old artery” must be higher than the pressure in the “young artery.” Indeed, arterial pressures are increased in the elderly due to decreased arterial compliance. Pressures in the Cardiovascular System Blood pressures are not equal throughout the cardio- vascular system. If they were equal, blood would not flow, since flow requires a driving force (i.e., a pressure difference). The pressure differences that exist between the heart and blood vessels are the driving force for blood flow. Table 4.1 provides a summary of pressures in the systemic and pulmonary circulations. between the motionless layer of blood right at the wall and the next layer in. Shear is lowest at the center of the blood vessel, where the velocity of blood is highest but where the adjacent layers of blood are essentially moving at the same velocity. One consequence of shear is that it breaks up aggregates of red blood cells and decreases blood viscosity. Therefore at the wall, where shear rate is normally highest, red blood cell aggrega- tion and viscosity are lowest. Compliance of Blood Vessels The compliance or capacitance of a blood vessel describes the volume of blood the vessel can hold at a given pressure. Compliance is related to distensibility and is given by the following equation: C V P= where C Compliance or capacitance mL/mm Hg V Volume mL P Pressur = = = ( ) ( ) ee mm Hg( ) The equation for compliance states that the higher the compliance of a vessel, the more volume it can hold at a given pressure. Or, stated differently, compliance describes how the volume of blood contained in a vessel changes for a given change in pressure (ΔV/ΔP). Figure 4.7 illustrates the principle of compliance and shows the relative compliance of veins and arteries. Pressure Volume Vein Artery Artery (aging) C = highest C = low C = lowest Fig. 4.7 Capacitance of veins and arteries. Volume is plotted as a function of pressure. The slopes of the curves are capacitance (C).Www.Medicalstudyzone.com
128 • Physiology Pressure Profile in the Vasculature Figure 4.8 is a profile of pressures within the systemic vasculature. First, examine the smooth profile, ignoring the pulsations. The smooth curve gives mean pressure, which is highest in the aorta and large arteries and decreases progressively as blood flows from the arter- ies, to the arterioles, to the capillaries, to the veins, and back to the heart. This decrease in pressure occurs as blood flows through the vasculature because energy is consumed in overcoming the frictional resistances. Mean pressure in the aorta is high, averaging 100 mm Hg (see Table 4.1 and Fig. 4.8). This high mean arterial pressure is a result of two factors: the large volume of blood pumped from the left ventricle into the aorta (cardiac output) and the low compliance of the arterial wall. (Recall that a given volume causes greater pressure when compliance of the vessel is low.) The pressure remains high in the large arteries, which branch off the aorta, because of the high elastic recoil of the arterial walls. Thus little energy is lost as blood flows from the aorta through the arterial tree. Beginning in the small arteries, arterial pressure decreases, with the most significant decrease occurring in the arterioles. At the end of the arterioles, mean TABLE 4.1 Pressures in the Cardiovascular System Location Mean Pressure (mm Hg) Systemic Aorta 100 Large arteries 100 (systolic, 120; diastolic, 80) Arterioles 50 Capillaries 20 Vena cava 4 Right atrium 0–2 Pulmonary Pulmonary artery 15 (systolic, 25; diastolic, 8) Capillaries 10 Pulmonary vein 8 Left atriuma 2–5 aPressures on the left side of the heart are difficult to measure directly. However, left atrial pressure can be measured by the pulmonary wedge pressure. With this technique, a catheter is inserted into the pulmonary artery and advanced into a small branch of the pulmonary artery. The catheter wedges and blocks all blood flow from that branch. Once the flow is stopped, the catheter senses the pressure in the left atrium almost directly. Pressure (mm Hg) 120 20 0 40 60 80 100 Aorta Large arteries Small arteries Arterioles Capillaries Venules Veins Largest pressure drop Fig. 4.8 Pressure profile in the vasculature. The smooth curve is the mean pressure. Pulsa- tions, when present, are superimposed on the mean pressure.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 129 ♦ Systolic pressure is the highest arterial pressure measured during a cardiac cycle. It is the pressure in the arteries after blood has been ejected from the left ventricle during systole. The “blip” in the arterial pressure curve, called the dicrotic notch (or inci- sura), is produced when the aortic valve closes. Aortic valve closure produces a brief period of ret- rograde flow from the aorta back toward the valve, briefly decreasing the aortic pressure below the systolic value. ♦ Pulse pressure is the difference between systolic pressure and diastolic pressure. If all other factors are equal, the magnitude of the pulse pressure reflects the volume of blood ejected from the left ventricle on a single beat, or the stroke volume. Pulse pressure can be used as an indicator of stroke volume because of the relationships between pressure, volume, and compliance. Recall that com- pliance of a blood vessel is the volume the vessel can hold at a given pressure (C = V/P). Thus assum- ing that arterial compliance is constant, arterial pressure depends on the volume of blood the artery contains at any moment in time. For example, the volume of blood in the aorta at a given time is determined by the balance between inflow and outflow of blood. When the left ventricle contracts, it rapidly ejects a stroke volume into the aorta, and the pressure rises rapidly to its highest level, the systolic pressure. Blood then begins to flow from the aorta into the rest of the arterial tree. Now, as the volume in the aorta decreases, the pressure also pressure is approximately 30 mm Hg. This dramatic decrease in pressure occurs because the arterioles constitute a high resistance to flow. Since total blood flow is constant at all levels of the cardiovascular system, as resistance increases, downstream pressure must necessarily decrease (Q = ΔP/R, or ΔP = Q × R). In the capillaries, pressure decreases further for two reasons: frictional resistance to flow and filtration of fluid out of the capillaries (refer to the discussion on microcirculation). When blood reaches the venules and veins, pressure has decreased even further. (Recall that because capacitance of the veins is high, the veins can hold large volumes of blood at this low pressure.) Pressure in the vena cava is only 4 mm Hg and in the right atrium is even lower at 0–2 mm Hg. Arterial Pressure in the Systemic Circulation Further examination of Figure 4.8 reveals that although mean pressure in the arteries is high and constant, there are oscillations or pulsations of arterial pressure. These pulsations reflect the pulsatile activity of the heart: ejecting blood during systole, resting during diastole, ejecting blood, resting, and so forth. Each cycle of pulsation in the arteries coincides with one cardiac cycle. Figure 4.9 shows an expanded version of two such cycles of pulsations in a large artery. ♦ Diastolic pressure is the lowest arterial pressure measured during a cardiac cycle and is the pressure in the arteries during ventricular relaxation when no blood is being ejected from the left ventricle. Arterial pressure (mm Hg) Time Mean pressure Diastolic pressure Systolic pressure Pulse pressure 120 40 0 80 Fig. 4.9 Systemic arterial pressure during the cardiac cycle. Systolic pressure is the highest pressure measured during systole. Diastolic pressure is the lowest pressure measured during diastole. Pulse pressure is the difference between systolic pressure and diastolic pressure. (See the text for a discussion of mean arterial pressure.)Www.Medicalstudyzone.com
130 • Physiology more compliant the blood vessel, the more volume that can be added to it without causing an increase in pressure. Several pathologic conditions alter the arterial pres- sure curve in a predictable way (Fig. 4.10). As previ- ously noted, pulse pressure is the change in arterial pressure that occurs when a stroke volume is ejected from the left ventricle into the aorta. Logically, then, pulse pressure will change if stroke volume changes, or if the compliance of the arteries changes. ♦ Arteriosclerosis (see Fig. 4.10). In arteriosclerosis, plaque deposits in the arterial walls decrease the diameter of the arteries and make them stiffer and less compliant. Because arterial compliance is decreased, ejection of a stroke volume from the left ventricle causes a much greater change in arterial pressure than it does in normal arteries (C = ΔV/ΔP or ΔP = ΔV/C). Thus in arteriosclerosis, systolic pressure, pulse pressure, and mean pressure all will be increased. ♦ Aortic stenosis (see Fig. 4.10). If the aortic valve is stenosed (narrowed), the size of the opening through which blood can be ejected from the left ventricle into the aorta is reduced. Thus stroke volume is decreased, and less blood enters the aorta on each beat. Systolic pressure, pulse pressure, and mean pressure all will be decreased. ♦ Aortic regurgitation (not shown). When the aortic valve is incompetent (e.g., due to a congenital abnormality), the normal one-way flow of blood from the left ventricle into the aorta is disrupted. Instead, blood that was ejected into the aorta flows backward into the ventricle. Such retrograde flow can occur because the ventricle is relaxed (is at low pressure) and because the incompetent aortic valve cannot prevent it, as it normally does. Venous Pressures in the Systemic Circulation By the time blood reaches the venules and veins, pres- sure is less than 10 mm Hg; pressure will decrease even further in the vena cava and the right atrium. The reason for the continuing decrease in pressure is now familiar: The resistance provided by the blood vessels at each level of the systemic vasculature causes a fall in pressure. Table 4.1 and Figure 4.8 show the mean values for venous pressures in the systemic circulation. Pressures in the Pulmonary Circulation Table 4.1 also compares pressures in the pulmonary circulation with pressures in the systemic circulation. As the table shows, the entire pulmonary vasculature is at much lower pressure than the systemic vascula- ture. The pattern of pressures within the pulmonary decreases. Arterial pressure reaches its lowest level, the diastolic pressure, when the ventricle is relaxed and blood is returning from the arterial system back to the heart. ♦ Mean arterial pressure is the average pressure in a complete cardiac cycle and is calculated as follows: Mean arterial pressure Diastolic pressure Pulse pressure= + 1 3 Notice that mean arterial pressure is not the simple mathematical average of diastolic and systolic pressures. This is because a greater fraction of each cardiac cycle is spent in diastole than in systole. Thus the calculation of mean arterial pressure gives more weight to diastolic pressure than systolic pressure. Interestingly, the pulsations in large arteries are even greater than the pulsations in the aorta (see Fig. 4.8). In other words, systolic pressure and pulse pressure are higher in the large arteries than in the aorta. It is not immediately obvious why pulse pressure should increase in the “downstream” arteries. The explanation resides in the fact that, following ejection of blood from the left ventricle, the pressure wave travels at a higher velocity than the blood itself travels (due to the inertia of the blood), augmenting the downstream pressure. Furthermore, at branch points of arteries, pressure waves are reflected backward, which also tends to augment pressure at those sites. (Given that blood flows from the aorta to the large arteries, it may seem odd that systolic pressure and pulse pressure are higher in the downstream arteries. We know that the direction of blood flow must be from high to low pressure and not the other way around! The explana- tion is that the driving force for blood flow in the arteries is the mean arterial pressure, which is influ- enced more by diastolic pressure than by systolic pressure (because a greater proportion of each cardiac cycle is spent in diastole). Note in Figure 4.8 that while systolic pressure is higher in the large arteries than in the aorta, diastolic pressure is lower; thus mean arterial pressure is lower downstream.) Although systolic pressure and pulse pressure are augmented in the large arteries (compared with the aorta), from that point on, there is damping of the oscillations. The pulse pressure is still evident, but decreased, in the smaller arteries; it is virtually absent in the arterioles; and it is completely absent in the capillaries, venules, and veins. This damping and loss of pulse p
4—Cardiovascular Physiology • 131 Ultimately, the function of the heart is to pump blood through the vasculature. To serve as a pump, the ventricles must be electrically activated and then con- tract. In cardiac muscle, electrical activation is the cardiac action potential, which normally originates in the sinoatrial (SA) node. The action potentials initiated in the SA node then are conducted to the entire myo- cardium in a specific, timed sequence. Contraction follows, also in a specific sequence. “Sequence” is especially critical because the atria must be activated and contract before the ventricles, and the ventricles must contract from apex to base for efficient ejection of blood. Cardiac Action Potentials Origin and Spread of Excitation Within the Heart The heart consists of two kinds of muscle cells: con- tractile cells and conducting cells. Contractile cells constitute the majority of atrial and ventricular tissues and are the working cells of the heart. Action potentials in contractile cells lead to contraction and generation of force or pressure. Conducting cells constitute the tissues of the SA node, the atrial internodal tracts, the AV node, the bundle of His, and the Purkinje system. Conducting cells are specialized muscle cells that do not contribute significantly to generation of force; instead, they function to rapidly spread action potentials over the entire myocardium. Another feature of the specialized conducting tissues is their capacity circulation is analogous to the systemic circulation, however. Blood is ejected from the right ventricle into the pulmonary artery, where pressure is highest. There- after, the pressure decreases as blood flows through the pulmonary arteries, arterioles, capillaries, venules, and veins and back to the left atrium. An important implication of these lower pressures on the pulmonary side is that pulmonary vascular resistance is much lower than systemic vascular resistance. This conclusion can be reached by recalling that the total flow through the systemic and pulmonary circulations must be equal (i.e., cardiac output of the left and right hearts is equal). Because pressures on the pulmonary side are much lower than pressures on the systemic side, to achieve the same flow, pulmonary resistance must be lower than systemic resistance (Q = ΔP/R). (The pulmonary circulation is discussed in more detail in Chapter 5.) CARDIAC ELECTROPHYSIOLOGY Cardiac electrophysiology includes all of the processes involved in the electrical activation of the heart: the cardiac action potentials; the conduction of action potentials along specialized conducting tissues; excit- ability and the refractory periods; the modulating effects of the autonomic nervous system on heart rate, conduction velocity, and excitability; and the electro- cardiogram (ECG). Arterial pressure (mm Hg) Time 120 160 40 0 80 Normal Aortic stenosisArteriosclerosis Fig. 4.10 Effect of arteriosclerosis and aortic stenosis on arterial pressures.Www.Medicalstudyzone.com
132 • Physiology tissues. Slow conduction through the AV node ensures that the ventricles have sufficient time to fill with blood before they are activated and contract. Increases in conduction velocity of the AV node can lead to decreased ventricular filling and decreased stroke volume and cardiac output. 4. Bundle of His, Purkinje system, and ventricles. From the AV node, the action potential enters the specialized conducting system of the ventricles. The action potential is first conducted to the bundle of His through the common bundle. It then invades the left and right bundle branches and then the smaller bundles of the Purkinje system. Conduction through the His-Purkinje system is extremely fast, and it rapidly distributes the action potential to the ven- tricles. The action potential also spreads from one ventricular muscle cell to the next, via low-resistance pathways between the cells. Rapid conduction of the action potential throughout the ventricles is essential and allows for efficient contraction and ejection of blood. to generate action potentials spontaneously. Except for the SA node, however, this capacity normally is suppressed. Figure 4.11 is a schematic drawing showing the relationships of the SA node, atria, ventricles, and specialized conducting tissues. The action potential spreads throughout the myocardium in the following sequence: 1. SA node. Normally, the action potential of the heart is initiated in the specialized tissue of the SA node, which serves as the pacemaker. After the action potential is initiated in the SA node, there is a specific sequence and timing for the conduction of action potentials to the rest of the heart. 2. Atrial internodal tracts and atria. The action poten- tial spreads from the SA node to the right and left atria via the atrial internodal tracts. Simultaneously, the action potential is conducted to the AV node. 3. AV node. Conduction velocity through the AV node is considerably slower than in the other cardiac Sinoatrial node Atrioventricular node Bundle of His (common bundle) Right bundle branch Purkinje fibers Left bundle branchRight ventricle Left atrium Left ventricle Right atrium Fig. 4.11 Schematic diagram showing the sequence of activation of the myocardium. The cardiac action potential is initiated in the sinoatrial node and spreads throughout the myo- cardium, as shown by the arrows.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 133 the cell, which is called an inward current. Hyper- polarization means the membrane potential has become more negative, and it occurs when there is net movement of positive charge out of the cell, which is called an outward current. 7. Two basic mechanisms can produce a change in membrane potential. In one mechanism, there is a change in the electrochemical gradient for a per- meant ion, which changes the equilibrium potential for that ion. The permeant ion then will flow into or out of the cell in an attempt to reestablish electro- chemical equilibrium, and this current flow will alter the membrane potential. For example, consider the effect of decreasing the extracellular K+ concentra- tion on the resting membrane potential of a myocar- dial cell. The K+ equilibrium potential, calculated by the Nernst equation, will become more negative. K+ ions will then flow out of the cell and down the now larger electrochemical gradient, driving the resting membrane potential toward the new, more negative K+ equilibrium potential. In the other mechanism, there is a change in conductance to an ion. For example, the resting permeability of ventricular cells to Na+ is quite low, and Na+ contributes minimally to the resting mem- brane potential. However, during the upstroke of the ventricular action potential, Na+ conductance dra- matically increases, Na+ flows into the cell down its electrochemical gradient, and the membrane poten- tial is briefly driven toward the Na+ equilibrium potential (i.e., is depolarized). 8. Threshold potential is the potential difference at which there is a net inward current (i.e., inward current becomes greater than outward current). At threshold potential, the depolarization becomes self- sustained and gives rise to the upstroke of the action potential. Action Potentials of Ventricles, Atria, and the Purkinje System The ionic basis for the action potentials in the ventricles, atria, and Purkinje system is identical. The action potential in these tissues shares the following charac- teristics (Table 4.2): ♦ Long duration. In each of these tissues, the action potential is of long duration. Action potential duration varies from 150 ms in atria, to 250 ms in ventricles, to 300 ms in Purkinje fibers. These durations can be compared with the brief duration of the action potential in nerve and skeletal muscle (1–2 ms). Recall that the duration of the action potential also determines the duration of the refractory periods: The longer the action potential, the longer the cell is refractory to firing another action potential. Thus The term normal sinus rhythm has a specific meaning. It means that the pattern and timing of the electrical activation of the heart are normal. To qualify as normal sinus rhythm, the following three criteria must be met: (1) The action potential must originate in the SA node. (2) The SA nodal impulses must occur regularly at a rate of 60–100 impulses per minute. (3) The activation of the myocardium must occur in the correct sequence and with the correct timing and delays. Concepts Associated With Cardiac Action Potentials The concepts applied to cardiac action potentials are the same concepts that are applied to action potentials in nerve, skeletal muscle, and smooth muscle. The following section is a summary of those principles, which are discussed in Chapter 1: 1. The membrane potential of cardiac cells is deter- mined by the relative conductances (or permeabili- ties) to ions and the concentration gradients for the permeant ions. 2. If the cell membrane has a high conductance or permeability to an ion, that ion will flow down its electrochemical gradient and attempt to drive the membrane potential toward its equilibrium poten- tial (calculated by the Nernst equation). If the cell membrane has low conductance or permeability to an ion or is impermeable to the ion, that ion will make little or no contribution to the membrane potential. 3. By convention, membrane potential is expressed in millivolts (mV), and intracellular potential is expressed relative to extracellular potential; for example, a membrane potential of −85 mV means 85 mV, cell interior negative. 4. The resting membrane potential of cardiac cells is determined primarily by potassium ions (K+). The conductance to K+ at rest is high, and the resting membrane potential is close to the K+ equilibrium potential. Since the conductance to sodium (Na+) at rest is low, Na+ contributes little to the resting mem- brane potential. 5. The role of Na+-K+ ATPase is primarily to maintain Na+ and K+ concentration gradients across the cell membrane, although it makes a small direct electro- genic contribution to the membrane potential. 6. Changes in membrane potential are caused by the flow of ions into or out of the cell. For ion flow to occur, the cell membrane must be permeable to that ion. Depolarization means the membrane potential has become less negative. Depolarization occurs when there
134 • Physiology would look similar to that in the ventricular fiber, but its duration would be slightly longer. The phases of the action potential are described subsequently and cor- respond to the numbered phases shown in Figure 4.12A and B. The ventricular action potential has also been redrawn in Figure 4.13 to show the ionic currents responsible for each phase. Some of this information also is summarized in Table 4.2. 1. Phase 0, upstroke. In ventricular, atrial, and Pur- kinje fibers, the action potential begins with a phase of rapid depolarization, called the upstroke. As in nerve and skeletal muscle, the upstroke is caused by a transient increase in Na+ conductance (gNa), pro- duced by depolarization-induced opening of activa- tion gates on the Na+ channels. When gNa increases, there is an inward Na+ current (influx of Na+ into the cell), or INa, which drives the membrane potential toward the Na+ equilibrium potential of approxi- mately +65 mV. The membrane potential does not quite reach the Na+ equilibrium potential because, atrial, ventricular, and Purkinje cells have long refractory periods compared with other excitable tissues. ♦ Stable resting membrane potential. The cells of the atria, ventricles, and Purkinje system exhibit a stable, or constant, resting membrane potential. (AV nodal and Purkinje fibers can develop unstable resting membrane potentials, and under special conditions, they can become the heart’s pacemaker, as discussed in the section on latent pacemakers.) ♦ Plateau. The action potential in cells of the atria, ventricles, and Purkinje system is characterized by a plateau. The plateau is a sustained period of depolarization, which accounts for the long duration of the action potential and, consequently, the long refractory periods. Figure 4.12A and B illustrate the action potential in a ventricular muscle fiber and an atrial muscle fiber. An action potential in a Purkinje fiber (not shown) TABLE 4.2 Comparison of Action Potentials in Cardiac Tissues Cardiac Tissue Action Potential Duration (ms) Upstroke Plateau Phase 4 Depolarization Sinoatrial node 150 Inward Ca2+ current Ca2+ channels None Inward Na+ current (If) Normal pacemaker Atrium 150 Inward Na+ current Inward Ca2+ current (slow inward current) L-type Ca2+ channels None Ventricle 250 Inward Na+ current Inward Ca2+ current (slow inward current) L-type Ca2+ channels None Purkinje fibers 300 Inward Na+ current Inward Ca2+ current (slow inward current) L-type Ca2+ channels Latent pacemaker 0 1 2 3 4 0 1 2 3 4 0 3 4 Membrane potential (mV) Ventricle +20 –40 –60 –80 –100 –20 0 100 ms Atrium CARDIAC ACTION POTENTIALS 100 ms Sinoatrial node A B C 100 ms Fig. 4.12 Cardiac action potentials in the ventricle, atrium, and sinoatrial node. A–C, The numbers correspond to the phases of the action potentials.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 135 resting membrane potential is relatively depolarized (e.g., −60 mV), the inactivation gates on the Na+ channels tend to be closed and fewer Na+ channels are available to open during the upstroke. dV/dT also correlates with the size of the inward current (i.e., in ventricular, atrial, and Purkinje fibers, the size of the inward Na+ current). 2. Phase 1, initial repolarization. Phase 1 in ventricu- lar, atrial, and Purkinje fibers is a brief period of repolarization, which immediately follows the upstroke. Recall that, for repolarization to occur, there must be a net outward current. There are two explanations for the occurrence of the net outward current during phase 1. First, the inactivation gates on the Na+ channels close in response to depolariza- tion. When these gates close, gNa decreases and the inward Na+ current (which caused the upstroke) ceases. Second, there is an outward K+ current, caused by the large driving force on K+ ions: At the peak of the upstroke, both the chemical and the electrical driving forces favor K+ movement out of the cell (the intracellular K+ concentration is higher than extracellular K+ concentration, and the cell interior is electrically positive). Because the K+ as in nerve, the inactivation gates on the Na+ chan- nels close in response to depolarization (albeit more slowly than the activation gates open). Thus the Na+ channels open briefly and then close. At the peak of the upstroke, the membrane potential is depolarized to a value of about +20 mV. The rate of rise of the upstroke is called dV/dT. dV/dT is the rate of change of the membrane poten- tial as a function of time, and its units are volts per second (V/s). dV/dT varies, depending on the value of the resting membrane potential. This depen- dence is called the responsiveness relationship. Thus dV/dT is greatest (the rate of rise of the upstroke is fastest) when the resting membrane potential is most negative, or hyperpolarized (e.g., −90 mV), and dV/dT is lowest (the rate of rise of the upstroke is slowest) when the resting membrane potential is less negative, or depolarized (e.g., −60 mV). This correlation is based on the relation- ship between membrane potential and the position of the inactivation gates on the Na+ channel (see Chapter 1). When the resting membrane potential is relatively hyperpolarized (e.g., −90 mV), the voltage- dependent inactivation gates are open and many Na+ channels are available for the upstroke. When the Membrane potential (mV) +20 –40 –60 –80 –100 Current Na Ca Ca Na, Ca K K K K –20 0 EK ENa ECF ICF ECa 0 1 2 3 4 Fig. 4.13 Currents responsible for ventricular action potential. The length of the arrows shows the relative size of each ionic current. E, Equilibrium potential; ECF, extracellular fluid; ICF, intracellular fluid.Www.Medicalstudyzone.com
136 • Physiology 5. Phase 4, resting membrane potential, or electrical diastole. The membrane potential fully repolarizes during phase 3 and returns to the resting level of approximately −85 mV. During phase 4, the mem- brane potential is stable again, and inward and outward currents are equal. The resting membrane potential approaches, but does not fully reach, the K+ equilibrium potential, reflecting the high resting conductance to K+. The K+ channels, and the result- ing K+ current, responsible for phase 4 are different from those responsible for repolarization in phase 3. In phase 4, the K+ conductance is called gK1 and the K+ current is called, accordingly, IK1. The stable membrane potential in phase 4 means that inward and outward currents are equal. The high conductance to K+ produces an outward K+ current (IK1), which has already been described. The inward current that balances this outward current is carried by Na+ and Ca2+ (see Fig. 4.13), even though the conductances to Na+ and Ca2+ are low at rest. The question may arise: How can the sum of inward Na+ and Ca2+ currents be the same magnitude as the outward K+ current, given that gNa and gCa are very low and gK1 is very high? The answer lies in the fact that, for each ion, current = conductance × driving force. Although gK1 is high, the driving force on K+ is low because the resting membrane potential is close to the K+ equilibrium potential; thus the outward K+ current is relatively small. On the other hand, gNa and gCa are both low, but the driving forces on Na+ and Ca2+ are high because the resting mem- brane potential is far from the Na+ and Ca2+ equilib- rium potentials; thus the sum of the inward currents carried by Na+ and Ca2+ is equal to the outward current carried by K+. Action Potentials in the Sinoatrial Node The SA node is the normal pacemaker of the heart. The configuration and ionic basis for its action potential differ in several important aspects from those in atrial, ventricular, and Purkinje fibers (see Fig. 4.12C). The following features of the action potential of the SA node are different from those in atria, ventricles, and Purkinje fibers: (1) The SA node exhibits automaticity; that is, it can spontaneously generate action potentials without neural input. (2) It has an unstable resting membrane potential, in direct contrast to cells in atrial, ventricular, and Purkinje fibers. (3) It has no sustained plateau. The phases of the SA node action potential are described here and correspond to the numbered phases shown in Figure 4.12C. 1. Phase 0, upstroke. Phase 0 (as in the other cardiac cells) is the upstroke of the action potential. Note that the upstroke is not as rapid or as steep as in the other types of cardiac tissues. The ionic basis for the conductance (gK) is high, K+ flows out of the cell, down this steep electrochemical gradient. 3. Phase 2, plateau. During the plateau, there is a long period (150–200 ms) of relatively stable, depolar- ized membrane potential, particularly in ventricular and Purkinje fibers. (In atrial fibers, the plateau is shorter than in ventricular fibers.) Recall that for the membrane potential to be stable, inward and outward currents must be equal such that there is no net current flow across the membrane. How is such a balance of inward and outward currents achieved during the plateau? There is an increase in calcium (Ca2+) conductance (gCa), which results in an inward Ca2+ current. Inward Ca2+ current is also called slow inward current, reflect- ing the slower kinetics of these channels (compared with the fast Na+ channels of the upstroke). The Ca2+ channels that open during the plateau are L-type channels and are inhibited by the Ca2+ channel blockers nifedipine, diltiazem, and verapamil. To balance the inward Ca2+ current, there is an outward K+ current, driven by the electrochemical driving force on K+ ions (as described for phase 1). Thus during the plateau, the inward Ca2+ current is bal- anced by the outward K+ current, the net current is zero, and the membrane potential remains at a stable depolarized value. (See Fig. 4.13, where during phase 2, the inward Ca2+ current is shown as equal in magnitude to the outward K+ current.) The significance of the inward Ca2+ current extends beyond its effect on membrane potential. This Ca2+ entry during the plateau of the action potential initiates the release of more Ca2+ from intracellular stores for excitation-contraction cou- pling. This process of so-called Ca2+-induced Ca2+ release is discussed in the section on cardiac muscle contraction. 4. Phase 3, repolarization. Repolarization begins gradually at the end of phase 2, and then there is rapid repolarization to the resting membrane poten- tial during phase 3. Recall that repolarization is produced when outward currents are greater than inward currents. During phase 3, repolarization results from a combination of a decrease in gCa (previously increased during the plateau) and an increase in
4—Cardiovascular Physiology • 137 include the cells of the AV node, bundle of His, and Purkinje fibers. Although each of these cells has the potential for automaticity, it normally is not expressed. The rule is that the pacemaker with the fastest rate of phase 4 depolarization controls the heart rate. Nor- mally, the SA node has the fastest rate of phase 4 depolarization, and therefore it sets the heart rate (Table 4.3). Recall also that, of all myocardial cells, the SA nodal cells have the shortest action potential dura- tion (i.e., the shortest refractory periods). Therefore SA nodal cells recover faster and are ready to fire another action potential before the other cell types are ready. When the SA node drives the heart rate, the latent pacemakers are suppressed, a phenomenon called overdrive suppression, which is explained as follows: The SA node has the fastest firing rate of all the poten- tial pacemakers, and impulses spread from the SA node to the other myocardial tissues in the sequence illus- trated in Figure 4.11. Although some of these tissues are potential pacemakers themselves (AV node, bundle of His, Purkinje fibers), as long as their firing rate is driven by the SA node, their own capacity to spontane- ously depolarize is suppressed. The latent pacemakers have an opportunity to drive the heart rate only if the SA node is suppressed or if the intrinsic firing rate of a latent pacemaker becomes faster than that of the SA node. Since the intrinsic rate of the latent pacemakers is slower than that of the SA node, the heart will beat at the slower rate if it is driven by a latent pacemaker (see Table 4.3). Under the following conditions a latent pacemaker takes over and becomes the pacemaker of the heart, in which case it is called an ectopic pacemaker, or ectopic focus. (1) If the SA node firing rate decreases (e.g., due to vagal stimulation) or stops completely (e.g., because the SA node is destroyed, removed, or suppressed by drugs), then one of the latent sites will assume the role of pacemaker in the heart. (2) Or, if the intrinsic rate of firing of one of the latent pacemak- ers should become faster than that of the SA node, then it will assume the pacemaker role. (3) Or, if the conduc- tion of action potentials from the SA node to the rest of the heart is blocked because of disease in the upstroke in the SA node differs as well. In the other myocardial cells, the upstroke is the result of an increase in gNa and an inward Na+ current. In the SA nodal cells, the upstroke is the result of an increase in gCa and an inward Ca2+ current carried primarily by L-type Ca2+ channels. There are also T-type Ca2+ channels in SA node, which carry part of the inward Ca2+ current of the upstroke. 2. Phases 1 and 2 are absent. 3. Phase 3, repolarization. As in the other myocardial tissues, repolarization in the SA node is due to an increase in gK. Because the electrochemical driving forces on K+ are large (both chemical and electrical driving forces favor K+ leaving the cell), there is an outward K+ current, which repolarizes the membrane potential. 4. Phase 4, spontaneous depolarization or pacemaker potential. Phase 4 is the longest portion of the SA node action potential. This phase accounts for the automaticity of SA nodal cells (the ability to spon- taneously generate action potentials without neural input). During phase 4, the most negative value of the membrane potential (called the maximum dia- stolic potential) is approximately −65 mV, but the membrane potential does not remain at this value. Rather, there is a slow depolarization, produced by the opening of Na+ channels and an inward Na+ current called If. The “f,” which stands for funny, denotes that this Na+ current differs from the fast Na+ current responsible for the upstroke in ventricu- lar cells. If is turned on by repolarization from the preceding action potential, thus ensuring that each action potential in the SA node will be followed by another action potential. Once If and slow depolar- ization bring the membrane potential to threshold, the Ca2+ channels are opened for the upstroke. The rate of phase 4 depolarization is one deter- minant of heart rate. If the rate of phase 4 depolar- ization increases, threshold is reached more quickly, the SA node will fire more action potentials per time, and heart rate will increase. Conversely, if the rate of phase 4 depolarization decreases, threshold is reached more slowly, the SA node will fire fewer action potentials per time, and heart rate will decrease. The effects of the autonomic nervous system on heart rate are based on such changes in the rate of phase 4 depolarization and are discussed later in the chapter. Latent Pacemakers The cells in the SA node are not the only myocardial cells with intrinsic automaticity; other cells, called latent pacemakers, also have the capacity for sponta- neous phase 4 depolarization. Latent pacemakers TABLE 4.3 Firing Rate of Sinoatrial Node and Latent Pace
138 • Physiology early (i.e., before they have time to fill with blood from the atria). On the other hand, the rapid conduction velocity of the Purkinje fibers ensures that the ventricles can be activated quickly and in a smooth sequence for efficient ejection of blood. Mechanism of Propagation of Cardiac Action Potential As in nerve and skeletal muscle fibers, the physiologic basis for conduction of cardiac action potentials is the spread of local currents (see Chapter 1). Action poten- tials at one site generate local currents at adjacent sites; the adjacent sites are depolarized to threshold as a result of this local current flow and fire action potentials themselves. This local current flow is the result of the inward current of the upstroke of the action potential. Recall that, in atrial, ventricular, and Purkinje fibers, this inward current of the upstroke is carried by Na+, and in the SA node, the inward current of the upstroke is carried by Ca2+. Conduction velocity depends on the size of the inward current during the upstroke of the action potential. The larger the inward current, the more rapidly local currents will spread to adjacent sites and depolarize them to threshold. Conduction velocity also correlates with dV/dT, the rate of rise of the upstroke of the action potential, because dV/dT also correlates with the size of the inward current, as discussed previously. Propagation of the action potential depends not only on the inward current of the upstroke to establish local currents but also on the cable properties of the conducting pathways, then a latent pacemaker can appear in addition to the SA node. Conduction Velocity Conduction of the Cardiac Action Potential In the heart, conduction velocity has the same meaning that it has in nerve and skeletal muscle fibers: It is the speed at which action potentials are propagated within the tissue. The units for conduction velocity are meters per second (m/s). Conduction velocity is not the same in all myocardial tissues: It is slowest in the AV node (0.01–0.05 m/s) and fastest in the Purkinje fibers (2–4 m/s), as shown in Figure 4.14. Conduction velocity determines how long it takes the action potential to spread to various locations in the myocardium. These times, in milliseconds, are superimposed on the diagram in Figure 4.14. The action potential originates in the SA node at what is called time zero. It then takes a total of 220 ms for the action potential to spread through the atria, AV node, and His-Purkinje system to the farthest points in the ven- tricles. Conduction through the AV node (called AV delay) requires almost one-half of the total conduction time through the myocardium. The reason for the AV delay is that, of all the myocardial tissues, conduction velocity in the AV node is slowest (0.01–0.05 m/s), making conduction time the longest (100 ms). Differences in conduction velocity among the cardiac tissues have implications for their physiologic func- tions. For example, the slow conduction velocity of the AV node ensures that the ventricles do not activate too 220 200 170 160 190 90 50 60 190 210 50 0 70 170 Conduction Velocity Atria 1 m/s AV node 0.01–0.05 m/s His-Purkinje 2–4 m/s Ventricle 1 m/s Fig. 4.14 Timing of activation of the myocardium. The numbers superimposed on the myocardium indicate the cumulative time, in milliseconds, from the initiation of the action potential in the sinoatrial node. AV, Atrioventricular.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 139 which causes further depolarization toward the Na+ equilibrium potential. This rapid depolarization is the upstroke of the action potential. However, inactivation gates on the Na+ channels also close with depolariza- tion (although they close more slowly than the activa- tion gates open). Therefore during those phases of the action potential when the membrane potential is depolarized, a portion of the Na+ channels will be closed and unavailable because the inactivation gates are closed. When the Na+ channels are closed and unavailable, inward depolarizing current cannot flow through them, there can be no upstroke or action potential, and the cell is called refractory. Once repo- larization occurs, the inactivation gates on the Na+ channels open and now the Na+ channels will be in the closed, but available state; the cell will once again be excitable and ready to fire another action potential. Figure 4.15 is a familiar diagram showing an action potential in ventricular muscle, with the refractory periods now superimposed on it. The following refrac- tory periods reflect differences in excitability over the duration of the action potential: ♦ Absolute refractory period (ARP). For most of the duration of the action potential, the ventricular cell is completely refractory to fire another action poten- tial. No matter how large a stimulus (i.e., inward current) might be applied, the cell is incapable of generating a second action potential during the ARP, because most of the Na+ channels are closed and unavailable to carry inward current. The ARP myocardial fibers. Recall that these cable properties are determined by cell membrane resistance (Rm) and internal resistance (Ri). For example, in myocardial tissue, Ri is particularly low because of low-resistance connections between the cells called gap junctions. Thus myocardial tissue is especially well suited to fast conduction. Conduction velocity does not depend on action potential duration, a point that can be confusing. Recall, however, that action potential duration is simply the time it takes a given site to go from depolarization to complete repolarization (e.g., action potential dura- tion in a ventricular cell is 250 ms). Action potential duration implies nothing about how long it takes for that action potential to spread to neighboring sites. Excitability and Refractory Periods Excitability is the capacity of myocardial cells to gener- ate action potentials in response to inward, depolarizing current. Strictly speaking, excitability is the amount of inward current required to bring a myocardial cell to the threshold potential. The excitability of a myocardial cell varies over the course of the action potential, and these changes in excitability are reflected in the refrac- tory periods. The physiologic basis for the refractory periods in myocardial cells is similar to that in nerve cells. Recall from Chapter 1 that activation gates on Na+ channels open when the membrane potential is depolarized to threshold, permitting a rapid influx of Na+ into the cell, Membrane potential (mV) +20 –40 –60 –80 –100 –20 0 RRP SNP ARP ERP Fig. 4.15 Refractory periods of the ventricular action potential. The effective refractory period (ERP) includes the absolute refractory period (ARP) and the first half of the relative refrac- tory period (RRP). The RRP begins when the ARP ends and includes the last portion of the ERP. The supranormal period (SNP) begins when the RRP ends.Www.Medicalstudyzone.com
140 • Physiology to depolarize the cell to the threshold potential. The physiologic explanation for this increased excit- ability is that the Na+ channels are recovered (i.e., the inactivation gates are open again), and because the membrane potential is closer to threshold than it is at rest, it is easier to fire an action potential than when the cell membrane is at the resting membrane potential. Autonomic Effects on the Heart and Blood Vessels Table 4.4 summarizes the effects of the autonomic nervous system on the heart and blood vessels. For convenience, the autonomic effects on heart rate, conduction velocity, myocardial contractility, and vas- cular smooth muscle are combined into one table. The effects on cardiac electrophysiology (i.e., heart rate and conduction velocity) are discussed in this section, and the other autonomic effects are discussed in later sections. Autonomic Effects on Heart Rate The effects of the autonomic nervous system on heart rate are called chronotropic effects. The effects of the sympathetic and parasympathetic nervous systems on heart rate are summarized in Table 4.4 and are illus- trated in Figure 4.16. Briefly, sympathetic stimulation increases heart rate and parasympathetic stimulation decreases heart rate. Figure 4.16A shows the normal firing pattern of the SA node. Recall that phase 4 depolarization is produced includes the upstroke, the entire plateau, and a portion of the repolarization. This period concludes when the cell has repolarized to approximately −50 mV. ♦ Effective refractory period (ERP). The ERP includes, and is slightly longer than, the ARP. At the end of the ERP, the Na+ channels start to recover (i.e., become available to carry inward current). The distinction between the absolute and ERPs is that absolute means absolutely no stimulus is large enough to generate another action potential; effective means that a conducted action potential cannot be generated (i.e., there is not enough inward current to conduct to the next site). ♦ Relative refractory period (RRP). The RRP begins at the end of the ARP and continues until the cell membrane has almost fully repolarized. During the RRP, even more Na+ channels have recovered to the closed, but available state and it is possible to gener- ate a second action potential, although a greater- than-normal stimulus is required. If a second action potential is generated during the RRP, it will have an abnormal configuration and a shortened plateau phase. ♦ Supranormal period (SNP). The SNP follows the RRP. It begins when the membrane potential is −70 mV and continues until the membrane is fully repolarized back to −85 mV. As the name suggests, the cell is more excitable than normal during this period. In other words, less inward current is required TABLE 4.4 Effects of Autonomic Nervous System on the Heart and Blood Vessels Sympathetic Parasympathetic Action Receptor Mechanism Action Receptor Mechanism Heart rate ↑ β1 ↑ If ↑ ICa ↓ M2 ↓ If ↑ IK-ACh ↓ ICa Conduction velocity ↑ β1 ↑ ICa ↓ M2 ↓ ICa ↑ IK-ACh Contractility ↑ β1 ↑ ICa Phosphorylation of phospholamban ↓ (Atria only) M2 ↓ ICa ↑ IK-Ach Vascular smooth muscle (skin, renal, and splanchnic) Constriction α1 — Dilation (releases EDRF) M3 — Vascular smooth muscle (skeletal muscle) Dilation β2 — Dilation (releases EDRF) M3 — Constriction α1 — EDRF, Endothelial-derived relaxing factor; ICa, inward Ca2+ current; If, inward Na+ current; IK-ACh, outward K+ current; M, muscarinic.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 141 Chapter 2). Activation of β1 receptors in the SA node produces an increase in If, which increases the rate of phase 4 depolarization. In addition, there is an increase in ICa, which means there are more func- tional Ca2+ channels and thus less depolarization is required to reach threshold (i.e., threshold potential decreases). Increasing the rate of phase 4 depolariza- tion and decreasing the threshold potential means that the SA node is depolarized to threshold potential more frequently and, as a consequence, fires more action potentials per unit time (i.e., increased heart rate). by opening Na+ channels, which leads to a slow depo- larizing, inward Na+ current called If. Once the mem- brane potential is depolarized to the threshold potential, an action potential is initiated. ♦ Positive chronotropic effects are increases in heart rate. The most important example is that of stimula- tion of the sympathetic nervous system, as illus- trated in Figure 4.16B. Norepinephrine, released from sympathetic nerve fibers, activates β1 receptors in the SA node. These β1 receptors are coupled to adenylyl cyclase through a Gs protein (see also Membrane potential (mV)Membrane potential (mV)Membrane potential (mV) Normal +20 –40 –60 –80 –100 –20 0 Sympathetic stimulation +20 –40 –60 –80 –100 –20 0 Parasympathetic stimulation A B C +20 –40 –60 –80 –100 –20 0 Slow Faster Slower Fig. 4.16 Effect of sympathetic and parasympathetic stimulation on the sinoatrial (SA) node action potential. A, The normal firing pattern of the SA node is shown. B, Sympathetic stimulation increases the rate of phase 4 depolarization and increases the frequency of action potentials. C, Parasympathetic stimulation decreases the rate of phase 4 depolarization and hyperpolarizes the maximum diastolic potential to decrease the frequency of action potentials.Www.Medicalstudyzone.com
142 • Physiology the AV node (as it is in the SA node). Thus increased ICa means increased inward current and increased conduction velocity. In a supportive role, the in- creased ICa shortens the ERP so that the AV nodal cells recover earlier from inactivation and can conduct the increased firing rate. Stimulation of the parasympathetic nervous system produces a decrease in conduction velocity through the AV node (negative dromotropic effect), which decreases the rate at which action potentials are con- ducted from the atria to the ventricles. The mechanism of the parasympathetic effect is a combination of decreased ICa (decreased inward current) and increased IK-ACh (increased outward K+ current, which further reduces net inward current). Additionally, the ERP of AV nodal cells is prolonged. If conduction velocity through the AV node is slowed sufficiently (e.g., by increased parasympathetic activity or by damage to the AV node), some action potentials may not be conducted at all from the atria to the ventricles, producing heart block. The degree of heart block may vary: In the ♦ Negative chronotropic effects are decreases in heart rate. The most important example is that of stimula- tion of the parasympathetic nervous system, illustrated in Figure 4.16C. Acetylcholine (ACh), released from parasympathetic nerve fibers, activates muscarinic (M2) receptors in the SA node. Activa- tion of muscarinic receptors in the SA node has two effects that combine to produce a decrease in heart rate. First, these muscarinic receptors are coupled to a type of Gi protein called GK that inhibits adenylyl cyclase and produces a decrease in If. A decrease in If decreases the rate of phase 4 depolarization. Second, GK directly increases the conductance of a K+ channel called K+-ACh and increases an outward K+ current (similar to IK1) called IK-ACh. Enhancing this outward K+ current hyperpolarizes the maximum diastolic potential so that the SA nodal cells are further from threshold potential. In addition, there is a decrease in ICa, which means there are fewer functional Ca2+ channels and thus more depolariza- tion is required to reach threshold (i.e., threshold potential increases). In sum, the parasympathetic nervous system decreases heart rate through three effects on the SA node: (1) slowing the rate of phase 4 depolarization, (2) hyperpolarizing the maximum diastolic potential so that more inward current is required to reach threshold potential, and (3) increasing the threshold potential. As a result, the SA node is depolarized to threshold less frequently and fires fewer action potentials per unit time (i.e., decreased heart rate) (Box 4.1). Autonomic Effects on Conduction Velocity in the Atrioventricular Node The effects of the autonomic nervous system on con- duction velocity are called dromotropic effects. Increases in conduction velocity are called positive dromotropic effects, and decreases in conduction veloc- ity are called negative dromotropic effects. The most important physiologic effects of the autonomic nervous system on conduction velocity are those on the AV node, which, in effect, alter the rate at which action potentials are conducted from the atria to the ventricles. Recall, in considering the mechanism of these auto- nomic effects, that conduction velocity correlates with the size of the inward current of the upstroke of the action potential and the rate of rise of the upstroke, dV/dT. Stimulation of the sympathetic nervous system produces an increase in conduction velocity through the AV node (positive dromotropic effect), which increases the rate at which action potentials are con- ducted from the atria to the ventricles. The mechanism of the sympathetic effect is increased ICa, which is responsible for the upstroke of the action potential in BOX 4.1 Clinical Physiology: Sinus Bradycardia DESCRIPTION OF CASE. A 72-year-old woman with hypertension is being treated with propranolol, a β-adrenergic blocking agent. She has experienced several episodes of light-headedness and syncope (fainting). An ECG shows sinus bradycardia: normal, regular P waves, followed by normal QRS complexes; however, the frequency of P waves is decreased, at 45/min. The physician tapers off and eventually discontinues the propranolol and then changes the woman’s medication to a different class of antihy- pertensive drugs. Upon discontinuation of proprano- lol, a repeat ECG shows a normal sinus rhythm with a frequency of P waves of 80/min. EXPLANATION OF CASE. The heart rate is given by the frequency of P waves. During treatment with propranolol, her heart rate was only 45 beats/min. The presence of P waves on the ECG indicates that the heart is being activated in the SA node, which is the normal pacemaker. However, the frequency of depolarization of the SA node is much lower than normal because she is being treated with propranolol, a β-adrenergic blocking agent. Recall that β-adrenergic agonists increase the rate of phase 4 depol
4—Cardiovascular Physiology • 143 The configuration of a normal ECG is shown in Figure 4.17. The nomenclature of the ECG is as follows: The various waves represent depolarization or repolar- ization of different portions of the myocardium and are given lettered names. Intervals and segments between the waves also are named. The difference between intervals and segments is that intervals include the waves, and segments do not. The following waves, intervals, and segments are seen on the ECG: 1. P wave. The P wave represents depolarization of the atria. The duration of the P wave correlates with conduction time through the atria; for example, if conduction velocity through the atria decreases, the P wave will spread out. Atrial repolarization is not seen on a normal ECG because it is “buried” in the QRS complex. 2. PR interval. The PR interval is the time from initial depolarization of the atria to initial depolarization of the ventricles. Thus the PR interval includes the P wave and the PR segment, an isoelectric (flat) portion of the ECG that corresponds to AV node conduction. Because the PR interval includes the PR milder forms, conduction of action potentials from atria to ventricles is simply slowed; in more severe cases, action potentials may not be conducted to the ventricles at all. Electrocardiogram The electrocardiogram (ECG or EKG) is a measurement of tiny potential differences on the surface of the body that reflect the electrical activity of the heart. Briefly, these potential differences or voltages are measurable on the body’s surface because of the timing and sequence of depolarization and repolarization of the heart. Recall that the entire myocardium is not depolar- ized at once: The atria depolarize before the ventricles; the ventricles depolarize in a specific sequence; the atria repolarize while the ventricles are depolarizing; and the ventricles repolarize in a specific sequence. As a result of the sequence and the timing of the spread of depolarization and repolarization in the myocardium, potential differences are established between different portions of the heart, which can be detected by elec- trodes placed on the body surface. P Q R T PR interval ST segment QT interval S Fig. 4.17 The electrocardiogram measured from lead II.Www.Medicalstudyzone.com
144 • Physiology decreases), there is a decrease in the duration of the action potential. Not only will there be more action potentials per time, but those action potentials will have a shorter duration and shorter refractory periods. Because of the relationship between heart rate and refractory period, increases in heart rate may be a factor in producing arrhythmias (abnormal heart rhythms). As heart rate increases and refractory periods shorten, the myocardial cells are excitable earlier and more often. CARDIAC MUSCLE CONTRACTION Myocardial Cell Structure There are several morphologic and functional differ- ences between cardiac muscle and skeletal muscle, but the basic contractile machinery in the two cell types is similar. As in skeletal muscle, the cardiac muscle cell is composed of sarcomeres. The sarcomeres, which run from Z line to Z line, are composed of thick and thin filaments. The thick filaments are composed of myosin, whose globular heads have actin-binding sites and ATPase activity. The thin filaments are composed of three proteins: actin, tropomyosin, and troponin. Actin is a globular protein with a myosin-binding site, which, when polymerized, forms two twisted strands. Tropomyosin runs along the groove of the twisted actin strands and functions to block the myosin-binding site. Troponin is a globular protein composed of a complex of three subunits; the troponin C subunit binds Ca2+. When Ca2+ is bound to troponin C, a conformational change occurs, which removes the tropomyosin inhibi- tion of actin-myosin interaction. As in skeletal muscle, contraction occurs according to the sliding filament model, which states that when cross-bridges form between myosin and actin and then break, the thick and thin filaments move past each other. As a result of this cross-bridge cycling, the muscle fiber produces tension. The transverse (T) tubules invaginate cardiac muscle cells at the Z lines, are continuous with the cell membranes, and function to carry action poten- tials to the cell interior. The T tubules form dyads with the sarcoplasmic reticulum, which is the site of storage and release of Ca2+ for excitation-contraction coupling. Excitation-Contraction Coupling As in skeletal and smooth muscle, excitation-contraction coupling in cardiac muscle translates the action poten- tial into the production of tension. The following steps are involved in excitation-contraction coupling in cardiac muscle. These steps correlate with the circled numbers shown in Figure 4.18. segment, it also correlates with conduction time through the AV node. Normally, the PR interval is 160 ms, which is the cumulative time from first depolarization of the atria to first depolarization of the ventricles (see Fig. 4.14). Increases in conduction velocity through the AV node decrease the PR interval (e.g., due to sym- pathetic stimulation), and decreases in conduction velocity through the AV node increase the PR interval (e.g., due to parasympathetic stimulation). 3. QRS complex. The QRS complex consists of three waves: Q, R, and S. Collectively, these waves repre- sent depolarization of the ventricles. Note that the total duration of the QRS complex is similar to that of the P wave. This fact may seem surprising because the ventricles are so much larger than the atria; however, the ventricles depolarize just as quickly as the atria because conduction velocity in the His- Purkinje system is much faster than in the atrial conducting system. 4. T wave. The T wave represents repolarization of the ventricles. 5. QT interval. The QT interval includes the QRS complex, the ST segment, and the T wave. It repre- sents first ventricular depolarization to last ventricu- lar repolarization. The ST segment is an isoelectric portion of the QT interval that correlates with the plateau of the ventricular action potential. Heart rate is measured by counting the number of QRS complexes (or R waves because they are most prominent) per minute. Cycle length is the R-R inter- val (the time between one R wave and the next). Heart rate is related to cycle length as follows: Heart rate Cycle length= 1 SAMPLE PROBLEM. If the R-R interval is 800 ms (0.8 s), what is the heart rate? If the heart rate is 90 beats/min, what is the cycle length? SOLUTION. The R-R interval is the cycle length. If the cycle length is 0.8 s, then the heart rate = 1/cycle length or 1.25 beats/s or 75 beats/min (1 beat/0.8 s). If the heart rate is 90 beats/min, then the cycle length = 1/heart rate or 0.66 s or 660 ms. A longer cycle length signifies a slower heart rate, and a shorter cycle length signifies a faster heart rate. Changes in heart rate (and cycle length) change the duration of the action potential and, as a result, change the durations of the refractory periods and excitability. For example, if heart rate increases (and cycle lengthWww.Medicalstudyzone.com
4—Cardiovascular Physiology • 145 size of the inward Ca2+ current during the plateau of the action potential. 3 and 4. Ca2+ release from the sarcoplasmic reticulum causes the intracellular Ca2+ concentration to increase even further. Ca2+ now binds to troponin C, tropo- myosin is moved out of the way, and the interaction of actin and myosin can occur. Actin and myosin bind, cross-bridges form and then break, the thin and thick filaments move past each other, and tension is produced. Cross-bridge cycling, fueled by adenosine triphosphate (ATP), continues as long as intracellular Ca2+ concentration is high enough to occupy the Ca2+-binding sites on troponin C. 5. A critically important concept is that the magnitude of the tension developed by myocardial cells is pro- portional to the intracellular Ca2+ concentration. Therefore it is a logical extension of this concept that hormones, neurotransmitters, and drugs that alter the inward Ca2+ current during the action potential plateau or that alter sarcoplasmic reticulum Ca2+ stores would be expected to change the amount of tension produced by myocardial cells. Relaxation occurs when Ca2+ is reaccumulated in the sarcoplasmic reticulum by the action of the Ca2+ ATPase. In addition, Ca2+, which entered the cell during the plateau of the action potential, is extruded from the cell by Ca2+ ATPase and Ca2+-Na+ exchange in the sar- colemmal membrane; these sarcolemmal transporters pump Ca2+ out of the cell against its electrochemical gradient, with the Ca2+ ATPase using ATP directly and the Ca2+-Na+ exchanger using energy from the inward Na+ gradient. As a result of these transport processes, the intracellular Ca2+ concentration falls to resting levels, Ca2+ dissociates from troponin C, actin-myosin interaction is blocked, and relaxation occurs. Contractility Contractility, or inotropism, is the intrinsic ability of myocardial cells to develop force at a given muscle cell length. Agents that produce an increase in contractility are said to have positive inotropic effects. Positive inotropic agents increase both the rate of tension devel- opment and the peak tension. Agents that produce a decrease in contractility are said to have negative inotropic effects. Negative inotropic agents decrease both the rate of tension development and the peak tension. Mechanisms for Changing Contractility Contractility correlates directly with the intracellular Ca2+ concentration, which in turn depends on the amount of Ca2+ released from sarcoplasmic reticulum stores during excitation-contraction coupling. The 1. The cardiac action potential is initiated in the myo- cardial cell membrane, and the depolarization spreads to the interior of the cell via the T tubules. Recall that a unique feature of the cardiac action potential is its plateau (phase 2), which results from an increase in gCa and an inward Ca2+ current in which Ca2+ flows through L-type Ca2+ channels (dihydropyridine receptors) from extracellular fluid (ECF) to intracellular fluid (ICF). 2. Entry of Ca2+ into the myocardial cell produces an increase in intracellular Ca2+ concentration. This increase in intracellular Ca2+ concentration is not sufficient alone to initiate contraction, but it triggers the release of more Ca2+ from stores in the sarcoplas- mic reticulum through Ca2+ release channels (ryano- dine receptors). This process is called Ca2+-induced Ca2+ release, and the Ca2+ that enters during the plateau of the action potential is called the trigger Ca2+. Two factors determine how much Ca2+ is released from the sarcoplasmic reticulum in this step: the amount of Ca2+ previously stored and the Ca2+-induced Ca2+ release from SR Ca2+ binds to troponin C Ca2+ reaccumulated in SR Relaxation Cross-bridge cycling TENSION Ca2+ enters cell during plateau Cardiac action potential 5 4 2 1 3 Fig. 4.18 Excitation-contraction coupling in myocardial cells. See the text for an explanation of the circled numbers. SR, Sarcoplasmic reticulum.Www.Medicalstudyzone.com
146 • Physiology is mediated via muscarinic receptors, which are coupled via a Gi protein called GK to adenylyl cyclase. Because the G protein in this case is inhibitory, contractility is decreased (opposite of the effect of activation of β1 receptors by catecholamines). Two factors are responsible for the decrease in atrial contractility caused by parasympathetic stimulation. (1) ACh decreases inward Ca2+ current during the plateau of the action potential. (2) ACh increases IK-ACh, thereby shortening the duration of action potential and, indirectly, decreasing the inward Ca2+ current (by shortening the plateau phase). Together, these two effects decrease the amount of Ca2+ enter- ing atrial cells during the action potential, decrease the trigger Ca2+, and decrease the amount of Ca2+ released from the sarcoplasmic reticulum. Effect of Heart Rate on Contractility Perhaps surprisingly, changes in heart rate produce changes in contractility: When the heart rate increases, contractility increases; when the heart rate decreases, contractility decreases. The mechanism can be under- stood by recalling that contractility correlates directly with intracellular Ca2+ concentration during excitation- contraction coupling. For example, an increase in heart rate produces an increase in contractility, which can be explained as follows: (1) When heart rate increases, there are more action potentials per unit time and an increase in the total amount of trigger Ca2+ that enters the cell during the plateau phases of the action potentials. Furthermore, if the increase in heart rate is caused by sympathetic stimulation or by catecholamines, then the size of the inward Ca2+ current with each action potential also is increased. (2) Because there is greater influx of Ca2+ into the cell during the action potentials, the sarcoplasmic reticulum accumulates more Ca2+ for subsequent release (i.e., increased stored Ca2+). Again, if the increase in heart rate is caused by sym- pathetic stimulation, then phospholamban, which aug- ments Ca2+ uptake by the sarcoplasmic reticulum Ca2+ ATPase, will be phosphorylated, further increasing the uptake process. Two specific examples of the effect of heart rate on contractility, the positive staircase effect and postextrasystolic potentiation, are illustrated in Figure 4.19. ♦ Positive staircase effect. The positive staircase effect is also called the Bowditch staircase, or treppe (see Fig. 4.19A). When heart rate doubles, for example, the tension developed on each beat increases in a stepwise fashion to a maximal value. This increase in tension occurs because there are more action potentials per unit time, more total Ca2+ entering the cell during the plateau phases, and more Ca2+ for accumulation by the sarcoplasmic reticulum (i.e., amount of Ca2+ released from the sarcoplasmic reticu- lum depends on two factors: the size of the inward Ca2+ current during the plateau of the myocardial action potential (the size of the trigger Ca2+) and the amount of Ca2+ previously stored in the sarcoplasmic reticulum for release. Therefore the larger the inward Ca2+ current and the larger the intracellular stores, the greater the increase in intracellular Ca2+ concentration and the greater the contractility. Effects of the Autonomic Nervous System on Contractility The effects of the autonomic nervous system on con- tractility are summarized in Table 4.4. Of these effects, the most important is the positive inotropic effect of the sympathetic nervous system. ♦ Sympathetic nervous system. Stimulation of the sympathetic nervous system and circulating catechol- amines have a positive inotropic effect on the myocardium (i.e., increased contractility). This posi- tive inotropic effect has three important features: increased peak tension, increased rate of tension development, and faster rate of relaxation. Faster relaxation means that the contraction (twitch) is shorter, allowing more time for refilling. This effect, like the sympathetic effect on heart rate, is mediated via activation of β1 receptors, which are coupled via a Gs protein to adenylyl cyclase. Activation of adeny- lyl cyclase leads to the production of cyclic adenosine monophosphate (cAMP), activation of protein kinase A, and phosphorylation of proteins that produce the physiologic effect of increased contractility. Two different proteins are phosphorylated to produce the increase in contractility. The coordi- nated actions of these phosphorylated proteins then produce an increase in intracellular Ca2+ concentra- tion. (1) There is phosphorylation of the sarcolemmal Ca2+ channels that carry inward Ca2+ current during the plateau of the action potential. As a result, there is increased inward Ca2+ current during the plateau and increased trigger Ca2+, which increases the amount of Ca2+ released from the sarcoplasmic reticulum. (2) There is phosphorylation of phos- pholamban, a protein that regulates Ca2+ ATPase in the sarcoplasmic reticulum. When phosphoryl
4—Cardiovascular Physiology • 147 2. When the Na+-K+ ATPase is inhibited, less Na+ is pumped out of the cell, increasing the intracellular Na+ concentration. 3. The increase in intracellular Na+ concentration alters the Na+ gradient across the myocardial cell mem- brane, thereby altering the function of a Ca2+-Na+ exchanger. This exchanger pumps Ca2+ out of the cell against an electrochemical gradient in exchange for Na+ moving into the cell down an electrochemi- cal gradient. (Recall that Ca2+-Na+ exchange is one of the mechanisms that extrudes the Ca2+ that entered the cell during the plateau of the myocardial cell action potential.) The energy for pumping Ca2+ uphill comes from the downhill Na+ gradient, which is normally maintained by the Na+-K+ ATPase. When the intracellular Na+ concentration increases, the inwardly directed Na+ gradient decreases. As a result, Ca2+-Na+ exchange decreases because it depends on the Na+ gradient for its energy source. 4. As less Ca2+ is pumped out of the cell by the Ca2+- Na+ exchanger, the intracellular Ca2+ concentration increases. 5. Since tension is directly proportional to the intracel- lular Ca2+ concentration, cardiac glycosides produce an increase in tension by increasing intracellular Ca2+ concentration—a positive inotropic effect. The major therapeutic use of cardiac glycosides is in the treatment of congestive heart failure, a condition characterized by decreased contractility of ventricular muscle (i.e., negative inotropism). When the failure occurs on the left side of the heart, the left ventricle is unable to develop normal tension when it contracts and is unable to eject a normal stroke volume into the aorta. When the failure occurs on the right side of the heart, the right ventricle is unable to develop normal tension more stored Ca2+). Notice that the very first beat after the increase in heart rate shows no increase in tension because extra Ca2+ has not yet accumulated. On subsequent beats, the effect of the extra accumu- lation of Ca2+ by the sarcoplasmic reticulum becomes evident. Tension rises stepwise, like a staircase: With each beat, more Ca2+ is accumulated by the sarco- plasmic reticulum, until a maximum storage level is achieved. ♦ Postextrasystolic potentiation. When an extrasys- tole occurs (an anomalous “extra” beat generated by a latent pacemaker), the tension developed on the next beat is greater than normal (see Fig. 4.19B). Although the tension developed on the extrasystolic beat itself is less than normal, the very next beat exhibits increased tension. An unexpected or “extra” amount of Ca2+ entered the cell during the extrasys- tole and was accumulated by the sarcoplasmic reticulum (i.e., increased stored Ca2+). Effect of Cardiac Glycosides on Contractility Cardiac glycosides are a class of drugs that act as posi- tive inotropic agents. These drugs are derived from extracts of the foxglove plant, Digitalis purpurea. The prototype drug is digoxin; other drugs in this class include digitoxin and ouabain. The well-known action of the cardiac glycosides is inhibition of Na+-K+ ATPase. In the myocardium, inhibi- tion of Na+-K+ ATPase underlies the positive inotropic effect of the cardiac glycosides, as explained in Figure 4.20. The circled numbers in the figure correlate with the following steps: 1. The Na+-K+ ATPase is located in the cell membrane of the myocardial cell. Cardiac glycosides inhibit Na+-K+ ATPase at the extracellular K+-binding site. Tension Positive staircase Time Tension Extrasystole Postextrasystole Postextrasystolic potentiation A B Time Fig. 4.19 Examples of the effect of heart rate on contractility. A, Positive staircase; B, postextrasystolic potentiation. Tension is used as a measure of contractility. The frequency of the bars shows the heart rate, and the height of the bars shows the tension produced on each beat.Www.Medicalstudyzone.com
148 • Physiology ventricle. The length of a single left ventricular muscle fiber just prior to contraction corresponds to left ven- tricular end-diastolic volume. The tension of a single left ventricular muscle fiber corresponds to the tension or pressure developed by the entire left ventricle. When these substitutions are made, a curve can be developed that shows ventricular pressure during systole as a function of ventricular end-diastolic volume (Fig. 4.21). and is unable to eject a normal stroke volume into the pulmonary artery. Either situation is serious and potentially life-threatening. By increasing the intracel- lular Ca2+ concentration of the ventricular cells, cardiac glycosides have a positive inotropic action, which may counteract the negative inotropism of the failed ventricle. Length-Tension Relationship in Cardiac Muscle Just as in skeletal muscle, the maximal tension that can be developed by a myocardial cell depends on its resting length. Recall that the physiologic basis for the length-tension relationship is the degree of overlap of thick and thin filaments and the number of possible sites for actin-myosin interaction and cross-bridge for- mation. (The intracellular Ca2+ concentration then determines what fraction of these possible cross-bridges will actually form and cycle.) In myocardial cells, maximal tension development occurs at cell lengths of about 2.2 μm, or Lmax. At this length, there is maximal overlap of thick and thin filaments; at either shorter or longer cell lengths, the tension developed will be less than maximal. In addition to the degree of overlap of thick and thin filaments, there are two additional length-dependent mechanisms in cardiac muscle that alter the tension developed: Increasing muscle length increases the Ca2+ sensitivity of troponin C, and increas- ing muscle length increases Ca2+ release from the sar- coplasmic reticulum. The length-tension relationship for single myocardial cells can be extended to a length-tension relationship for the ventricles. For example, consider the left ATPATPATP [Na+] Positive inotropic effect POSITIVE INOTROPIC EFFECT OF CARDIAC GLYCOSIDES [Ca2+] Ca2+ 3Na+2K+ Cardiac glycosides 3Na+ 1 3 2 4 5 Fig. 4.20 Mechanism of the positive inotropic effect of cardiac glycosides. See the text for an explanation of the circled numbers. ATP, Adenosine triphosphate. Ventricular end-diastolic volume Ventricular pressure Systole Diastole Fig. 4.21 Systolic and diastolic left ventricular pressure- volume curves. The systolic curve shows active pressure as a function of end-diastolic volume (fiber length). The diastolic curve shows passive pressure as a function of end-diastolic volume.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 149 Stroke Volume, Ejection Fraction, and Cardiac Output The function of the ventricles is described by the fol- lowing three parameters: (1) Stroke volume is the volume of blood ejected by the ventricle on each beat; (2) Ejection fraction is the fraction of the end-diastolic volume ejected in each stroke volume, which is a measure of ventricular efficiency; and (3) Cardiac output is the total volume ejected by the ventricle per unit time. Stroke Volume The volume of blood ejected on one ventricular con- traction is the stroke volume. Stroke volume is the difference between the volume of blood in the ventricle before ejection (end-diastolic volume) and the volume remaining in the ventricle after ejection (end-systolic volume). Typically, stroke volume is about 70 mL. Thus Stroke volume End-diastolic volume End-systolic volume= − where Stroke volume Volume ejected on one beat mL End-diastolic v = ( ) oolume Volume in the ventricle before ejection mL End-systo = ( ) llic volume Volume in the ventricle after ejection mL = ( ) Ejection Fraction The effectiveness of the ventricles in ejecting blood is described by the ejection fraction, which is the fraction of the end-diastolic volume that is ejected in one stroke volume. Normally, ejection fraction is approximately 0.55, or 55%. The ejection fraction is an indicator of contractility, with increases in ejection fraction reflect- ing an increase in contractility and decreases in ejection fraction reflecting a decrease in contractility. Thus Ejection fraction Stroke volume End-diastolic volume = Cardiac Output The total volume of blood ejected per unit time is the cardiac output. Thus cardiac output depends on the volume ejected on a single beat (stroke volume) and the number of beats per minute (heart rate). Cardiac output is approximately 5000 mL/min in a 70-kg man (based on a stroke volume of 70 mL and a heart rate of 72 beats/min). Thus The upper curve is the relationship between ven- tricular pressure developed during systole and end- diastolic volume (or end-diastolic fiber length). This pressure development is an active mechanism. On the ascending limb of the curve, pressure increases steeply as fiber length increases, reflecting greater degrees of overlap of thick and thin filaments, greater cross-bridge formation and cycling, and greater tension developed. The curve eventually levels off when overlap is maximal. If end-diastolic volume were to increase further and the fibers were stretched to even longer lengths, overlap would decrease and the pres- sure would decrease (descending limb of the curve). In contrast to skeletal muscle, which operates over the entire length-tension curve (see Chapter 1, Fig. 1.27), cardiac muscle normally operates only on the ascend- ing limb of the curve. The reason for this difference is that cardiac muscle is much stiffer than skeletal muscle. Thus cardiac muscle has high resting tension, and small increases in length produce large increases in resting tension. For this reason, cardiac muscle is “held” on the ascending limb of its length-tension curve, and it is difficult to lengthen cardiac muscle fibers beyond Lmax. For example, the “working length” of cardiac muscle fibers (the length at the end of diastole) is 1.9 μm (<Lmax, which is 2.2 μm). This systolic pressure-volume (i.e., length-tension) relationship for the ventricle is the basis for the Frank-Starling relationship in the heart. The lower curve is the relationship between ventricular pressure and ventricular volume during diastole, when the heart is not contracting. As end- diastolic volume increases, ventricular pressure in- creases through passive mechanisms. The increasing pressure in the ventricle reflects the increasing tension of the muscle fibers as they are stretched to longer lengths. The terms “preload” and “afterload” can be applied to cardiac muscle just as they are applied to skeletal muscle. ♦ The preload for the left ventricle is left ventricular end-diastolic volume, or end-diastolic fiber length; that is, preload is the resting length from which the muscle contracts. The relationship between preload and developed tension or pressure, illustrated in the upper (systolic) curve in Figure 4.21, is based on the degree of overlap of thick and thin filaments. ♦ The afterload for the left ventricle is aortic pres- sure. The velocity of shortening of cardiac muscle is maximal when afterload is zero, and velocity of shortening decreases as afterload increases. (The relationship between the ventricular pressure devel- oped and aortic pressure or afterload is discussed more fully in the section on ventricular pressure- volume loops.)Www.Medicalstudyzone.com
150 • Physiology returned to the heart, or the venous return. Therefore stroke volume and cardiac output correlate directly with end-diastolic volume, which correlates with venous return. The Frank-Starling relationship governs normal ventricular function and ensures that the volume the heart ejects in systole equals the volume it receives in venous return. Recall from a previous discus- sion that, in the steady state, cardiac output equals venous return. It is the Frank-Starling law of the heart that underlies and ensures this equality. The Frank-Starling relationship is illustrated in Figure 4.22. Cardiac output and stroke volume are plotted as a function of ventricular end-diastolic volume or right atrial pressure. (Right atrial pressure may be substituted for end-diastolic volume because both parameters are related to venous return.) There is a curvilinear relationship between stroke volume or cardiac output and ventricular end-diastolic volume. As venous return increases, end-diastolic volume increases, and because of the length-tension relationship in the ventricles, stroke volume increases accordingly. In the physiologic range, the relationship between stroke volume and end-diastolic volume is nearly linear. Only when end-diastolic volume becomes high does the curve start to bend: At these high levels, the ventricle reaches a limit and simply is not able to “keep up” with venous return. Also illustrated in Figure 4.22 are the effects of changing contractility on the Frank-Starling relation- ship. Agents that increase contractility have a positive inotropic effect (uppermost curve). Positive inotropic agents (e.g., digoxin) produce increases in stroke volume and cardiac output for a given end-diastolic volume. The result is that a larger fraction of the end- diastolic volume is ejected per beat and there is an increase in ejection fraction. Agents that decrease contractility have a negative inotropic effect (lowermost curve). Negative inotropic agents produce decreases in stroke volume and cardiac output for a given end-diastolic volume. The result is that a smaller fraction of the end-diastolic volume is ejected per beat and there is a decrease in ejection fraction. Ventricular Pressure-Volume Loops Normal Ventricular Pressure-Volume Loop The function of the left ventricle can be observed over an entire cardiac cycle (diastole plus systole) by com- bining the two pressure-volume relationships from Figure 4.21. By connecting these two pressure-volume curves, it is possible to construct a so-called ventricular pressure-volume loop (Fig. 4.23). Recall that the sys- tolic pressure-volume relationship in Figure 4.21 shows the maximum developed ventricular pressure for a given ventricular volume. To facilitate understanding, a portion of that systolic pressure-volume curve is Cardiac output Stroke volume Heart rate= × where Cardiac output Volume ejected per minute mL/min Stroke vol = ( ) uume Volume ejected in one beat mL Heart rate Beats per mi = = ( ) nnute beats/min( ) SAMPLE PROBLEM. A man has an end-diastolic volume of 140 mL, an end-systolic volume of 70 mL, and a heart rate of 75 beats/min. What are his stroke volume, his cardiac output, and his ejection fraction? SOLUTION. These calculations are basic and important. The stroke volume is the volume ejected from the ventricle on a single beat; therefore it is the difference between the volume in the ventricle before and after it contracts. Cardiac output is stroke volume multiplied by heart rate. The ejection frac- tion is the efficiency of the ventricle in ejecting blood, and it is the stroke volume divided by the end-diastolic volume. Stroke volume End-diastolic volume End-systolic volume = − = 140 mmL mL mL − = 70 70 Cardiac output Stroke volume Heart rate mL beats/min = × = × = 70 70 52250 mL/min Ejection fraction Stroke volume/End-diastolic volume mL/ = = 70 1140 0 50mL = . Frank-Starling Relationship The length-tension relationship for ventricular systole has already been described. This relationship now can be understood, using the parameters of stroke volume, ejection fraction, and cardiac output. The German physiologist Otto Frank first described the relationship between the pressure developed during systole in a frog ventricle and the volume present in the ventricle just prior to systole. Building on Frank’s observations, the British physiologist Ernest Starling demonstrated, in an isolated dog heart, that the volume the ventricle ejected in systole was determined by the end-diastolic volume. Recall that the principle underly- ing this relationship is the length-tension relationship in cardiac muscle fibers. The Frank-Starling law of the heart, or the Frank- Starling relationship, is based on these landmark experiments. It states that the volume of blood ejected by the ventricle depends on the volume present in the ventricle at the end of diastole. The volume present at the end of diastole, in turn, depends on the volumeWww.Medicalstudyzone
4—Cardiovascular Physiology • 151 superimposed as a dashed line on the ventricular pressure-volume loop. The dashed line shows the maximum possible pressure that can be developed for a given ventricular volume during systole (i.e., when the ventricle is contracting). Note that point 3 on the pressure-volume loop touches the systolic pressure- volume curve (dashed line). Also, it may not be evident that the portion of the loop between points 4 and 1 corresponds to a portion of the diastolic pressure- volume curve from Figure 4.21. The ventricular pressure-volume loop describes one complete cycle of ventricular contraction, ejection, relaxation, and refilling as follows: ♦ Isovolumetric contraction (1 → 2). Begin the cycle at point 1, which marks the end of diastole. The left ventricle has filled with blood from the left atrium, and its volume is the end-diastolic volume, 140 mL. The corresponding pressure is quite low because the ventricular muscle is relaxed. At this point, the ventricle is activated, it contracts, and ventricular pressure increases dramatically. Because all valves are closed, no blood can be ejected from the left Ventricular end-diastolic volume or right atrial pressure Cardiac output or stroke volume Positive inotropic effect Control Negative inotropic effect Fig. 4.22 Frank-Starling relationship in the heart. The effects of positive and negative inotropic agents are shown with respect to the normal Frank-Starling relationship. 1 2 3 4 Left ventricular volume (mL) Left ventricular pressure (mm Hg) 500 100 150 0 75 150 Fig. 4.23 Left ventricular pressure-volume loop. One complete left ventricular cycle is shown. (Refer to the text for a complete explanation.) The dashed line shows a portion of the systolic pressure-volume curve from Figure 4.21.Www.Medicalstudyzone.com
152 • Physiology open. The left ventricle fills with blood from the left atrium passively and also actively, as a result of atrial contraction in the next cycle. Left ventricular volume increases back to the end-diastolic volume of 140 mL. During this last phase, the ventricular muscle is relaxed, and pressure increases only slightly as the compliant ventricle fills with blood. Changes in Ventricular Pressure-Volume Loops Ventricular pressure-volume loops can be used to visualize the effects of changes in preload (i.e., changes in venous return or end-diastolic volume), changes in afterload (i.e., changes in aortic pressure), or changes in contractility (Fig. 4.24). The solid lines depict a single, normal ventricular cycle and are identical to the pressure-volume loop shown in Figure 4.23. The dashed lines demonstrate the effects of various changes on a single ventricular cycle (but they do not include any compensatory responses that may occur later). ♦ Figure 4.24A illustrates the effect of increased preload on the ventricular cycle. Recall that preload is end-diastolic volume. In this example, preload is increased because venous return is increased, which increases end-diastolic volume (point 1). Afterload and contractility remain constant. As the ventricle proceeds through its cycle of contraction, ejection, relaxation, and refilling, the effect of this increase in preload can be appreciated: Stroke volume, as mea- sured by the width of the pressure-volume loop, increases. This increase in stroke volume is based on the Frank-Starling relationship, which states that the greater the end-diastolic volume (end-diastolic fiber length), the greater the stroke volume ejected in systole. ♦ Figure 4.24B illustrates the effect of increased after- load or increased aortic pressure on the ventricular ventricle, and ventricular volume is constant, although ventricular pressure becomes quite high (point 2). Thus this phase of the cycle is called isovolumetric contraction. ♦ Ventricular ejection (2 → 3). At point 2, left ven- tricular pressure becomes higher than aortic pres- sure, causing the aortic valve to open. (You may wonder why the pressure at point 2 does not reach the systolic pressure-volume curve shown by the dashed gold line. The simple reason is that it does not have to. The pressure at point 2 is determined by aortic pressure. Once ventricular pressure reaches the value of aortic pressure, the aortic valve opens and the rest of the contraction is used for ejection of the stroke volume through the open aortic valve.) Once the valve is open, blood is rapidly ejected, driven by the pressure gradient between the left ventricle and the aorta. During this phase, left ven- tricular pressure remains high because the ventricle is still contracting. Ventricular volume decreases dramatically, however, as blood is ejected into the aorta. The volume remaining in the ventricle at point 3 is the end-systolic volume, 70 mL. The width of the pressure-volume loop is the volume of blood ejected, or the stroke volume. The stroke volume in this ventricular cycle is 70 mL (140 mL − 70 mL). ♦ Isovolumetric relaxation (3 → 4). At point 3, systole ends and the ventricle relaxes. Ventricular pressure decreases below aortic pressure and the aortic valve closes. Although ventricular pressure decreases rapidly during this phase, ventricular volume remains constant (isovolumetric) at the end-systolic value of 70 mL because all valves are closed again. ♦ Ventricular filling (4 → 1). At point 4, ventricular pressure has fallen to a level that now is less than left atrial pressure, causing the mitral (AV) valve to 1 2 3 4 1 2 3 4 1 2 3 4 Increased preload Increased afterload Increased contractility A B CLeft ventricular volume Left ventricular volume Left ventricular volume Left ventricular pressure Fig. 4.24 Changes in the left ventricular pressure-volume loop. A, Increased preload; B, increased afterload; C, increased contractility. The normal ventricular cycle is shown by the solid lines, and the effect of the change is shown by the dashed lines.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 153 work contributes a small percentage. These observa- tions explain why overall myocardial O2 consumption correlates poorly with cardiac output: The largest per- centage of the O2 consumption is for pressure work (internal work or heat), which is not cardiac output. It can be further concluded that, in conditions where a larger-than-normal percentage of the total cardiac work is pressure work, the cost in terms of O2 con- sumption increases. For example, in aortic stenosis, myocardial O2 consumption is greatly increased because the left ventricle must develop extremely high pressures to pump blood through the stenosed aortic valve (even though cardiac output actually is reduced). On the other hand, during strenuous exercise when cardiac output becomes very high, volume work con- tributes a greater-than-normal percentage of the total cardiac work (up to 50%). Although myocardial O2 consumption increases during exercise, it does not increase as much as when pressure work increases. Another consequence of the greater O2 consumption of pressure work is that the left ventricle must work harder than the right ventricle. Although cardiac output is the same on both sides of the heart, mean aortic pressure (100 mm Hg) is much higher than mean pulmonary artery pressure (15 mm Hg). Thus the pres- sure work of the left ventricle is much greater than the pressure work of the right ventricle, although the volume work is the same. In fact, the left ventricular wall is thicker than the right ventricular wall as a compensatory mechanism for performing more pres- sure work. In pathologic conditions such as systemic hyper- tension (elevated arterial pressure in the systemic circulation), the left ventricle must perform even more pressure work than it does normally. Because aortic pressure is elevated, the left ventricular wall hypertro- phies (thickens) as a compensation for the increased workload. The greater thickness of the normal left ventricular wall and the compensatory hypertrophy of the left ventricular wall in systemic hypertension are adaptive mechanisms for performing more pressure work. These adaptive mechanisms are explained by the law of Laplace. The law of Laplace for a sphere (i.e., the approximate shape of the heart) states that pressure correlates directly with tension and wall thickness and correlates inversely with radius. Thus P HT r = 2 where P Pressure H Thickness height T Tension r Radius = = = = ( ) cycle. In this example, the left ventricle must eject blood against a greater-than-normal pressure. To eject blood, ventricular pressure must rise to a greater-than-normal level during isovolumetric con- traction (point 2) and during ventricular ejection (i.e., 2 → 3). A consequence of the increased after- load is that less blood is ejected from the ventricle during systole; thus stroke volume decreases, more blood remains in the ventricle at the end of systole, and end-systolic volume increases. One can envi- sion the effect of increased afterload as follows: if more of the contraction is “spent” in isovolumetric contraction to match the higher afterload, then less of the contraction is “leftover” and available for ejection of the stroke volume. ♦ Figure 4.24C illustrates the effect of increased con- tractility on the ventricular cycle. When contractility increases, the ventricle can develop greater tension and pressure during systole and eject a larger volume of blood than normal. Stroke volume increases, as does ejection fraction; less blood remains in the ventricle at the end of systole, and, consequently, end-systolic volume decreases (points 3 and 4). Cardiac Work Work is defined as force times distance. In terms of myocardial function, “work” is stroke work or the work the heart performs on each beat. For the left ventricle, stroke work is stroke volume multiplied by aortic pressure, where aortic pressure corresponds to force and stroke volume corresponds to distance. The work of the left ventricle can also be thought of as the area within the pressure-volume loop, such as the loop illustrated in Figure 4.23. Minute work or power is defined as work per unit time. In terms of myocardial function, cardiac minute work is cardiac output multiplied by aortic pressure. Therefore, cardiac minute work can be considered to have two components: volume work (i.e., cardiac output) and pressure work (i.e., aortic pressure). Sometimes the volume work component is called “external” work, and the pressure work component is called “internal” work (or heat). Thus increases in cardiac output (due to an increase in stroke volume and/or an increase in heart rate) or increases in aortic pressure will increase the energy consumption of the heart. Myocardial Oxygen Consumption Myocardial O2 consumption correlates directly with cardiac minute work. Of the two components of cardiac minute work, in terms of O2 consumption, pressure work is far more costly than volume work. In other words, press
154 • Physiology where Cardiac output Cardiac output mL/min O consumption O consu = = ( ) 2 2 mmption by whole body (mL O /min O O contepulmonary vein 2 2 2 ) [ ] = nnt of pulmonary venous blood mL O /mL blood O pulmonary ( ) [ ] 2 2 aartery O content of pulmonary arterial blood mL O /mL bloo = 2 2( dd) The total O2 consumption of the body typically is 250 mL/min in a 70-kg man. The O2 content of pulmo- nary venous blood can be measured by sampling peripheral arterial blood (because none of the O2 added to blood in the lungs has been consumed by the tissues yet). The O2 content of pulmonary arterial blood is equal to that of mixed venous blood and can be sampled either in the pulmonary artery itself or in the right ventricle. In words, the law of Laplace for a sphere states that the greater the thickness of the wall of the sphere (e.g., left ventricle), the greater the pressure that can be developed. Illustrating this point, the left ventricular wall is thicker than the right ventricular wall because the left ventricle must develop greater pressure to eject blood. It can be further concluded that ventricular wall thickness will increase as a compensatory mecha- nism if the ventricle has to pump against increased aortic pressure (e.g., hypertension). Thus in systemic hypertension the left ventricle hypertrophies; in pul- monary hypertension, the right ventricle hypertrophies. Unfortunately, this type of compensatory ventricular hypertrophy also may lead to ventricular failure and, eventually, be harmful or even fatal. Measurement of Cardiac Output— Fick Principle Cardiac output has previously been defined as the volume ejected by the left ventricle per unit time and is calculated as the product of stroke volume and heart rate. Cardiac output can be measured using the Fick principle, whose fundamental assumption is that, in the steady state, the cardiac output of the left and right ventricles is equal. The Fick principle states that there is conservation of mass, a concept that can be applied to the utilization of O2 by the body. In the steady state, the rate of O2 consumption by the body must equal the amount of O2 leaving the lungs in the pulmonary vein minus the amount of O2 returning to the lungs in the pulmonary artery. Each of these parameters can be measured. Total O2 consumption can be measured directly. The amount of O2 in the pulmonary veins is pulmonary blood flow multiplied by the O2 content of pulmonary venous blood. Likewise, the amount of O2 returned to the lungs via the pulmonary artery is pulmonary blood flow multiplied by the O2 content of pulmonary arterial blood. Recall that pulmonary blood flow is the cardiac output of the right heart and is equal to the cardiac output of the left heart. Thus stating these equalities mathematically, O consumption Cardiac output O Cardiac ou pulmonary vein2 2= × − [ ] pput O pulmonary artery× [ ]2 or, rearranging to solve for cardiac output: Cardiac output O consumption O Opulmonary vein pulmona = − 2 2 2[ ] [ ] rry artery SAMPLE PROBLEM. A man has a resting O2 con- sumption of 250 mL O2/min, a femoral arterial O2 content of 0.20 mL O2/mL blood, and a pulmonary arterial O2 content of 0.15 mL O2/mL blood. What is his cardiac output? SOLUTION. To calculate cardiac output using the Fick principle, the following values are required: total body O2 consumption, pulmonary venous O2 content (in this example, femoral arterial O2 content), and pulmonary arterial O2 content. Cardiac output O consumption O Opulmonary vein pulmona = − 2 2 2[ ] [ ] rry artery Cardiac output mL O /min mL O /mL blood mL O /mL = − 250 0 20 0 15 2 2 2. . blood mL/min= 5000 Not only is the Fick principle applicable to measure- ment of cardiac output (essentially the blood flow to the whole body), but it also can be applied to the measurement of blood flow to individual organs. For example, renal blood flow can be measured by dividing the O2 consumption of the kidneys by the difference in O2 content of renal arterial blood and renal venous blood. CARDIAC CYCLE Figure 4.25 illustrates the mechanical and electrical events that occur during a single cardiac cycle. The cycle is divided into seven phases (Fig. 4.25, letters A through G), which are separated by vertical lines in the figure. The ECG marks the electrical events of theWww.Medicalstudyzone.com
4—Cardiovascular Physiology • 155 atria. Contraction of the left atrium causes an increase in left atrial pressure. When this increase in atrial pres- sure is reflected back to the veins, it appears on the venous pulse record as the a wave. The left ventricle is relaxed during this phase, and because the mitral valve (AV valve of the left side of the heart) is open, the ventricle is filling with blood from the atrium, even prior to atrial systole. Atrial systole causes a further increase in ventricular volume as blood is actively ejected from the left atrium to the left ventricle through the open mitral valve. The corresponding “blip” in left ventricular pressure reflects this additional volume added to the ventricle from atrial systole. The fourth heart sound (S4) is not audible in normal adults, although it may be heard in ventricular hypertrophy, where ventricular compliance is decreased. When present, S4 coincides with atrial contraction. The sound cardiac cycle. Left ventricular pressure and volume, aortic and left atrial pressures, venous pulse, and heart sounds are all plotted simultaneously. The points at which the mitral and aortic valves open and close are shown by arrows. Figure 4.25 is best studied vertically, one phase at a time, so that all of the cardiovascular parameters in a given phase of the cycle can be correlated. The ECG can be used as a time/event marker. The cycle begins with depolarization and contraction of the atria. Table 4.5 can be used in conjunction with Figure 4.25 to learn the events of the cardiac cycle. Atrial Systole (A) Atrial systole is atrial contraction. It is preceded by the P wave on the ECG, which marks depolarization of the TABLE 4.5 Events of the Cardiac Cycle Phase of Cardiac Cyclea Major Events Electrocardiogram Valves Heart Sounds Atrial Systole (A) Atria contract Final phase of ventricular filling P wave PR interval — Fourth heart sound Isovolumetric Ventricular Contraction (B) Ventricles contract Ventricular pressure increases Ventricular volume is constant (all valves are closed) QRS complex Mitral valve closes First heart sound Rapid Ventricular Ejection (C) Ventricles contract Ventricular pressure increases and reaches maximum Ventricles eject blood into arteries Ventricular volume decreases Aortic pressure increases and reaches maximum ST segment Aortic valve opens — Reduced Ventricular Ejection (D) Ventricles eject blood into arteries (slower rate) Ventricular volume reaches minimum Aortic pressure starts to fall as blood runs off into arteries T wave — — Isovolumetric Ventricular Relaxation (E) Ventricles relaxed Ventricular pressure decreases Ventricular volume is constant (all valves are closed) — Aortic valve closes Second heart sound Rapid Ventricular Filling (F) Ventricles relaxed Ventricles fill passively with blood from atria Ventricular volume increases Ventricular pressure is low and constant — Mitral valve opens Third heart sound Reduced Ventricular Filling, or Diastasis (G) Ventricles relaxed Final phase of ventricular filling — — — aLettered phases of cardiac cycle correspond to phases in Figure 4.25.Www.Medicalstudyzone.com
156 • Physiology PP 0 20 40 60 80 100 120 Pressure (mm Hg) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Time (s) a c v Q T Venous pulse S R Ventricular volume PP Heart sounds 4 1 3 2 Aortic pressure Mitral valve opens Left ventricular pressure Aortic valve closes Aortic valve opens Mitral valve closes Left atrial pressure A B C D E F G Fig. 4.25 The cardiac cycle. The mechanical and electrical events that occur during one cycle are shown. Atrial systole (A); isovolumetric ventricular contraction (B); rapid ventricular ejection (C); reduced ventricular ejection (D); isovolumetric ventricular relaxation (E); rapid ventricular filling (F); reduced ventricular filling (diastasis) (G).Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 157 Isovolumetric Ventricular Relaxation (E) Isovolumetric ventricular relaxation begins after the ventricles are fully repolarized, marked by the end of the T wave on the ECG. Because the left ventricle is relaxed, left ventricular pressure decreases dramati- cally. When left ventricular pressure falls below aortic pressure, the aortic valve closes. The aortic valve closes slightly before the pulmonic valve, producing the second heart sound (S2). Inspiration delays closure of the pulmonic valve and causes splitting of the second heart sound; that is, during inspiration, the pulmonic valve closes distinctly after the aortic valve. Splitting occurs during inspiration because the associated decrease in intrathoracic pressure produces an increase in venous return to the right side of the heart. The resulting increase in right ventricular end-diastolic volume causes an increase in right ventricular stroke volume by the Frank-Starling mechanism and prolongs right ventricular ejection time; the prolongation of ejec- tion time delays closure of the pulmonic valve relative to the aortic valve. At the point where the aortic valve closes, the aortic pressure curve shows a “blip,” called the dicrotic notch or incisura. Because all valves are closed again, no blood can be ejected from the left ventricle, nor can the left ventricle fill with blood from the atria. Therefore during this phase, ventricular volume is constant (isovolumetric). Rapid Ventricular Filling (F) When ventricular pressure falls to its lowest level (and slightly below left atrial pressure), the mitral valve opens. Once the mitral valve opens, the ventricle begins to fill with blood from the left atrium, and ventricular volume increases rapidly. Ventricular pressure remains low, however, because the ventricle is still relaxed and compliant. (The high compliance of the ventricle means that volume can be added to it without changing pressure.) The rapid flow of blood from the atria to the ventricles produces the third heart sound (S3), which is normal in children but is not heard in normal adults; in middle-aged or older adults, the presence of S3 indicates volume overload, as in congestive heart failure or advanced mitral or tricuspid regurgitation. During this phase (and for the remainder of the cardiac cycle), aortic pressure decreases as blood runs off from the aorta into the arterial tree, to the veins, and then back to the heart. Reduced Ventricular Filling (Diastasis) (G) Reduced ventricular filling, or diastasis, is the longest phase of the cardiac cycle and includes the final portion of ventricular filling, which occurs at a slower rate than in the previous phase. Atrial systole marks the end of is caused by the atrium contracting against, and trying to fill, a stiffened ventricle. Isovolumetric Ventricular Contraction (B) Isovolumetric ventricular contraction begins during the QRS complex, which represents the electrical activation of the ventricles. When the left ventricle contracts, left ventricular pressure begins to increase. As soon as left ventricular pressure exceeds left atrial pressure, the mitral valve closes. (In the right heart, the tricuspid valve closes.) Closure of the AV valves produces the first heart sound (S1), which may be split because the mitral valve closes slightly before the tricuspid valve. Ventricular pressure increases dramatically during this phase, but ventricular volume remains constant because all valves are closed (the aortic valve has remained closed from the previous cycle). Rapid Ventricular Ejection (C) The ventricle continues to contract, and ventricular pressure reaches its highest value. When ventricular pressure becomes greater than aortic pressure, the aortic valve opens. Now blood is rapidly ejected from the left ventricle into the aorta through the open aortic valve, driven by the pressure gradient between the left ventricle and the aorta. Most of the stroke volume is ejected during rapid ventricular ejection, dramatically decreasing ventricular volume. Concomitantly, aortic pressure increases as a result of the large volume of blood that is suddenly added to the aorta. During this phase, atrial filling begins and left atrial pressure slowly increases as blood is returned to the left heart from the pulmonary circulation. This blood will, of course, be ejected from the left heart in the next cycle. The end of this phase coincides with the end of the ST segment (or the beginning of the T wave) on the ECG and with the end of ventricular contraction. Reduced Ventricular Ejection (D) During reduced ventricular ejection, the ventricles begin to repolarize, which is marked by the beginning of the T wave on the ECG. Ventricular pressure falls because the ventricles are no longer contracting. Because the aortic valve is still open, blood continues to be ejected from the left ventricle into the aorta, albeit at a reduced rate; ventricular volume also continues to fall, but at a r
158 • Physiology reaches a value of approximately 4 mm Hg, cardiac output can no longer keep up with venous return and the cardiac function curve levels off. This maximum level of cardiac output is approximately 9 L/min. Vascular Function Curve The vascular function curve or venous return curve, shown in Figure 4.26, depicts the relationship between venous return and right atrial pressure. Venous return is blood flow through the systemic circulation and back to the right heart. The inverse relationship between venous return and right atrial pressure is explained as follows: Venous return back to the heart, like all blood flow, is driven by a pressure gradient. The lower the pressure in the right atrium, the higher the pressure gradient between the systemic arteries and the right atrium and the greater the venous return. Thus as right atrial pressure increases, this pressure gradient decreases and venous return also decreases. The knee (flat portion) of the vascular function curve occurs at negative values of right atrial pressure. At such negative values, the veins collapse, impeding blood flow back to the heart. Although the pressure gradient has increased (i.e., as right atrial pressure becomes negative), venous return levels off because the veins have collapsed, creating a resistance to blood flow. diastole, at which point ventricular volume is equal to end-diastolic volume. Changes in heart rate alter the time available for diastasis because it is the longest phase of the cardiac cycle. For example, increases in heart rate reduce the time interval before the next P wave (i.e., the next cycle) and reduce, or even eliminate, this final portion of ventricular filling. If diastasis is reduced by such an increase in heart rate, ventricular filling will be com- promised, end-diastolic volume will be reduced, and, as a consequence, stroke volume also will be reduced (recall the Frank-Starling relationship). RELATIONSHIPS BETWEEN CARDIAC OUTPUT AND VENOUS RETURN It should be clear from the previous discussion that one of the most important factors determining cardiac output is left ventricular end-diastolic volume. In turn, left ventricular end-diastolic volume depends on venous return, which also determines right atrial pressure. Thus it follows that there is not only a relationship between cardiac output and end-diastolic volume but also a relationship between cardiac output and right atrial pressure. Cardiac output and venous return each can be examined separately as a function of right atrial pres- sure. These separate relationships also can be combined in a single graph to visualize the normal interrelation- ship between cardiac output and venous return (see Fig. 4.25). The combined graphs can be used to predict the effects of changes in various cardiovascular param- eters on cardiac output, venous return, and right atrial pressure. Cardiac Function Curve The cardiac function curve or cardiac output curve, shown in Figure 4.26, is based on the Frank-Starling relationship for the left ventricle. The cardiac function curve is a plot of the relationship between cardiac output of the left ventricle and right atrial pressure. Again, recall that right atrial pressure is related to venous return, end-diastolic volume, and end-diastolic fiber length: As venous return increases, right atrial pressure increases, and end-diastolic volume and end- diastolic fiber length increase. Increases in end-diastolic fiber length produce increases in cardiac output. Thus in the steady state the volume of blood the left ventricle ejects as cardiac output equals or matches the volume it receives in venous return. Increases in end-diastolic volume (i.e., right atrial pressure) produce increases in cardiac output by the Frank-Starling mechanism. However, this “matching” occurs only up to a point: When right atrial pressure Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) 0–2 +2 +10+4 +6 +8 2 0 4 6 8 10 Cardiac function curve Vascular function curve Mean systemic pressure Fig. 4.26 Cardiac and vascular function curves. The cardiac function curve is cardiac output as a function of right atrial pres- sure. The vascular function curve is venous return as a function of right atrial pressure. The curves intersect at the steady state operating point (filled circle) where cardiac output and venous return are equal.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 159 unstressed volume (the veins), producing no pres- sure, and the mean systemic pressure will be zero. When blood volume is greater than 4 L, some of the blood will be in the stressed volume (the arteries) and produce pressure. For example, if the total blood volume is 5 L, 4 L is in the unstressed volume, producing no pressure, and 1 L is in the stressed volume, producing a pressure of approximately 7 mm Hg (on the graph, read mean systemic pres- sure as 7 mm Hg at a blood volume of 5 L). It now should be clear how changes in blood volume can alter the mean systemic pressure (see Fig. 4.26). If blood volume increases, the amount of blood in the unstressed volume will be unaffected (if it is already full), but the amount of blood in the stressed volume will increase. When stressed volume increases, mean systemic pressure increases and the vascular function curve and its intersection point with the X-axis shift to the right. If blood volume decreases, then stressed volume decreases, mean systemic pressure decreases, and the vascular func- tion curve and its intersection point with the X-axis shift to the left. ♦ Redistribution of blood between the unstressed volume and the stressed volume also produces changes in mean systemic pressure. For example, if the compliance of the veins decreases (e.g., veno- constriction), the veins can hold less blood and blood shifts from the unstressed volume to the stressed volume. Although total blood volume is unchanged, the shift of blood increases the mean systemic pressure and shifts the vascular function curve to the right. Conversely, if the compliance of the veins increases (e.g., venodilation), the veins can hold more blood. Hence, the unstressed volume will increase, the stressed volume and mean systemic pressure will decrease, and the vascular function curve shifts to the left. In summary, increased blood volume and decreased compliance of the veins produce an increase in mean systemic pressure and shift the vascular function curve to the right. Decreased blood volume and increased compliance of the veins produce a decrease in mean systemic pressure and shift the vascular function curve to the left. Slope of the Vascular Function Curve If mean systemic pressure is fixed or constant, the slope of the vascular function curve can be changed by rotat- ing it. The slope of the vascular function curve is determined by total peripheral resistance (TPR). Recall that TPR is determined primarily by the resis- tance of the arterioles. The effect of TPR on venous return and the vascular function curve is explained as follows (see Fig. 4.26): Mean Systemic Pressure The value for right atrial pressure at which venous return is zero is called the mean systemic pressure. It is the point at which the vascular function curve inter- sects the X-axis (i.e., where venous return is zero and right atrial pressure is at its highest value). Mean systemic pressure or mean circulatory pressure is the pressure that would be measured throughout the car- diovascular system if the heart were stopped. Under these conditions, pressure would be the same through- out the vasculature and, by our definition, would be equal to the mean systemic pressure. When pressures are equal throughout the vasculature, there is no blood flow, and therefore venous return is zero (because there is no pressure gradient or driving force). Two factors influence the value for mean systemic pressure: (1) the blood volume and (2) the distribu- tion of blood between the unstressed volume and the stressed volume. In turn, the value for mean systemic pressure determines the intersection point (zero flow) of the vascular function curve with the X-axis. Figure 4.27 reviews the concepts of unstressed volume and stressed volume and relates them to mean systemic pressure. The unstressed volume (thought of as the volume of blood that the veins can hold) is the volume of blood in the vasculature that produces no pressure. The stressed volume (thought of as the volume in the arteries) is the volume that produces pressure by stretching the elastic fibers in the blood vessel walls. ♦ Consider the effect of changing blood volume on mean systemic pressure. When the blood volume ranges from 0 to 4 L, all of the blood will be in the Blood volume (L) 20 4 6 Unstressed volume Stressed volume Mean systemic pressure (mm Hg) 2 0 4 6 8 10 Fig. 4.27 Effect of changes in stressed volume on mean systemic pressure. Total blood volume is the sum of unstressed volume (in the veins) and stressed volume (in the arteries). Increases in stressed volume produce increases in mean systemic pressure.Www.Medicalstudyzone.com
160 • Physiology Combining these curves provides a useful tool for predicting the changes in cardiac output that will occur when various cardiovascular parameters are altered. Cardiac output can be altered by changes in the cardiac function curve, by changes in the vascular function curve, or by simultaneous changes in both curves. The basic premise of this approach is that, after such a change, the system will move to a new steady state. In the new steady state, the operating point at which the cardiac and the vascular function curves intersect will have changed. This new operating point tells what the new cardiac output and the new venous return are in the new steady state. Changes in cardiac output can be produced by any of the following mechanisms: (1) positive or negative inotropic effects that alter the cardiac function curve; (2) changes in blood volume or venous compliance that alter the vascular function curve by changing mean systemic pressure; and (3) changes in TPR that alter both the cardiac and vascular function curves. Inotropic Effects Inotropic agents alter the cardiac function curve (Fig. 4.28). Recall that positive inotropic agents cause an increase in contractility for a given end-diastolic volume (or right atrial pressure), and negative inotropic agents produce a decrease in contractility. ♦ The effect of a positive inotropic agent (e.g., ouabain, digitalis, or digoxin) on the cardiac func- tion curve is shown in Figure 4.28A. Positive inotro- pic agents produce an increase in contractility, an increase in stroke volume, and an increase in cardiac output for any level of right atrial pressure. Thus the cardiac function curve shifts upward, but the vascu- lar function curve is unaffected. The point of inter- section (the steady state point) of the two curves now has shifted upward and to the left. In the new steady state, cardiac output is increased and right atrial pressure is decreased. The decrease in right atrial pressure reflects the fact that more blood is ejected from the heart on each beat as a result of the increased contractility and increased stroke volume. ♦ Figure 4.28B shows the effect of a negative inotropic agent. The effect is just the opposite of a positive inotropic agent: There is a decrease in contractility and a decrease in cardiac output for any level of right atrial pressure. The cardiac function curve shifts downward, and the vascular function curve is unchanged. In the new steady state, cardiac output is decreased and right atrial pressure is increased. Right atrial pressure is increased because less blood is ejected from the heart on each beat, due to decreased contractility and decreased stroke volume. ♦ A decrease in TPR causes a clockwise rotation of the vascular function curve. A clockwise rotation means that, for a given right atrial pressure, venous return is increased. In other words, decreased resis- tance of the arterioles (decreased TPR) makes it easier for blood to flow from the arterial to the venous side of the circulation and back to the heart. ♦ An increase in TPR causes a counterclockwise rota- tion of the vascular function curve. A counterclock- wise rotation means that, for a given right atrial pressure, venous return is decreased. In other words, increased resistance of the arterioles (increased TPR) makes it more difficult for blood to flow from the arterial to the venous side of the circulation and back to the heart. Combining Cardiac and Vascular Function Curves The interaction between cardiac output and venous return can be visualized by combining the cardiac and vascular function curves (see Fig. 4.26). The point at which the two curves intersect is the unique operating or equilibrium point of the system in the steady state. In the steady state, cardiac output and venous return are, by definition, equal at the point of intersection. Why then do the cardiac and vascular function curves go in opposite directions and why do they have opposite relationships with right atrial pressure? The answers lie in the way the two curves are determined. The cardiac function curve is determined as follows: As right atrial pressure and end-diastolic volume are increased, there is increased ventricular fiber length, which leads to increased stroke volume and cardiac output. The higher the right atrial pressure, the higher the cardiac output—this is the Frank-Starling relationship for the heart. The vascular function curve is determined as follows: As right atrial pressure is decreased, venous return increases because of the greater pressure gradient driving blood flow back to the heart. The lower the right atrial pressure, the higher the venous return. Now, to the questions! We have established that cardiac and vascular function curves have opposite relationships with right atrial pressure. But how can this be true if cardiac output and venous return are always equal? When cardiac output and venous return are plotted simultaneously as a function of right a
4—Cardiovascular Physiology • 161 blood volume increase the amount of blood in the stressed volume and therefore increase the mean systemic pressure. Mean systemic pressure is the point on the vascular function curve where venous return is zero. Increases in blood volume shift this intersection point to the right and therefore shift the curve to the right in a parallel manner. (The shift is parallel because there is no accompanying change Effects of Changes in Blood Volume Changes in blood volume alter mean systemic pres- sure and thereby alter the vascular function curve (Fig. 4.29). ♦ The effects of increases in blood volume (e.g., transfusion) are shown in Figure 4.29A. Increases in Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Positive inotropic effect Negative inotropic effect A B Fig. 4.28 Effects of positive inotropic agents (A) and negative inotropic agents (B) on the cardiac and vascular function curves. The solid lines show the normal relationships, and the dashed lines show changes. The circle intersecting the dashed line shows the new steady state operating point. Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Increased blood volume Decreased blood volume A B Fig. 4.29 Effects of increased blood volume (A) and decreased blood volume (B) on the cardiac and vascular function curves. The solid lines show the normal relationships, and the dashed lines show changes. The circle intersecting the dashed line shows the new steady state operating point.Www.Medicalstudyzone.com
162 • Physiology in TPR alter both arterial blood pressure and venous return to the heart. For example, an increase in TPR, by restricting the flow of blood out of the arteries, produces an increase in arterial blood pressure and, concomitantly, a decrease in venous return. The effects of changes in TPR on the cardiac and vascular function curves are therefore more compli- cated than those produced by changes in contractility or blood volume. Changes in TPR alter both curves: The cardiac function curve changes because of a change in afterload (arterial blood pressure), and the vascular function curve changes because of a change in venous return (Fig. 4.30). ♦ The effects of an increase in TPR (i.e., constriction of the arterioles) are shown in Figure 4.30A. (1) Increases in TPR cause an increase in arterial pres- sure by “holding” blood in the arteries. This increase in arterial pressure produces an increase in afterload on the heart, which decreases cardiac output. The cardiac function curve shifts downward as a result of the increased afterload. (2) The increase in TPR produces a counterclockwise rotation of the vascular function curve. This rotation means that less blood returns to the heart for a given right atrial pressure— venous return is decreased. (3) The combination of these two changes is shown in Figure 4.30A. The curves intersect at a new steady state point at which both cardiac output and venous return are decreased. In the figure, right atrial pressure is shown as unchanged. Actually, the final effect of increased in TPR, which determines the slope of the vascular function curve.) In the new steady state, the cardiac and vascular function curves intersect at a new point at which cardiac output is increased and right atrial pressure is increased. ♦ The effects of decreases in blood volume (e.g., hemorrhage) are shown in Figure 4.29B. The decrease in blood volume decreases the amount of blood in the stressed volume and mean systemic pressure, which shifts the vascular function curve to the left in a parallel manner. In the new steady state, cardiac output is decreased and right atrial pressure is decreased. ♦ Changes in venous compliance produce effects similar to those produced by changes in blood volume. Decreases in venous compliance cause a shift of blood out of the unstressed volume and into the stressed volume and produce changes similar to those caused by increases in blood volume, a parallel shift to the right. Likewise, increases in venous compliance cause a shift of blood into the unstressed volume and out of the stressed volume and produce changes similar to those caused by decreased blood volume, a parallel shift to the left. Effects of Changes in Total Peripheral Resistance Changes in TPR reflect changes in the degree of con- striction of the arterioles. Such changes alter the extent to which blood is “held” on the arterial side of the circulation (i.e., in the stressed volume). Thus changes Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Right atrial pressure (mm Hg) Cardiac output or venous return (L/min) Increased TPR Decreased TPR A B Fig. 4.30 Effects of increased total peripheral resistance (TPR) (A) and decreased TPR (B) on the cardiac and vascular function curves. The solid lines show the normal relationships, and the dashed lines show the changes. The circle intersecting the dashed lines shows the new steady state operating point.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 163 The mechanisms that help to maintain Pa at a con- stant value are discussed in this section. The basis for this regulation can be appreciated by examining the equation for Pa: P Cardiac output TPRa = × where P Mean arterial pressure mm Hg Cardiac output Cardiac out a = = ( ) pput mL/min TPR Total peripheral resistance mm Hg/mL per m ( ) ( = iin) Notice that the equation for Pa is simply a variation of the familiar equation for pressure, flow, and resis- tance, used previously in this chapter. Inspection of the equation reveals that Pa can be changed by altering the cardiac output (or any of its parameters), altering the TPR (or any of its parameters), or altering both cardiac output and TPR. Be aware that this equation is deceptively simple, because cardiac output and TPR are not independent variables. In other words, changes in TPR can alter cardiac output and changes in cardiac output can indirectly alter TPR. Therefore it cannot be stated that if TPR doubles, Pa also doubles. (In fact, when TPR doubles, cardiac output simultaneously is almost halved and Pa will increase only modestly.) Likewise, it cannot be stated that if cardiac output is halved, Pa also will be halved. (Rather, if cardiac output is halved, there is a compensatory increase in TPR and Pa will decrease but not be halved.) This section discusses the mechanisms responsible for maintaining a constant value for arterial pressure. These mechanisms closely monitor Pa and compare it with the set-point value of approximately 100 mm Hg. If Pa increases above the set point or decreases below the set point, the cardiovascular system makes adjust- ments in cardiac output, in TPR, or in both, attempting to return Pa to the set-point value. Pa is regulated by two major systems. The first system is neurally mediated and known as the baroreceptor reflex. The baroreceptor reflex attempts to restore Pa to its set-point value in a matter of seconds. The second system is hormonally mediated and includes the renin- angiotensin-aldosterone system, which regulates Pa more slowly, primarily by its effect on blood volume. Baroreceptor Reflex The baroreceptor mechanisms are fast, neurally medi- ated reflexes that attempt to keep arterial pressure constant via changes in the output of the sympathetic and parasympathetic nervous systems to the heart and TPR on right atrial pressure is not easily predict- able because TPR has different directional effects via the cardiac and vascular function curves. An increase in TPR decreases cardiac output, which increases right atrial pressure (less blood is pumped out of the heart). And, an increase in TPR decreases venous return, which decreases right atrial pressure (less flow back to the heart). Depending on the relative magnitude of the effects on the cardiac and vascular function curves, right atrial pressure can be slightly increased, slightly decreased, or unchanged. The figure shows it as unchanged—the compromise position. ♦ The effects of a decrease in TPR (i.e., dilation of the arterioles) are shown in Figure 4.30B. (1) Decreases in TPR cause a decrease in arterial pressure and a decrease in afterload, causing the cardiac function curve to shift upward. (2) The decrease in TPR produces a clockwise rotation of the vascular function curve, which means that more blood returns to the heart for a given right atrial pressure—venous return is increased. The curves intersect at a new steady state point at which both cardiac output and venous return are increased. In the figure, right atrial pressure is shown as unchanged. However, the effect of decreased TPR on right atrial pressure is not easily predicted because a change in TPR has different effects via the cardiac and vascular function curves. A decrease in TPR increases cardiac output, which decreases right atrial pressure (more blood is pumped out of the heart). And a decrease in TPR increases venous return, which increases right atrial pressure (increased flow back to the heart). Depending on the relative mag- nitude of the effects, right atrial pressure can be slightly increased, slightly decreased, or unchanged. In the figure, it is shown as the compromise, or unchanged. REGULATION OF ARTERIAL PRESSURE The overall function of the cardiovascular system is to deliver blood to the tissues so that O2 and nutrients can be provided and waste products carried away. Blood flow to the tissues is driven by the difference in pressure between the arterial and venous sides of the circulation. Mean arterial pressure (Pa) is the driving force for blood flow, and it must be maintained at a high, constant level of approximately 100 mm Hg. Because of the parallel arrangement of arteries off the aorta, the pressure in the major artery serving each organ is equal to Pa. (The blood flow to each organ is then independently regulated by changing the resistance of its arterioles through local control mechanisms.)Www.Medicalstudyzone.com
164 • Physiology The baroreceptors are mechanoreceptors, which are sensitive to pressure or stretch. Thus changes in arterial pressure cause more or less stretch on the mechanore- ceptors, resulting in a change in their membrane potential. Such a change in membrane potential is a receptor potential, which increases or decreases the likelihood that action potentials will be fired in the afferent nerves that travel from the baroreceptors to the brain stem. (If the receptor potential is depolarizing, then action potential frequency increases; if the recep- tor potential is hyperpolarizing, then action potential frequency decreases.) Increases in arterial pressure cause increased stretch on the baroreceptors and increased firing rate in the afferent nerves. Decreases in arterial pressure cause decreased stretch on the baroreceptors and decreased firing rate in the afferent nerves. Although the baroreceptors are sensitive to the absolute level of pressure, they are even more sensitive to changes in pressure and the rate of change of pres- sure. The strongest stimulus for the baroreceptors is a rapid change in arterial pressure! blood vessels (Fig. 4.31). Pressure sensors, the barore- ceptors, are located within the walls of the carotid sinus and the aortic arch and relay information about blood pressure to cardiovascular vasomotor centers in the brain stem. The vasomotor centers, in turn, coor- dinate a change in output of the autonomic nervous system to effect the desired change in Pa. Thus the reflex arc consists of sensors for blood pressure; affer- ent neurons, which carry the information to the brain stem; brain stem centers, which process the informa- tion and coordinate an appropriate response; and efferent neurons, which direct changes in the heart and blood vessels. Baroreceptors The baroreceptors are located in the walls of the carotid sinus, where the common carotid artery bifurcates into the internal and external carotid arteries, and in the aortic arch. The carotid sinus baroreceptors are respon- sive to increases or decreases in arterial pressure, whereas the aortic arch baroreceptors are primarily responsive to increases in arterial pressure. + + + ++ + – + – Carotid sinus baroreceptors Aortic arch baroreceptors CN IX CN X Cardiac decelerator Sinoatrial node Contractility Cardiac accelerator Vasoconstrictor Blood vesselsHeart VeinsArterioles BARORECEPTORS MEDULLA HEART AND BLOOD VESSELS Nucleus tractus solitarius SympatheticParasympathetic Fig. 4.31 Response of baroreceptor reflex to increased arterial pressure. The + symbol shows increases in activity; the − symbol shows decreases in activity; the dashed lines show inhibitory pathways. CN, Cranial nerve.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 165 ♦ The cardiac accelerator center. Efferent neurons from the cardiac accelerator center are also part of the sympathetic nervous system and synapse in the spinal cord, in sympathetic ganglia, and finally in the heart. In the heart, the effects of this activity are an increased firing rate of the SA node (to increase heart rate), increased conduction velocity through the AV node, and increased contractility. ♦ The cardiac decelerator center. Efferent fibers from the cardiac decelerator center are part of the para- sympathetic nervous system: They travel in the vagus nerve and synapse on the SA node to decrease heart rate. Integrated Function of the Baroreceptor Reflex The function of the baroreceptor reflex can be illus- trated by examining its response to an increase in arterial pressure as follows (see Fig. 4.31): 1. An increase in Pa is detected by baroreceptors in the carotid sinus and in the aortic arch. This increase in pressure results in increased firing rate of the carotid sinus nerve (glossopharyngeal nerve, CN IX) and in afferent fibers in the vagus nerve (CN X). 2. The glossopharyngeal and vagus nerve fibers synapse in the nucleus tractus solitarius of the medulla, where they transmit information about blood pres- sure. In this example, the Pa sensed by the barorecep- tors is higher than the set-point pressure in the medulla. 3. The nucleus tractus solitarius directs a series of coordinated responses, using the medullary cardio- vascular centers, to reduce Pa back to normal. These responses include an increase in parasympathetic outflow to the heart and a decrease in sympathetic outflow to the heart and blood vessels. 4. The increase in parasympathetic activity to the SA node (via the vagus nerve) results in a decrease in heart rate. The decrease in sympathetic activ- ity to the SA node complements the increase in parasympathetic activity and also decreases heart rate. Decreased sympathetic activity also decreases cardiac contractility. Together, the decreased heart rate and decreased cardiac contractility produce a decrease in cardiac output, which tends to reduce Pa back to normal. (Recall that Pa = Cardiac output × TPR.) The decrease in sympathetic activity also affects the tone of the blood vessels. First, there is decreased constriction of arterioles, or arteriolar vasodilation, which decreases TPR and reduces Pa. (Again, recall that Pa = Cardiac output × TPR.) Second, there is decreased constriction of veins, which increases the compliance of the veins, thereby increasing The sensitivity of the baroreceptors can be altered by disease. For example, in chronic hypertension (elevated blood pressure), the baroreceptors do not “see” the elevated blood pressure as abnormal. In such cases, the hypertension will be maintained, rather than corrected, by the baroreceptor reflex. The mechanism of this defect is either decreased sensitivity of the baroreceptors to increases in arterial pressure or an increase in the blood pressure set point of the brain stem centers. Information from the carotid sinus baroreceptors is carried to the brain stem on the carotid sinus nerve, which joins the glossopharyngeal nerve (cranial nerve [CN] IX). Information from the aortic arch barorecep- tors is carried to the brain stem on the vagus nerve (CN X). Brain Stem Cardiovascular Centers Brain stem cardiovascular centers are located in the reticular formations of the medulla and in the lower one-third of the pons. These centers function in a coordinated fashion, receiving information about blood pressure from the baroreceptors and then directing changes in output of the sympathetic and parasympa- thetic nervous systems to correct the blood pressure as needed. As described, blood pressure is sensed by barorecep- tors in the carotid sinus and aortic arch. Afferent information about blood pressure is then sent to the medulla via the glossopharyngeal (CN IX) and vagus (CN X) nerves. This information is integrated in the nucleus tractus solitarius, which then directs changes in the activity of several cardiovascular centers. These cardiovascular centers are tonically active, and the nucleus tractus solitarius simply directs, via the centers, increases or decreases in outflow from the sympathetic and parasympathetic nervous systems. The parasympathetic outflow is the effect of the vagus nerve on the SA node to decrease the heart rate. The sympathetic outflow has four components: an effect on the SA node to increase heart rate, an effect on cardiac muscle to increase contractility and stroke volume, an effect on the arterioles to produce vasocon- striction and increase TPR, and an effect on veins to produce venoconstriction and decrease unstressed volume. The cardiovascular brain stem centers are as follows: ♦ The vasoconstrictor center (also called C1) is located in the upper medulla and the lower pons. Efferent neurons from this vasomotor center are part of the sympathetic nervous system and
166 • Physiology for the response to an increase in Pa. Decreases in Pa produce decreased stretch on the baroreceptors and decreased firing rate of the carotid sinus nerve. This information is received in the nucleus tractus solitarius of the medulla, which produces a coordinated decrease in parasympathetic activity to the heart and an increase in sympathetic activity to the heart and blood vessels. Heart rate and contractility increase, which, together, produce an increase in cardiac output. There is increased constriction of arterioles, which produces an increase in TPR, and increased constriction of the veins, which decreases unstressed volume. The constriction of the veins increases venous return to contribute to the increase in cardiac output (Frank- Starling mechanism). Test of Baroreceptor Reflex: Valsalva Maneuver The integrity of the baroreceptor reflex can be tested with the Valsalva maneuver, which is expiring against a closed glottis as during coughing, defecation, or heavy lifting. When the subject expires against a closed the unstressed volume. When unstressed volume increases, stressed volume decreases, which further contributes to a reduction in Pa. 5. Once these coordinated reflexes reduce Pa back to the set-point pressure (i.e., to 100 mm Hg), then activity of the baroreceptors and the cardiovascular brain stem centers will return to the tonic (baseline) level. Response of the Baroreceptor Reflex to Hemorrhage A second example of the operation of the baroreceptor reflex is the response to loss of blood volume or hemor- rhage. Hemorrhage produces a decrease in Pa because, as blood volume decreases, stressed volume also decreases (see Fig. 4.27). In response to an acute reduc- tion in Pa, the baroreceptor reflex is activated and attempts to restore blood pressure back toward normal (Fig. 4.32). The responses of the baroreceptor reflex to a decrease in Pa are the exact opposite of those described previously Stretch on carotid sinus baroreceptors Pa Parasympathetic activity to heart Sympathetic activity to heart and blood vessels Constriction of arterioles ( TPR) Constriction of veins Heart rate Contractility Unstressed volume Venous return Firing rate of carotid sinus nerve Heart rate Pa TOWARD NORMAL BARORECEPTOR REFLEX Fig. 4.32 Response of the baroreceptor reflex to acute hemorrhage. The reflex is initiated by a decrease in mean arterial pressure ( Pa). The compensatory responses attempt to increase Pa back to normal. TPR, Total peripheral resistance.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 167 such as losartan, block the actions of angiotensin II at the level of the target tissues. ♦ Angiotensin II acts on the zona glomerulosa cells of the adrenal cortex to stimulate the synthesis and secretion of aldosterone. Aldosterone then acts on the principal cells of the renal distal tubule and collecting duct to increase Na+ reabsorption and, thereby, to increase ECF volume and blood volume. The actions of aldosterone require gene transcription and new protein synthesis in the kidney. These processes require hours to days to occur and account for the slow response time of the renin–angiotensin II–aldosterone system. ♦ Angiotensin II also has its own direct action on the kidney, independent of its actions through aldosterone. Angiotensin II stimulates Na+-H+ exchange in the renal proximal tubule and increases the reabsorption of Na+ and HCO3−. ♦ Angiotensin II acts on the hypothalamus to increase thirst and water intake. It also stimulates secretion of antidiuretic hormone (ADH), which increases water reabsorption in collecting ducts. By increasing total body water, these effects complement the increases in Na+ reabsorption (caused by aldosterone and Na+-H+ exchange), thereby increasing ECF volume, blood volume, and blood pressure. ♦ Angiotensin II also acts directly on the arterioles by binding to G protein–coupled AT1 receptors and activating an inositol 1,4,5-triphosphate (IP3)/Ca2+ second messenger system to cause vasoconstriction. The resulting increase in TPR leads to an increase in Pa. In summary, a decrease in Pa activates the renin– angiotensin II–aldosterone system, producing a set of responses that attempt to increase Pa back to normal. The most important of these responses is the effect of aldosterone to increase renal Na+ reabsorption. When Na+ reabsorption is increased, total body Na+ content increases, which increases ECF volume and blood volume. Increases in blood volume produce an increase in venous return and, through the Frank-Starling mechanism, an increase in cardiac output. The increase in cardiac output produces an increase in Pa. There also is a direct effect of angiotensin II to constrict arterioles, increasing TPR and contributing to the increase in Pa (Box 4.2). Other Regulatory Mechanisms In addition to the baroreceptor reflex and the renin– angiotensin II–aldosterone system, other mechanisms that may aid in regulating mean arterial pressure include chemoreceptors for O2 in the carotid and aortic glottis, there is an increase in intrathoracic pressure, which decreases venous return to the heart. This decrease in venous return produces a decrease in cardiac output (Frank-Starling mechanism) and a con- sequent decrease in arterial pressure. If the baroreceptor reflex is intact, the decrease in arterial pressure is sensed by the baroreceptors, and the nucleus tractus solitarius directs an increase in sympathetic outflow and a decrease in parasympathetic outflow to the heart and blood vessels. In the test, an increase in heart rate is noted. When the subject stops the maneuver, there is a rebound increase in venous return, cardiac output, and arterial pressure. The increase in arterial pressure is sensed by the baroreceptors, and they direct a decrease in heart rate. Renin–Angiotensin II–Aldosterone System The renin–angiotensin II–aldosterone system regulates Pa primarily by regulating blood volume. This system is much slower than the baroreceptor reflex because it is hormonally, rather than neurally, mediated. The renin–angiotensin II–aldosterone system is activated in response to a decrease in the Pa. Activation of this system, in turn, produces a series of responses that attempt to restore arterial pressure to normal. This mechanism, shown in Figure 4.33, has the following steps: 1. A decrease in Pa causes a decrease in renal perfusion pressure, which is sensed by mechanoreceptors in afferent arterioles of the kidney. The decrease in Pa causes prorenin to be converted to renin in the juxtaglomerular cells (by mechanisms not entirely understood). Renin secretion by the juxtaglomerular cells is also increased by stimulation of renal sym- pathetic nerves and by β1 agonists such as isopro- terenol; renin secretion is decreased by β1 antagonists such as propranolol. 2. Renin is an enzyme. In plasma, renin catalyzes the conversion of angiotensinogen (renin substrate) to angiotensin I, a decapeptide. Angiotensin I has little biologic activity, other than to serve as a precursor to angiotensin II. 3. In the lungs and kidneys, angiotensin I is converted to angiotensin II, catalyzed by angiotensin-converting enzyme (ACE). An angiotensin-converting enzyme inhibitor (ACEi), such as captopril, blocks the pro- duction of angiotensin II and all of its physiologic actions. 4. Angiotensin II is an octapeptide with the following biologic actions in the adrenal cortex, vascular smooth muscle, kidneys, and brain, where it acti- vates type 1 G protein–coupled angiote
168 • Physiology particularly when PO2 is simultaneously decreased. In other words, the response of the peripheral chemore- ceptors to decreased arterial PO2 is greater when the PCO2 is increased or the pH is decreased. When arterial PO2 decreases, there is an increased firing rate of afferent nerves from the carotid and aortic bodies that activates sympathetic vasoconstrictor centers. As a result, there is arteriolar vasoconstric- tion in skeletal muscle, renal, and splanchnic vascular beds. In addition, there is an increase in parasympa- thetic outflow to the heart that produces a transient decrease in heart rate. The slowing of the heart rate is only transient, however, because these peripheral bodies, chemoreceptors for CO2 in the brain, ADH, and atrial natriuretic peptide (ANP). Peripheral Chemoreceptors in Carotid and Aortic Bodies Peripheral chemoreceptors for O2 are located in the carotid bodies near the bifurcation of the common carotid arteries and in the aortic bodies along the aortic arch. The carotid and aortic bodies have high blood flow, and their chemoreceptors are primarily sensitive to decreases in the partial pressure of O2 (PO2). The chemoreceptors also are sensitive to increases in the partial pressure of CO2 (PCO2) and decreases in pH, Pa RENIN–ANGIOTENSIN II–ALDOSTERONE SYSTEM Renin Angiotensin IAngiotensinogen (renin substrate) Renal perfusion pressure angiotensin-converting enzyme Na+ reabsorption Na+ reabsorption ECF volume ECF volume Pa TOWARD NORMAL TPR Aldosterone Na+-H+ noitcirtsnocosaVegnahcxe Thirst Angiotensin II Fig. 4.33 Renin–angiotensin II–aldosterone system. The system is described in terms of the response to a decrease in Pa. ECF, Extracellular fluid; Pa, mean arterial pressure; TPR, total peripheral resistance.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 169 flow. When intracranial pressure increases (e.g., tumors, head injury), there is compression of cerebral arteries, which results in decreased perfusion of the brain. There is an immediate increase in PCO2 and a decrease in pH because CO2 generated from brain tissue is not ade- quately removed by blood flow. The medullary chemo- receptors respond to these changes in PCO2 and pH by directing an increase in sympathetic outflow to the blood vessels. Again, the overall effect of these changes is to increase TPR and dramatically increase Pa. Antidiuretic Hormone ADH, a hormone secreted by the posterior lobe of the pituitary gland, regulates body fluid osmolarity and participates in the regulation of arterial blood pressure. There are two types of receptors for ADH: V1 recep- tors, which are present in vascular smooth muscle, and V2 receptors, which are present in principal cells of the renal collecting ducts. When activated, the V1 receptors cause vasoconstriction of arterioles and increased TPR. The V2 receptors are involved in water reabsorption in the collecting ducts and the maintenance of body fluid osmolarity. ADH secretion from the posterior pituitary is increased by two types of stimuli: by increases in serum osmolarity and by decreases in blood volume and blood pressure. The blood volume mechanism is chemoreceptors are primarily involved in control of breathing (see Chapter 5). The decrease in arterial PO2 also produces an increase in ventilation that indepen- dently decreases parasympathetic outflow to the heart, which increases the heart rate (the lung inflation reflex). Central Chemoreceptors The brain is intolerant of decreases in blood flow, and therefore it is not surprising that chemoreceptors are located in the medulla itself. These chemoreceptors are most sensitive to CO2 and pH and less sensitive to O2. Changes in PCO2 or pH stimulate the medullary chemo- receptors, which then direct changes in outflow of the medullary cardiovascular centers. The reflex that involves cerebral chemoreceptors operates as follows: If the brain becomes ischemic (i.e., there is decreased cerebral blood flow), cerebral PCO2 immediately increases and pH decreases. The medullary chemoreceptors detect these changes and direct an increase in sympathetic outflow that causes intense arteriolar vasoconstriction in many vascular beds and an increase in TPR. Blood flow is thereby redirected to the brain to maintain its perfusion. As a result of this vasoconstriction, Pa increases dramati- cally, even to life-threatening levels. The Cushing reaction illustrates the role of the cerebral chemoreceptors in maintaining cerebral blood BOX 4.2 Clinical Physiology: Renal Vascular Hypertension DESCRIPTION OF CASE. A 65-year-old woman visits her physician complaining of “not feeling well” and decreased urination. Her diastolic blood pressure is elevated at 115 mm Hg, and she has abdominal bruits (sounds). She is immediately admitted to the hospital and has a workup for hypertension. Laboratory tests reveal the following information: Her blood pressure continues to be dangerously ele- vated, and her glomerular filtration rate (GFR) is sig- nificantly decreased, at 30 mL/min. Renal vascular disease is suspected. Renal angiography shows 90% stenosis of the right renal artery. Her plasma renin activity is elevated, and renin levels are much higher in right renal venous blood than in left renal venous blood. An attempt to dilate the right renal artery with angioplasty is unsuccessful. The woman is treated with captopril, an ACEi. EXPLANATION OF CASE. The woman has stenosis of her right renal artery, which reduces blood flow to her right kidney. The abdominal bruits are heard because blood flow through the stenosed renal artery is turbu- lent (i.e., Reynolds number is increased). As a result of the decreased renal blood flow, her GFR and her urine output are decreased. The woman’s hypertension is secondary to the decrease in renal blood flow. Renal perfusion pressure to the right kidney is significantly decreased. The right kidney “thinks” that arterial pressure is low and that aldosterone is needed. Thus renin secretion by the right kidney increases, which results in renin levels in the right renal vein higher than those in the left renal vein. Increased circulating renin activity results in increased production of angiotensin II and aldosterone. Angioten- sin II causes vasoconstriction of arterioles, which ele- vates TPR and mean arterial pressure. Aldosterone increases renal Na+ reabsorption, elevating total body Na+ content, ECF volume, and blood volume. The increase in blood volume leads to the increased dia- stolic blood pressure. TREATMENT. Because an attempt to dilate the ste- nosed renal artery is unsuccessful, the woman is treated with an ACEi to interrupt the cycle that produced the hypertension (i.e., to block the conversion of angioten- sin I to angiotensin II). Although the right kidney will co
170 • Physiology volume is too high, direct an increase in heart rate and thus an increase in cardiac output; the increase in cardiac output leads to increased renal perfusion and increased Na+ and water excretion. MICROCIRCULATION The term “microcirculation” refers to the functions of the smallest blood vessels, the capillaries and the neighboring lymphatic vessels. Delivery of blood to and from the capillaries is critically important because the capillaries are the site of exchange of nutrients and waste products in the tissues, as well as the site of fluid exchange between the vascular and interstitial compartments. The anatomy of capillary beds has been discussed previously. To briefly review, blood is delivered to the capillary beds via the arterioles. The capillaries merge into venules, which carry effluent blood from the tissues to the veins. The capillaries are the site of the exchange of nutrients, wastes, and fluid. Capillaries are thin walled and are composed of a single layer of endothelial cells with water-filled clefts between the cells. The degree of constriction or relaxation of the arte- rioles markedly affects blood flow to the capillaries (in addition to determining TPR). The capillaries them- selves branch off metarterioles; a band of smooth muscle, called the precapillary sphincters, precedes the capillaries. The precapillary sphincters function like “switches”: By opening or closing, these switches determine blood flow to the capillary bed. Exchange of Substances Across the Capillary Wall The exchange of solutes and gases across the capillary wall occurs by simple diffusion. Some solutes can diffuse through the endothelial cells, and others must diffuse between the cells. Generally, the route for diffu- sion depends on whether the solute or gas is lipid soluble. Gases such as O2 and CO2 are highly lipid soluble. These gases readily cross the capillary wall by diffusing through the endothelial cells; diffusion is driven by the partial pressure gradient for the individual gas. Recall that the rate of diffusion depends on the driving force (in the case of O2 and CO2, the partial pressure differ- ence for the gas) and the surface area available for diffusion. Thus the greater the number of open capil- laries, the greater the surface area for diffusion. Water-soluble substances such as water itself, ions, glucose, and amino acids are not lipid soluble; thus they cannot cross the endothelial cell membranes. The diffusion of water-soluble substances is limited to the discussed at this time, and osmoregulation is discussed in Chapter 6. Cardiopulmonary (Low-Pressure) Baroreceptors In addition to the high-pressure baroreceptors that regulate arterial pressure (i.e., baroreceptor reflex), there are also low-pressure baroreceptors located in the veins, atria, and pulmonary arteries. These so-called cardiopulmonary baroreceptors sense changes in blood volume, or the “fullness” of the vascular system. They are located on the venous side of the circulation because that is where most of the blood volume is held. For example, when there is an increase in blood volume, the resulting increase in venous and atrial pressure is detected by the cardiopulmonary barorecep- tors. The function of the cardiopulmonary barorecep- tors is then coordinated to return blood volume to normal, primarily by increasing the excretion of Na+ and water. The responses to an increase in blood volume include the following: ♦ Increased secretion of ANP. ANP is secreted by the atria in response to increased atrial pressure. ANP has multiple effects, but the most important is binding to ANP receptors on vascular smooth muscle, causing relaxation, vasodilation, and decreased TPR. In the kidneys, this vasodilation leads to increased Na+ and water excretion, thereby decreas- ing total body Na+ content, ECF volume, and blood volume. ♦ Decreased secretion of ADH. Pressure receptors in the atria also project to the hypothalamus, where the cell bodies of neurons that secrete ADH are located. In response to increased atrial pressure, ADH secre- tion is inhibited and, as a consequence, there is decreased water reabsorption in collecting ducts, resulting in increased water excretion. ♦ Renal vasodilation. There is inhibition of sympa- thetic vasoconstriction in renal arterioles, leading to renal vasodilation and increased Na+ and water excretion, complementing the action of ANP on the kidneys. ♦ Increased heart rate. Information from the low- pressure atrial receptors travels in the vagus nerve to the nucleus tractus solitarius (as does information from the high-pressure arterial receptors involved in the baroreceptor reflex). The difference lies in the response of the medullary cardiovascular centers to the low- and high-pressure receptors. Whereas an increase in pressure at the arterial high-pressure receptors produces a decrease in heart rate (trying to lower arterial pressure back to normal), an increase in pressure at the venous low-pr
4—Cardiovascular Physiology • 171 The Starling equation states that fluid movement (Jv) across a capillary wall is determined by the net pressure across the wall, which is the sum of hydrostatic pressure and oncotic pressures. The direction of fluid movement can be either into or out of the capillary. When net fluid movement is out of the capillary into the interstitial fluid, it is called filtration; when net fluid movement is from the interstitium into the capillary, it is called absorption. The magnitude of fluid move- ment is determined by the hydraulic conductance, Kf (water permeability), of the capillary wall. The hydrau- lic conductance determines how much fluid movement will be produced for a given pressure difference. Figure 4.34 is a pictorial presentation of the Starling pressures. Each of the four Starling pressures is repre- sented by an arrow. The direction of the arrow indicates whether that pressure favors filtration out of the capil- lary or absorption into the capillary. The size of the arrow shows the relative magnitude of the pressure. The numerical value of the pressure, in mm Hg, has a plus (+) sign if the pressure favors filtration and a minus (−) sign if the pressure favors absorption. The net pressure, which is the net driving force, is the algebraic sum of the four pressures. In the example in Figure 4.34A, the sum of the four Starling pressures is a net pressure of +6 mm Hg, indicating that there will be net filtration out of the capillary. In the example in Figure 4.34B, the sum of the four pressures is a net pressure of −5 mm Hg, indicating that there will be net absorption into the capillary. By understanding how each parameter of the Starling equation affects fluid movement across the capillary wall, it is possible to predict the effects of changes in these parameters. Each of the parameters in the Starling equation is described as follows: ♦ Kf, hydraulic conductance, is the water permeabil- ity of the capillary wall. It varies among different types of tissues, depending on the anatomic charac- teristics of the capillary wall (e.g., the size of the clefts between endothelial cells; whether the capil- laries are fenestrated). Therefore the magnitude of fluid movement for a given pressure difference is largest in capillaries with the highest Kf (e.g., glo- merular capillaries), and it is lowest in capillaries with the lowest Kf (e.g., cerebral capillaries). Kf is not influenced by such factors as changes in arterio- lar resistance, hypoxia, or buildup of metabolites. However, Kf is increased in capillary injury (e.g., toxins or in burns). Such increases in Kf will increase the capillary permeability to water and also will result in the loss of protein from the capillary. ♦ Pc, capillary hydrostatic pressure, is a force favor- ing filtration out of the capillary. The value for Pc is determined by both arterial and venous pressures (the capillary being interposed between the arteries aqueous clefts between endothelial cells; hence, the surface area for their diffusion is much less than that for the lipid-soluble gases. By far, the most important mechanism for fluid transfer across the capillary wall is osmosis, driven by hydrostatic and osmotic pressures. These pressures are called the Starling pressures or Starling forces. Proteins are generally too large to cross the capillary walls via the clefts between endothelial cells and are retained in the vascular compartment. In some tissues, such as brain, the clefts are particularly “tight,” and little protein leaves these capillaries. In the kidney and intestine, the capillaries are fenestrated or perforated, which permits the passage of limited amounts of protein. In other capillaries, proteins may cross in pinocytotic vesicles. Fluid Exchange Across Capillaries Fluid movement by osmosis is described in Chapter 1. Briefly, fluid will flow by osmosis across a biologic membrane (or the capillary wall) if the membrane has aqueous pores (i.e., permits the passage of water) and if there is a pressure difference across the membrane. The pressure difference can be a hydrostatic pressure difference, an effective osmotic pressure difference, or a combination of hydrostatic and effective osmotic pressures. In capillaries, fluid movement is driven by the sum of hydrostatic and effective osmotic pressures. Recall that solutes with reflection coefficients of 1.0 contribute most to the effective osmotic pressure. When the reflection coefficient is 1.0, the solute cannot cross the membrane and it exerts its full osmotic pres- sure. In capillary blood, only protein contributes to the effective osmotic pressure because it is the only solute whose reflection coefficient at the capillary wall is approximately 1.0. The effective osmotic pressure contributed by protein is called the colloid osmotic pressure or oncotic pressure. Starling Equation Fluid movement across a capillary wall is driven by the Starling pressures across the wall and is described
172 • Physiology and veins), although the value for Pc is closer to arterial pressure than to venous pressure. Further- more, Pc is more affected by changes in venous pressure than by changes in arterial pressure. Except in glomerular capillaries, Pc declines along the length of the capillary because of the filtration of fluid. Therefore Pc is highest at the arteriolar end of the capillary and lowest at the venous end. ♦ Pi, interstitial hydrostatic pressure, is a force opposing filtration. Normally, Pi is nearly zero, or it may be slightly negative. ♦ πc, capillary oncotic pressure, is a force opposing filtration. As previously noted, πc is the effective osmotic pressure of capillary blood due to the pres- ence of plasma proteins, and according to the van’t Hoff equation (see Chapter 1), it is determined by the protein concentration of capillary blood. There- fore increases in protein concentration of blood cause increases in πc and decrease filtration, and decreases in protein concentration of blood cause decreases in πc and increase filtration. ♦ πi, interstitial oncotic pressure, is a force favoring filtration. πi is determined by the interstitial fluid protein concentration. Normally, because there is little loss of protein from capillaries, there is little protein in interstitial fluid, making πi quite low. +30 –26 +25 –32 Pi Pi –1 –1 πi Capillary Interstitial fluid Net filtration Net pressure = +6 mm Hg Net absorption A B Net pressure = –5 mm Hg Pc πc +30 –26 Capillary Interstitial fluid Pc πc +25 –32 +3 πi +3 Fig. 4.34 Examples of Starling pressures across the capillary wall. A, Net pressure favors filtration; B, net pressure favors absorption. Arrows pointing out of the capillary show the Starling pressures that favor filtration (+). Arrows pointing into the capillary show the Starling pressures that oppose filtration (−). Numbers give the magnitude of each pressure. πc, Capillary oncotic pressure; πi, intersitial oncotic pressure; Pc, capillary hydrostatic pressure; Pi, interstitial oncotic pressure. SAMPLE PROBLEM. In a skeletal muscle capillary, the following Starling pressures were measured: P mm Hg P mm Hg mm Hg mm Hg c i c i , , , , 30 1 26 3 π π Assuming that Kf is 0.5 mL/min per mm Hg, what are the direction and magnitude of fluid movement across this capillary? SOLUTION. There are two approaches to solving this problem. One is to apply the Starling equation directly by substituting the values for the Starling pressures and Kf. The other is to use the pictorial approach shown in Figure 4.34 to calculate the net pressure and determine its direction and then to multiply the net pressure by Kf to obtain the magni- tude of fluid movement. The pictorial approach is preferred because there is no equation to memorize and the student must understand how each pressure affects fluid movement. The numerical values in this problem are identi- cal to those in Figure 4.34A. Use the figure to solve the problem pictorially. If the pressure favors filtra- tion, the arrow points out of the capillary and the numerical value is assigned a plus sign. If the pres- sure favors absorption, the arrow points into the capillary and the numerical value is assigned a minus sign. Two pressures, Pc and πi, are assigned a plus sign because they favor filtration. Two pres- sures, πc and Pi, are assigned a minus sign because they favor absorption. The four pressures are now added algebraically to calculate the net pressure of +6 mm Hg (i.e., net pressure = +30 − 1 − 26 + 3 mm Hg = +6 mm Hg). The direction of the net pressure favors filtration because it carries a plus sign. The magnitude of fluid movement is calculated as Kf multiplied by the net pressure: Fluid movement K net pressure mL/min per mm Hg mm Hg m f= × = × = 0 5 6 3 . LL/minWww.Medicalstudyzone.com
4—Cardiovascular Physiology • 173 through the lungs, allowing O2 to be added to it and CO2 to be removed from it. No other organ receives the entire cardiac output! The kidneys, gastrointestinal tract, and skeletal muscle all have high blood flow, each receiving approximately 25% of cardiac output. Other organs receive smaller percentages of the cardiac output. These interorgan differences in blood flow are the result of differences in vascular resistance. Furthermore, blood flow to a specific organ or organ system can increase or decrease, depending on its metabolic demands. For example, exercising skeletal muscle has greater demand for O2 than does resting skeletal muscle. To meet the greater demand for O2, blood flow to skeletal muscle must temporarily increase above the resting level. Changes in blood flow to an individual organ are achieved by altering arteriolar resistance. The mecha- nisms that regulate blood flow to the various organs are broadly categorized as local (intrinsic) control and neural or hormonal (extrinsic) control. Local control of blood flow is the primary mechanism utilized for matching blood flow to the metabolic needs of a tissue. Local control is exerted through the direct action of local metabolites on arteriolar resistance. Neural or hormonal control of blood flow includes such mecha- nisms as the action of the sympathetic nervous system on vascular smooth muscle and the actions of vasoac- tive substances such as histamine, bradykinin, and prostaglandins. Changes in Starling Forces Changes in Starling forces can influence the direction and magnitude of fluid movement across capillaries. For example, consider the various changes that would produce increased filtration out of capillaries. In prin- ciple, increases in filtration will be caused by an increase in any of the Starling forces that favor filtration or by a decrease in any of the Starling forces that favor absorption. Thus increases in filtration would be produced by increases in Pc resulting from increases in arterial pressure or venous pressure (but more so from increases in venous pressure). Increases in filtra- tion also would be produced by decreases in πc result- ing from dilution of plasma protein concentration. Lymph The lymphatic system is responsible for returning interstitial fluid and proteins to the vascular compart- ment. The lymphatic capillaries lie in the interstitial fluid, close to the vascular capillaries. The lymphatic capillaries possess one-way flap valves, which permit interstitial fluid and protein to enter, but not leave, the capillaries. These capillaries merge into larger lym- phatic vessels and eventually into the largest lymphatic vessel, the thoracic duct, which empties lymph into the large veins. The lymphatic vessels have a smooth muscle wall, which has intrinsic contractile ability. Lymph flow back to the thoracic duct is promoted by contraction of the smooth muscle in the lymph vessels and by compression of the lymph vessels by activity of the surrounding skeletal muscle. An increase in interstitial fluid volume is called edema (swelling). By definition, edema forms when the volume of interstitial fluid (due to filtration out of the capillaries) exceeds the ability of the lymphatics to return it to the circulation. Thus edema can form when there is increased filtration or when lymphatic drainage is impaired (Table 4.6). Various mechanisms for producing increased filtra- tion have been discussed previously in this chapter (e.g., increased Pc; decreased πc; increased Kf due to destruction of the capillary wall). Lymphatic drainage is impaired when the lymph nodes are surgically removed or irradiated (e.g., in malignancy); in filariasis, a parasitic infection of the lymph nodes; or when there is lack of muscular activity (e.g., a soldier standing at attention). SPECIAL CIRCULATIONS Blood flow is variable between one organ and another, depending on the overall demands of each organ system (see Fig. 4.1). For example, blood flow to the lungs is equal to the cardiac output because all blood must pass TABLE 4.6 Causes and Examples of Edema Formation Cause Examples ↑ Pc (capillary hydrostatic pressure) Arteriolar dilation Venous constriction Increased venous pressure Heart failure Extracellular fluid volume expansion ↓ πc (capillary oncotic pressure) Decreased plasma protein concentration Severe liver failure (failure to synthesize protein) Protein malnutrition Nephrotic syndrome (loss of protein in urine) ↑ Kf (hydraulic conductance) Burn Inflammation (release of histamine; cytokines) Impaired lymphatic drainage Standing (lack of skeletal muscle compression of lymphatics) Removal or irradiation of lymph nodes Parasitic infection of lymph nodesWww.Medicalstudyzone.com
174 • Physiology flow in the face of increased pressure (recall that Q = ΔP/R). Conversely, if arterial pressure suddenly decreases, there is less stretch on the arterioles, causing them to relax and arteriolar resistance to decrease. Thus constant flow can be maintained in the face of increased or decreased arterial pressure by changing arteriolar resistance. One can also think about the myogenic mecha- nism in terms of maintaining arteriolar wall tension. Blood vessels, such as arterioles, are built to with- stand the wall tensions they normally “see.” In the example of a sudden increase in arterial pressure, the increased pressure, if unopposed, will cause an increase in arteriolar wall tension. Such an increase in wall tension is undesirable for the arteriole. Thus in response to the stretch, arteriolar vascular smooth muscle contracts, decreasing the arteriolar radius and returning wall tension back to normal. This relationship is explained by the law of Laplace for a cylinder, which states that T = P × r. If pressure (P) increases and radius (r) decreases, then wall tension (T) can remain constant. (Of course, the other consequence of the decreased radius, discussed previously, is increased arteriolar resistance; in the face of increased pressure, increased resistance allows blood flow to be maintained constant, i.e., autoregulation.) ♦ Metabolic hypothesis. The metabolic hypothesis can be invoked to explain each of the phenomena of local control of blood flow. The basic premise of this hypothesis is that O2 delivery to a tissue can be matched to O2 consumption of the tissue by altering the resistance of the arterioles, which in turn alters blood flow. As a result of metabolic activity, the tissues produce various vasodilator metabolites (e.g., CO2, H+, K+, lactate, and adenosine). The greater the level of metabolic activity, the greater the production of vasodilator metabolites. These metabolites produce vasodilation of arterioles, which decreases resistance and therefore increases flow to meet the increased demand for O2. The tissues vary according to which vasodilator metabo- lite is primarily responsible for vasodilation; for example, the coronary circulation is most sensitive to PO2 and adenosine, whereas the cerebral circula- tion is most sensitive to PCO2 (Table 4.7). The following two examples illustrate how the metabolic hypothesis explains active hyperemia: (1) The first example considers strenuous exercise. During strenuous exercise, metabolic activity in the exercising skeletal muscle increases and produc- tion of vasodilator metabolites, such as lactate, increases. These metabolites cause local vasodila- tion of skeletal muscle arterioles, which increases local blood flow and increases O2 delivery to meet Mechanisms for Control of Regional Blood Flow Local Control of Blood Flow There are several examples of local (intrinsic) control of blood flow including autoregulation, active hyper- emia, and reactive hyperemia. Each example of local control is discussed generally, followed by a more detailed explanation of the mechanism. ♦ Autoregulation is the maintenance of a constant blood flow to an organ in the face of changing arterial pressure. Several organs exhibit autoregula- tion of blood flow including the kidneys, brain, heart, and skeletal muscle. For example, if arterial pressure in a coronary artery suddenly decreases, an attempt will be made to maintain constant blood flow through this coronary artery. Such autoregula- tion can be achieved by an immediate compensatory vasodilation of the coronary arterioles, decreasing the resistance of the coronary vasculature and keeping flow constant in the face of decreased pressure. ♦ Active hyperemia illustrates the concept that blood flow to an organ is proportional to its metabolic activity. As noted previously, if metabolic activity in skeletal muscle increases as a result of strenuous exercise, then blood flow to the muscle will increase proportionately to meet the increased metabolic demand. ♦ Reactive hyperemia is an increase in blood flow in response to or reacting to a prior period of decreased blood flow. For example, reactive hyperemia is the increase in blood flow to an organ that occurs fol- lowing a period of arterial occlusion. During the occlusion, an O2 debt is accumulated. The longer the period of occlusion, the greater the O2 debt and the greater the subsequent increase in blood flow above the preocclusion levels. The increase in blood flow continues until the O2 debt is “repaid.” Two basic mechanisms are proposed to explain the phenomena of autoregulation and active and reactive hyperemia: the myogenic hypothesis and the metabolic hypothesis. ♦ Myogenic hypothesis. The myogenic hypothesis can be invoked to explain autoregulation, but it does not explain active or reactive hyperemia. The myogenic hypothesis states that when vascular smooth muscle is stretched, it contracts. Thus if arterial pressure is suddenly increased, the a
4—Cardiovascular Physiology • 175 produces vasoconstriction via α1 receptors. In skeletal muscle, when the sympathetic nervous system is acti- vated, there can be vasoconstriction (sympathetic nerve fibers, α1 receptors) or vasodilation (epinephrine from adrenal medulla, β2 receptors). Other vasoactive substances include histamine, bradykinin, serotonin, and prostaglandins. Histamine is released in response to trauma and has powerful vascular effects. Simultaneously, it causes dilation of arterioles and constriction of venules, with the net effect being a large increase in Pc, which increases filtration out of capillaries, and local edema. Brady- kinin, like histamine, causes dilation of arterioles and constriction of venules, resulting in increased filtra- tion out of capillaries and local edema. Serotonin is released in response to blood vessel damage and causes local vasoconstriction (in an attempt to reduce blood flow and blood loss). Serotonin has been implicated in the pathophysiology of vascular spasms that occur in migraine headache. The prostaglandins produce various effects on vascular smooth muscle. Prostacyclin and the prostaglandin-E series are vasodilators in many vascular beds. Thromboxane A2 and the prostaglandin- F series are vasoconstrictors. Angiotensin II and vaso- pressin (via V1 receptors) are potent vasoconstrictors that increase TPR. ANP is a vasodilator hormone that the increased demand of the exercising muscle. (2) The second example considers a scenario in which there is a spontaneous increase in arterial pressure to an organ. Initially, the increased pressure will increase blood flow, which will deliver more O2 for metabolic activity and “wash out” vasodilator metabolites. As a result of this washout, there will be a local dilution of vasodilator metabolites, resulting in arteriolar vasoconstriction, increased resistance, and a compensatory decrease in blood flow back to the normal level. Neural and Hormonal Control of Blood Flow The most important example of neural (extrinsic) control of regional blood flow involves the sympathetic innervation of vascular smooth muscle in some tissues. The density of such sympathetic innervation varies widely from tissue to tissue. For example, blood vessels of the skin and skeletal muscle have a high density of sympathetic nerve fibers, whereas coronary, pulmo- nary, and cerebral vessels have little sympathetic innervation. It is important to note whether sympathetic innervation is absent or present and also, when present, whether it produces vasoconstriction or vasodilation (see Table 2.2). In skin, the sympathetic innervation TABLE 4.7 Control of Special Circulations Circulation Local Metabolic Control Vasoactive Metabolites Sympathetic Control Mechanical Effects Coronary Most important mechanism Hypoxia Adenosine Least important mechanism Mechanical compression during systole Cerebral Most important mechanism CO2 H+ Least important mechanism Increases in intracranial pressure decrease cerebral blood flow Skeletal Muscle Most important mechanism during exercise Lactate CO2 K+ Adenosine Most important mechanism at rest (α1 receptors, vasoconstriction; β2 receptors, vasodilation) Muscular activity compresses blood vessels Skin Least important mechanism — Most important mechanism for temperature regulation (α1 receptors, vasoconstriction) — Pulmonary Most important mechanism Hypoxia vasoconstricts Least important mechanism Lung inflation Renal Most important mechanism (myogenic; tubuloglomerular feedback) — Least important mechanism —Www.Medicalstudyzone.com
176 • Physiology Renal Circulation The regulation of renal blood flow is discussed in detail in Chapter 6. Briefly, renal blood flow is tightly auto- regulated so that flow remains constant even when renal perfusion pressure changes. Renal autoregulation is independent of sympathetic innervation, and it is retained even when the kidney is denervated (e.g., in a transplanted kidney). Autoregulation is presumed to result from a combination of the myogenic properties of the renal arterioles and tubuloglomerular feedback (see Chapter 6). Skeletal Muscle Circulation Blood flow to skeletal muscle is controlled both by local metabolites and by sympathetic innervation of its vascular smooth muscle. Incidentally, the degree of vasoconstriction of skeletal muscle arterioles is a major determinant of TPR because the mass of skel- etal muscle is so large, compared with that of other organs. ♦ At rest, blood flow to skeletal muscle is regulated primarily by its sympathetic innervation. Vascular smooth muscle in the arterioles of skeletal muscle is densely innervated by sympathetic nerve fibers that are vasoconstricting (α1 receptors). There are also β2 receptors on the vascular smooth muscle of skeletal muscle that are activated by epinephrine and cause vasodilation. Thus activation of α1 recep- tors causes vasoconstriction, increased resistance, and decreased blood flow. Activation of β2 receptors causes vasodilation, decreased resistance, and increased blood flow. Usually, vasoconstriction pre- dominates because norepinephrine, released from sympathetic adrenergic neurons, stimulates primar- ily α1 receptors. On the other hand, epinephrine released from the adrenal gland during the fight or flight response or during exercise activates β2 recep- tors and produces vasodilation. ♦ During exercise, blood flow to skeletal muscle is controlled primarily by local metabolites. Each of the phenomena of local control is exhibited: auto- regulation and active and reactive hyperemia. During exercise, the demand for O2 in skeletal muscle varies with the activity level, and, accordingly, blood flow is increased or decreased to deliver sufficient O2 to meet the demand. The local vasodilator substances in skeletal muscle are lactate, adenosine, and K+. Mechanical compression of the blood vessels in skeletal muscle can also occur during exercise and cause brief periods of occlusion. When the period of occlusion is over, a period of reactive hyperemia will occur, which increases blood flow and O2 delivery to repay the O2 debt. is secreted by the atria in response to increases in atrial pressure. Coronary Circulation Blood flow through the coronary circulation is con- trolled almost entirely by local metabolites, with sympathetic innervation playing only a minor role. The most important local metabolic factors are hypoxia and adenosine. For example, if there is an increase in myocardial contractility, there is increased O2 demand by the cardiac muscle and increased O2 consumption, causing local hypoxia. This local hypoxia causes vaso- dilation of the coronary arterioles, which then produces a compensatory increase in coronary blood flow and O2 delivery to meet the demands of the cardiac muscle (i.e., active hyperemia). An unusual feature of the coronary circulation is the effect of mechanical compression of the blood vessels during systole in the cardiac cycle. This compression causes a brief period of occlusion and reduction of blood flow. When the period of occlusion (i.e., systole) is over, reactive hyperemia occurs to increase blood flow and O2 delivery and to repay the O2 debt that was incurred during the compression. Cerebral Circulation The cerebral circulation is controlled almost entirely by local metabolites and exhibits autoregulation and active and reactive hyperemia. The most important local vasodilator in the cerebral circulation is CO2 (or H+). An increase in cerebral PCO2 (producing an increase in H+ concentration and a decrease in pH) causes vasodilation of the cerebral arterioles, which results in an increase in blood flow to assist in removal of the excess CO2. It is interesting that many circulating vasoactive substances do not affect the cerebral circulation because their large molecular size prevents them from crossing the blood-brain barrier. Pulmonary Circulation The regulation of pulmonary circulation is discussed fully in Chapter 5. Briefly, the pulmonary circulation is controlled by O2. The effect of O2 on pulmonary arteriolar resistance is the exact opposite of its effect in other vascular beds: In the pulmonary circulation, hypoxia causes vasoconstriction. This seemingly counterintuitive effect of O2 also is explained in Chapter 5. Briefly, regions of hypoxia in the lung cause local vasoconstriction, which effectively shunts blood away from poorly ventilated areas where the blood flow would be “wasted” and toward well-ventilated areas where gas exchange can occur.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 177 entirely clear, but it includes increased conversion of thyroxine (T4) to the active form, triiodothyronine (T3), in target tissues. Because thyroid hormones are thermogenic, it follows that an excess or deficit of thyroid hormones would cause disturbances in the regulation of body temperature. In hyperthyroidism (e.g., Graves disease, thyroid tumor), metabolic rate increases, O2 consump- tion increases, and heat production increases. In hypothyroidism (e.g., thyroiditis, surgical removal of the thyroid, iodine deficiency), there is a decreased metabolic rate, decreased O2 consumption, decreased heat production, and extreme sensitivity to cold. (For a complete discussion of this topic, refer to Chapter 9.) Sympathetic Nervous System Cold environmental temperatures activate the sympa- thetic nervous system. One consequence of this acti- vation is stimulation of β receptors in brown fat, which increases metabolic rate and heat production. This action of the sympathetic nervous system is synergistic with the actions of thyroid hormones: For thyroid hormones to produce maximal thermogenesis, the sympathetic nervous system must be simultaneously activated by cold temperatures. A second consequence of activation of the sympa- thetic nervous system is stimulation of α1 receptors in vascular smooth muscle of skin blood vessels, produc- ing vasoconstriction. Vasoconstriction reduces blood flow to the surface of the skin and, consequently, reduces heat loss. Shivering Shivering, which involves rhythmic contraction of skeletal muscle, is the most potent mechanism for increasing heat production in the body. Cold environ- mental temperatures activate centers in the posterior hypothalamus, which then activate the α and γ moto- neurons innervating skeletal muscle. The skeletal muscle contracts rhythmically, generating heat and raising body temperature. Mechanisms for Dissipating Heat When the environmental temperature increases, mechanisms are activated that result in increased heat loss from the body by radiation and convection. Since heat is a normal byproduct of metabolism, the body must dissipate this heat just to maintain body temperature at the set point. When the environmental temperature is increased, more heat than usual must be dissipated. Mechanisms for dissipating heat are coordinated in the anterior hypothalamus. Increased body tempera- ture decreases sympathetic activity in skin blood vessels. This decrease in sympathetic tone results in Skin Circulation The skin has blood vessels with dense sympathetic innervation, which controls its blood flow. The princi- pal function of the sympathetic innervation is to alter blood flow to the skin for regulation of body tempera- ture. For example, during exercise, as body temperature increases, sympathetic centers controlling cutaneous blood flow are inhibited. This selective inhibition pro- duces vasodilation in cutaneous arterioles so that warm blood from the body core can be shunted to the skin surface for dissipation of heat. Local vasodilator metabolites have little effect on cutaneous blood flow. The effects of vasoactive substances such as hista- mine have been discussed previously. In skin, the effects of histamine on blood vessels are visible. Trauma to the skin releases histamine, which produces a triple response in skin: a red line, a red flare, and a wheal. The wheal is local edema and results from histaminic actions that vasodilate arterioles and vasoconstrict veins. Together, these two effects produce increased Pc, increased filtration, and local edema. TEMPERATURE REGULATION Humans maintain a normal body temperature at a set point of 37°C (98.6°F). Because environmental temperatures vary greatly, the body has mechanisms, coordinated in the anterior hypothalamus, for both heat generation and heat loss to keep body temperature con- stant. When the environmental temperature decreases, the body generates and conserves heat. When the environmental temperature increases, the body reduces heat production and dissipates heat. Mechanisms for Generating Heat When environmental temperature is less than body temperature, mechanisms are activated that increase heat production and reduce heat loss. These mecha- nisms include stimulation of thyroid hormone produc- tion, activation of the sympathetic nervous system, and shivering. Behavioral components also may contribute by reducing the exposure of skin to the cold (e.g., wrapping arms around oneself, curling up in a ball, adding more clothing). Thyroid Hormones Thyroid hormones are thermogenic: Their actions on target tissues result in heat production. Major actions of thyroid hormone are stimulation of Na+-K+ ATPase, increased O2 consumption, increased metabolic rate, and increased heat production. Therefore it is logical that exposure to cold temperatures activates thyroid hormones. The mechanism for this activation is notWww.Medicalstudyzone.com
178 • Physiology interrupts the pathway that pyrogens utilize to raise the set-point temperature. When fever is treated with aspirin, the temperature sensors in the anterior hypo- thalamus now “see” body temperature as too high rela- tive to the set-point temperature and set in motion the mechanisms for dissipating heat including vasodilation and sweating. Disturbances of Temperature Regulation Heat exhaustion can occur as a consequence of the body’s responses to elevated environmental tempera- ture. Normally, the response to increased temperature includes vasodilation and sweating in order to dissipate heat. However, if the sweating is excessive, it can result in decreased ECF volume, decreased blood volume, decreased arterial pressure, and fainting. Heat stroke occurs when body temperature increases to the point of tissue damage. If the normal response to elevated environmental temperature is impaired (e.g., if sweating does not occur), then heat cannot be appropriately dissipated and core temperature increases to dangerous levels. Malignant hyperthermia is characterized by a massive increase in metabolic rate, increased O2 con- sumption, and increased heat production in skeletal muscle. The heat-dissipating mechanisms are unable to keep pace with the excessive heat production, and if the hyperthermia is not treated, body temperature may increase to dangerously high, or even fatal, levels. In susceptible individuals, malignant hyperthermia can be caused by inhalation anesthetics. INTEGRATIVE FUNCTIONS OF THE CARDIOVASCULAR SYSTEM The cardiovascular system always operates in an inte- grated manner. Thus it is impossible to discuss a change only in cardiac function (e.g., a change in contractility) without then considering the effect such a change would have on arterial pressure, on hemodynamics, on the reflexes involving the sympathetic and parasympa- thetic nervous systems, on the renin–angiotensin II– aldosterone system, on filtration from capillaries and lymph flow, and on the distribution of blood flow among the organ systems. The best and most enduring way to understand the integrative functions of the cardiovascular system is by describing its responses to exercise, to hemorrhage, and to changes in posture. Responses to Exercise The cardiovascular responses to exercise involve a combination of central nervous system (CNS) and local increased blood flow through skin arterioles and greater arteriovenous shunting of blood to venous plexuses near the surface of skin. In effect, warm blood from the body core is shunted to the body surface, and heat is then lost by radiation and convection. Shunting of blood to the surface is evidenced by redness and warmth of the skin. There also is increased activity of the sympathetic cholinergic fibers innervating thermo- regulatory sweat glands to produce increased sweating (cooling). The behavioral components to dissipate heat include increasing the exposure of skin to the air (e.g., removing clothing, fanning). Regulation of Body Temperature The temperature-regulating center is located in the anterior hypothalamus. This center receives informa- tion about environmental temperature from thermore- ceptors in the skin and about core temperature from thermoreceptors in the anterior hypothalamus itself. The anterior hypothalamus then orchestrates the appropriate responses, which may involve heat- generating or heat-dissipating mechanisms. If core temperature is below the set-point tempera- ture, then heat-generating and heat-retaining mecha- nisms are activated. As previously discussed, these mechanisms include increased metabolic rate (thyroid hormones, sympathetic nervous system), shivering, and vasoconstriction of blood vessels of the skin (increased sympathetic tone). If core temperature is above the set-point tempera- ture, then heat-dissipating mechanisms are activated. These mechanisms include vasodilation of blood vessels of the skin (decreased sympathetic tone) and increased activity of sympathetic cholinergic fibers to sweat glands. Fever Fever is an abnormal elevation of body temperature. Pyrogens produce fever by increasing the hypothalamic set-point temperature. The result of such a change in set point is that a normal core temperature is “seen” by the hypothalamic center as too low relative to the new set point. The anterior hypothalamus then acti- vates heat-generating mechanisms (e.g., shivering) to raise body temperature to the new set point. At the cellular level, the mechanism of pyrogen action is increased production of interleukin-1 (IL-1) in phagocytic cells. IL-1 then acts on the anterior hypothalamus to increase local production of prosta- glandins, which increase the set-point temperature. Fever can be reduced by aspirin, which inhibits the cyclooxygenase enzyme, necessary for the synthesis of prostaglandins. By inhibiting the production of prosta- glandins, aspirin (and other cyclooxygenase inhibitors)Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 179 constriction occurs via α1 receptors, which results in increased resistance and decreased blood flow to those organs. (2) In the exercising skeletal muscle, however, local metabolic effects override any sympathetic vaso- constricting effects, and arteriolar vasodilation occurs. (3) Other locations where vasoconstriction does not occur are in the coronary circulation (where blood flow increases to meet the increased level of myocardial O2 consumption) and the cerebral circulation. (4) In the cutaneous circulation, there is a biphasic response. Initially, vasoconstriction occurs (due to increased sym- pathetic outflow); later, however, as body temperature increases, there is selective inhibition of sympathetic cutaneous vasoconstriction (see Temperature Regula- tion, pages 177–178, resulting in vasodilation and dissipation of heat through the skin. In summary, there is vasoconstriction in some vas- cular beds so that blood flow can be redistributed to the exercising skeletal muscle and the heart, with blood flow being maintained in essential organs such as the brain. Local Responses in Muscle Local control of blood flow in the exercising skeletal muscle is orchestrated by active hyperemia. As the metabolic rate of the skeletal muscle increases, produc- tion of vasodilator metabolites such as lactate, K+, and adenosine also increases. These metabolites act directly on the arterioles of the exercising muscle to produce local vasodilation. Vasodilation of the arterioles results in increased blood flow to meet the increased meta- bolic demand of the muscle. This vasodilation in the exercising muscle also produces an overall decrease in TPR. (If these local metabolic effects in the exercising muscle did not occur, TPR would increase because the central command directs an increase in sympa- thetic outflow to the blood vessels, which produces vasoconstriction.) Overall Responses to Exercise The two components of the cardiovascular response to exercise, the central command and the effects of local metabolites, now can be viewed together (Table 4.8 and Fig. 4.35). The central command directs an increase in sympathetic outflow and a decrease in parasympa- thetic outflow. This produces an increase in cardiac output and vasoconstriction in several vascular beds (excluding exercising skeletal muscle, coronary, and cerebral circulations). The increase in cardiac output has two components: increased heart rate and increased contractility. The increase in contractility results in increased stroke volume and is represented by an increased pulse pressure (increased volume is pumped into the low-compliance arteries). Increased cardiac output is possible because venous return increases (Frank-Starling relationship). Venous return increases mechanisms. The CNS responses include a central command from the cerebral motor cortex, which directs changes in the autonomic nervous system. The local responses include effects of metabolites to increase blood flow and O2 delivery to the exercising skeletal muscle. Changes in arterial PO2, PCO2, and pH appar- ently play little role in directing these responses because none of these parameters changes significantly during moderate exercise. Central Command The central command refers to a series of responses, directed by the cerebral motor cortex, which are initi- ated by the anticipation of exercise. These reflexes are triggered by muscle mechanoreceptors, and possibly muscle chemoreceptors, when exercise is anticipated or initiated. Details concerning the afferent limb of this reflex (i.e., information traveling from the muscles to the CNS) are lacking. It is clear, however, that the efferent limb of the reflex produces increased sympa- thetic outflow to the heart and blood vessels and decreased parasympathetic outflow to the heart. One consequence of the central command is an increase in cardiac output. This increase is the result of two simultaneous effects on the heart. (1) The increase in sympathetic activity (β1 receptors) and the decrease in parasympathetic activity cooperate to produce an increase in heart rate. (2) The increase in sympathetic activity (β1 receptors) produces an increase in contractility and a resulting increase in stroke volume. Together, the increases in heart rate and stroke volume produce an increase in cardiac output. The increase in cardiac output is essential in the cardiovas- cular response to exercise. It ensures that more O2 and nutrients are delivered to the exercising skeletal muscle. (If cardiac output did not increase, for example, the only way to increase blood flow to the skeletal muscle would be through redistribution of blood flow from other organs.) Recall that cardiac output cannot increase without a concomitant increase in venous return (Frank- Starling relationship). In exercise, this concomitant increase in venous return is accomplished by two effects on the veins: The contraction of skeletal muscle around the v
180 • Physiology because there is sympathetic constriction of the veins (which reduces unstressed volume) and because of the squeezing action of the exercising skeletal muscle on the veins. A higher-than-normal percentage of this increased cardiac output will perfuse the exercising skeletal muscle because of local metabolic responses: Local metabolites produce vasodilation. Overall, TPR decreases because of this vasodilation in skeletal muscle, even though other vascular beds are vasocon- stricted. There is an increase in systolic arterial pressure and pulse pressure because of the increase in stroke volume. However, diastolic arterial pressure remains the same or may even decrease secondary to the decrease in TPR. TABLE 4.8 Summary of Cardiovascular Responses to Exercise Parameter Response to Exercise Heart rate ↑↑ Stroke volume ↑ Pulse pressure ↑ (increased stroke volume) Cardiac output ↑↑ Venous return ↑ Mean arterial pressure ↑ (slight) Total peripheral resistance (TPR) ↓↓ (vasodilation in skeletal muscle) Arteriovenous O2 difference ↑↑ (increased O2 consumption by tissues) EXERCISE LOCAL RESPONSES BLOOD FLOW TO SKELETAL MUSCLE Sympathetic outflow Parasympathetic outflow (heart rate only) Constriction of arterioles (splanchnic and renal) Cardiac output Constriction of veinsHeart rate Contractility Unstressed volume Venous return Vasodilator metabolites Dilation of skeletal muscle arterioles TPR CENTRAL COMMAND Fig. 4.35 Cardiovascular responses to exercise. TPR, Total peripheral resistance.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 181 Responses to Hemorrhage When a person loses a large quantity of blood, arterial pressure decreases rapidly, followed by a series of compensatory cardiovascular responses that attempt to restore arterial pressure back to normal and to sustain life (Fig. 4.36 and Box 4.3). Decreased Arterial Pressure—Initiating Event The initiating event in hemorrhage is loss of blood and decreased blood volume. Recall, by referring to Figure 4.29B, how a decrease in blood volume leads to a decrease in arterial pressure. When blood volume decreases, mean systemic pressure decreases and the vascular function curve shifts to the left. In the new steady state, the cardiac and vascular function curves intersect at a new equilibrium point, where both cardiac output and right atrial pressure are decreased. These events also can be understood without refer- ring to the graphs. Consider that when hemorrhaging Time (hours) 0 2 4 6 Mean arterial pressure (mm Hg) 50 100 Failure of compensatory responses Compensatory responses Hemorrhage Fig. 4.36 Effect of hemorrhage on mean arterial pressure (Pa). In some persons, compensatory responses to blood loss return Pa to normal within a few hours; in other persons, the compensatory response fails and irreversible shock and death occur. BOX 4.3 Clinical Physiology: Hypovolemic Shock DESCRIPTION OF CASE. Two teenagers, Adam and Ben, are involved in an automobile accident, and both suffer significant blood loss. They are taken to the nearest trauma center. Adam has a Pa of 55 mm Hg, a pulse pressure of 20 mm Hg, and a heart rate of 120 beats/min. He is anxious but alert, has a slightly decreased urine output, and has cool, pale skin. Ben has a Pa of 40 mm Hg, a barely measurable pulse pres- sure, and a heart rate of 160 beats/min. He is comatose, has no urine output, and is cold and cyanotic. Adam is treated by stopping the bleeding and admin- istering lactated Ringer solution intravenously and a blood transfusion. The physicians are prepared to administer a positive inotropic agent but find it unnec- essary because Adam shows signs of improvement. During the next 5 hours, Adam’s Pa increases back to normal and his heart rate simultaneously decreases to a normal value of 75 beats/min. His skin gradually warms, and the normal pink color returns. Ben is treated in the same way as Adam, but despite the efforts of the medical team, he dies. EXPLANATION OF CASE. These teenagers illustrate two different responses to significant blood loss. In the first patient, Adam, the blood loss led to decreased Pa (decreased blood volume → decreased mean systemic pressure → decreased venous return → decreased cardiac output → decreased Pa). The decreased Pa trig- gered the baroreceptor reflex, resulting in increased sympathetic outflow to the heart and blood vessels. As a result of the reflex, the patient’s heart rate increased in an attempt to increase cardiac output. There was vasoconstriction of several vascular beds (excluding the heart and brain) and increased TPR. Vasoconstriction of cutaneous blood vessels caused the skin to become cool and pale. Supportive therapy included intravenous infusion of buffered saline solution and transfusion, allowing the patient to fully recover. A positive inotro- pic agent might have been used to increase cardiac output; because the patient’s own reflex mechanisms increased myocardial contractility, it was unnecessary. In the second patient, Ben, the compensatory mechanisms failed. When compared with Adam, Ben’s Pa is lower, his stroke volume is much lower (he had no pulse pressure), his heart rate is much higher, and the vasoconstriction is more pronounced (his skin was cold). His kidneys are not producing urine, which may explain his deteriorating condition. Clearly, the barore- ceptor reflex is strongly activated because his heart rate is high and there is intense peripheral vasoconstriction. Vasoconstriction reduces blood flow to nonvital organs, such as skin, in order to preserve blood flow to vital organs such as the brain, heart, and kidneys. In this patient, vasoconstriction unfortunately extended to the vital organs, and the ischemic damage in them proved fatal. In this patient, myocardial ischemia and renal ischemia were particularly devastating: Without oxygen, his heart could not adequately function as a pump; without blood flow, his kidney could not produce urine. TREATMENT. Despite treatment, one patient dies. The other patient responds well to treatment, which includes stopping the bleeding and administering lactated Ringer solution and a blood transfusion.Www.Medicalstudyzone.com
182 • Physiology back toward the normal (prehemorrhagic) value. This increase in arterial pressure is the result of compensa- tory responses in the cardiovascular system (Fig. 4.37 and Table 4.9; see Fig. 4.36). In some persons the compensatory responses fail, and after a brief upswing, mean arterial pressure falls irreversibly and death ensues (i.e., irreversible shock). There are multiple reasons for this irreversible process including severe vasoconstriction of essential vascular beds and cardiac failure. Responses of the Baroreceptor Reflex Among the compensatory responses to a decrease in mean arterial pressure are those involved in the occurs, there is a decrease in total blood volume. The decrease in blood volume produces a decrease in venous return to the heart and a decrease in right atrial pressure. When venous return decreases, there is a corresponding decrease in cardiac output (Frank- Starling mechanism). The decrease in cardiac output then leads to a decrease in Pa because Pa is the product of cardiac output and TPR (Pa = cardiac output × TPR). Hence, cardiac output and Pa decrease almost immedi- ately, but thus far there has been no change in TPR (although TPR will change as a later compensatory response). Within the few hours immediately following hemor- rhage, arterial pressure gradually begins to increase Pa TOWARD NORMAL Sympathetic outflow Pc HEMORRHAGE BARORECEPTOR REFLEX CAPILLARIES Angiotensin II RENIN–ANGIOTENSIN II–ALDOSTERONE Pa Constriction of arterioles Constriction of veins TPR Unstressed volume Venous return Fluid absorptionAldosteroneTPR Blood volumeNa+ reabsorption Blood volume Cardiac output Heart rate Contractility Fig. 4.37 Cardiovascular responses to hemorrhage. Na+, Sodium; Pa, mean arterial pressure; Pc, capillary hydrostatic pressure; TPR, total peripheral resistance.Www.Medicalstudyzone.com
4—Cardiovascular Physiology • 183 blood being “held” on the arterial side (increased stressed volume and increased Pa). Responses of the Renin–Angiotensin II– Aldosterone System Another set of compensatory responses to the decrease in mean arterial pressure includes those of the renin– angiotensin II–aldosterone system. When Pa decreases, renal perfusion pressure decreases, which stimulates the secretion of renin from the renal juxtaglomerular cells. Renin, in turn, increases the production of angio- tensin I, which is then converted to angiotensin II. Angiotensin II has two major actions: (1) It causes arteriolar vasoconstriction, reinforcing and adding to the increase in TPR from the increased sympathetic outflow to the blood vessels. (2) It stimulates the secre- tion of aldosterone, which circulates to the kidney and causes increased reabsorption of Na+. By increasing total body Na+ content, aldosterone increases ECF volume, thereby raising blood volume and reinforcing the increase in stressed volume, which resulted from a shift of blood from the veins to the arteries. Responses in the Capillaries The compensatory responses to hemorrhage include changes in the Starling forces across capillary walls. These compensatory changes favor absorption of fluid into capillaries as follows: Increased sympathetic outflow to blood vessels and increased angiotensin II both produce arteriolar vasoconstriction. As a result of this vasoconstriction, there is a decrease in capillary hydrostatic pressure (Pc), which opposes filtration out of the capillary and favors absorption. Responses of Antidiuretic Hormone ADH is secreted in response to decreases in blood volume, mediated by volume receptors in the atria. ADH has two actions: (1) It increases water reabsorp- tion by the renal collecting ducts (V2 receptors), which helps to restore blood volume. (2) It causes arteriolar vasoconstriction (V1 receptors), which reinforces the vasoconstricting effects of sympathetic activity and angiotensin II. Other Responses in Hemorrhage If a person becomes hypoxemic (has decreased arterial PO2) following a hemorrhage, chemoreceptors in the carotid and aortic bodies sense the decrease in PO2 and respond by increasing sympathetic outflow to the blood vessels. As a result, there is vasoconstriction, increased TPR, and increased Pa. This mechanism aug- ments the baroreceptor reflex (which senses the decreased Pa rather than the decreased PO2). If cerebral ischemia occurs following a hemorrhage, there will be a local increase in PCO2 and a decrease in pH. These changes activate chemoreceptors in the baroreceptor reflex. Baroreceptors in the carotid sinus detect the decrease in Pa and relay the information to the medulla via the carotid sinus nerve. The medulla coordinates an output that is intended to increase Pa back toward normal: Sympathetic outflow to the heart and blood vessels increases, and parasympathetic outflow to the heart decreases. The four consequences of these autonomic reflexes are (1) increased heart rate, (2) increased contractility, (3) increased TPR (due to arteriolar vasoconstriction in many vascular beds, but sparing of the coronary and cerebral vas- cular beds), and (4) constriction of the veins, which reduces unstressed volume, increases venous return, and increases stressed volume. Notice that each of these four cardiovascular responses occurs in the direction of increasing Pa. Constriction of the veins (which decreases their compli- ance or capacitance) returns more blood to the heart, increases venous return and cardiac output, and shifts blood from the venous to the arterial side of the circula- tion. Increased heart rate and increased contractility result in increased cardiac output, which is possible because of the increased venous return. Finally, con- striction of arterioles and increased TPR result in more TABLE 4.9 Summary of Cardiovascular Responses to Hemorrhage Parameter Compensatory Response to Hemorrhagea Carotid sinus nerve firing rate ↓ Heart rate ↑ Contractility ↑ Cardiac output ↑ Unstressed volume ↓ (produces an increase in venous return) Total peripheral resistance (TPR) ↑ Renin ↑ Angiotensin II ↑ Aldosterone ↑ Circulating epinephrine ↑ (secreted from adrenal medulla) Antidiuretic hormone (ADH) ↑ (stimulated by decreased blood volume) aThese compensatory responses should be compared with values immediately after the hemorrhage occurs, not with the prehemor- rhagic values. For example, the compensatory increase in cardiac output does not mean that cardiac output is higher than it is in a normal person: It means that cardiac output is higher than just after the hemorrhage occurred.Www.Medicalstudyzone.com
184 • Physiology medullary vasomotor center to increase sympathetic outflow to blood vessels, resulting in peripheral vaso- constriction, increased TPR, and increased Pa. Responses to Changes in Posture The cardiovascular responses to a change in posture (or gravity) are illustrated in a person who changes from a supine (lying) position to a standing position. A person who stands up too quickly may briefly experi- ence orthostatic hypotension (i.e., a decrease in arte- rial blood pressure upon standing), light-headedness, and possibly fainting. Normally, a series of fast com- pensatory cardiovascular responses involving the baroreceptor reflex occurs to offset this brief, initial decrease in Pa (Fig. 4.38 and Table 4.10). Pooling of Blood in the Extremities— Initiating Event When a person moves from a supine to a standing position, blood pools in the veins of the lower extremi- ties. The capacitance of the veins allows for large blood STANDING Pa TOWARD NORMAL BARORECEPTOR REFLEX Constriction of arterioles Constriction of veins Unstressed volume Venous returnCardiac output Heart rate Contractility Pooling of blood in veins Sympathetic outflow Pa TPR Fig. 4.38 Cardiovascular responses in a person moving from a supine to a standing position. Pa, Mean arterial pressure; TPR, total peripheral resistance. volumes to accumulate. When blood pools in the veins, venous return to the heart decreases and cardiac output decreases (Frank-Starling mechanism), which results in a decrease in mean arterial pressure. Venous pooling also causes increased capillary hydro- static pressure in the veins of the legs, which results in increased filtration of fluid into the interstitial fluid with a loss of intravascular volume. For example, if a person stands for an extended period of time (e.g., a soldier who is standing at attention), filtration from capillaries can exceed the ability of the lymphatics to return fluid to the circulation, which results in edema formation in the lower extremities. Increased filtration of fluid out of the capillaries contributes further to the decreased venous return and decreased Pa. If the decrease in Pa is dramatic, then cerebral blood pressure may decrease and cause fainting. Response of the Baroreceptor Reflex The primary compensatory cardiovascular response to the decrease in mean arterial pressure involves the baroreceptor reflex. As blood pools in the veins of theWww.Medicalstudyzone.com
4—Cardiovascular Physiology • 185 TABLE 4.10 Summary of Cardiovascular Responses to Standing Parameter Initial Response to Standing Compensatory Response Mean arterial pressure ↓ ↑ (toward normal) Heart rate — ↑ Stroke volume ↓ (decreased venous return) ↑ (toward normal) Cardiac output ↓ (decreased stroke volume) ↑ (toward normal) Total peripheral resistance (TPR) — ↑ Central venous pressure ↓ (pooling of blood in lower extremities) ↑ (toward normal) BOX 4.4 Clinical Physiology: Orthostatic Hypotension DESCRIPTION OF CASE. A 32-year-old woman is recovering from a bout of “intestinal flu.” She has been unable to eat or drink for the past 36 hours. Feeling slightly better after a good night’s sleep, she decides that it’s time to return to work. Realizing that she has slept through her alarm, she jumps out of bed, feels light-headed, and fears that she might faint. She has the sensation that her heart is racing. Wisely, she returns to bed and decides to allow herself one more day of recovery. EXPLANATION OF CASE. The woman has the classic signs of orthostatic hypotension, whereby arterial pres- sure decreases on standing up. When a person moves from a supine (lying) to a standing position, blood pools in the veins of the legs. This pooling decreases venous return, which decreases cardiac output by the Frank-Starling mechanism. The decrease in cardiac output then causes a decrease in Pa. In this woman, the decrease in venous return, cardiac output, and Pa are exaggerated because of decreased ECF volume (volume depletion) secondary to gastrointestinal fluid losses. The woman feels light-headed because decreased Pa causes a decrease in cerebral blood flow. The sensation of a racing heart is a component of the baroreceptor reflex. Baroreceptors located in the carotid sinus and aortic arch sense the decrease in Pa. The baroreceptor reflex then orchestrates a series of compensatory responses, including increased sympa- thetic outflow to the heart and blood vessels. The four consequences of the increased sympathetic outflow include increased heart rate (racing heart), mediated by β1-adrenergic receptors in the sinoatrial node; increase contractility, mediated by β1-adrenergic recep- tors in ventricular muscle; increased TPR (arteriolar constriction), mediated by α1-adrenergic receptors on arterioles; and increased venous return (venoconstric- tion) mediated by β1-adrenergic receptors on veins. TREATMENT. The woman needs volume repletion to restore her ECF volume. Once her ECF volume is normal, then she will no longer experience an exagger- ated decrease in Pa on standing up. lower extremities and is not returned to the heart, both cardiac output and Pa decrease. The baroreceptors in the carotid sinus detect this decrease in Pa and send this information to the medullary vasomotor center. The vasomotor center directs an increase in sympa- thetic outflow to the heart and blood vessels and a decrease in parasympathetic outflow to the heart, attempting to increase Pa back to normal. The results of these autonomic changes now are familiar: increased heart rate, increased contractility, constriction of arte- rioles (increased TPR), and constriction of the veins (decreased unstressed volume and increased venous return). Collectively, these changes increase cardiac output and increase TPR, attempting to restore Pa back to normal (Box 4.4). Box 4.5 describes heart failure and further illustrates the integrative nature of the cardiovascular system.Www.Medicalstudyzone.com
186 • Physiology ■ Velocity of blood flow is proportional to the rate of volume flow and inversely proportional to the cross-sectional area. Velocity is lowest in the capil- laries, which have the largest cross-sectional area. ■ Blood flow is proportional to the size of the pressure gradient and inversely proportional to the resistance of the blood vessels. ■ Resistance to blood flow is proportional to the vis- cosity of blood and vessel length and inversely proportional to vessel radius to the fourth power. The arterioles are the site of highest resistance in the vasculature. Resistances can be arranged in series or in parallel. SUMMARY ■ The cardiovascular system is composed of the heart and blood vessels. The heart, by contracting, pumps blood through the systemic and pulmonary vascu- latures. Blood vessels act as conduits that deliver blood to the tissues. The thin-walled capillaries serve as the site of exchange of nutrients and waste products. ■ Hemodynamics are the principles that govern blood flow: velocity of flow; flow, pressure, and resistance relationships; and compliance of blood vessels. BOX 4.5 Clinical Physiology: Heart Failure DESCRIPTION OF CASE. A 60-year-old woman is admitted to the hospital after complaining of extreme fatigue and weakness, shortness of breath (dyspnea), and swelling of her ankles. Her clothes no longer fit around the waist, and she has gained 3 kg in the past month. She finds that breathing is particularly difficult when lying down (orthopnea). Sleeping propped on several pillows no longer brings her relief. She has a history of chest pain and shortness of breath upon exertion. Her physical examination reveals cyanosis (blue skin tone), rapid respirations, rapid pulse, distended neck veins, ascites (fluid) in the abdomen, edema in the ankles, and cold clammy skin. Her ventricular ejection fraction is 0.30. Her systolic pressure is 100 mm Hg, with a reduced pulse pressure. She is treated with digoxin and a diuretic and placed on a low-sodium diet. EXPLANATION OF CASE. The woman’s signs and symptoms are a classic presentation of heart failure. The history of angina (chest pain) suggests that block- age of the coronary arteries has resulted in insufficient blood flow to the heart. With insufficient coronary blood flow, there is inadequate oxygen delivery to the working myocardial cells and the ventricles are unable to develop normal pressures for ejection of blood during systole. A negative inotropic state develops in the ventricles, resulting in decreased contractility and decreased stroke volume for a given end-diastolic volume (downward shift of the Frank-Starling relation- ship; see Fig. 4.21). The decreased stroke volume is reflected both in the reduced pulse pressure and in the reduced ejection fraction of 0.30 (normal value is 0.55): A smaller-than-normal fraction of the end-diastolic volume is ejected during systole. Although not stated explicitly, cardiac output is also reduced. Cyanosis and easy fatigability are signs of inadequate blood flow to the tissues and inadequate oxygenation of blood. The woman has edema (accumulation of interstitial fluid) in the lungs, as evidenced by shortness of breath, and in the peripheral tissues. Edema fluid accumulates when filtration out of capillaries exceeds the capacity of the lymphatics. In her case, there is increased filtra- tion from capillaries because of a rise in venous pres- sure (note the distended neck veins). Venous pressure increases because blood “backs up” on the venous side of the circulation, as the ventricles are unable to effi- ciently eject blood during systole. Both left and right ventricles apparently have failed because edema has formed in the lungs (left heart failure) and in the periphery (right heart failure). The baroreceptor reflex is activated in response to the decrease in Pa. (Pa is decreased because blood has shifted from the arterial to the venous side of the cir- culation, as the ventricles failed to pump adequately.) The woman’s increased pulse rate and cold clammy skin result from the baroreceptor reflex: Decreased Pa activates the baroreceptors, causing an increased sym- pathetic outflow to the heart and blood vessels (increases heart rate and produces cutaneous vasocon- striction) and decreased parasympathetic outflow to the heart (also increases heart rate). TPR, if measured, would be increased as a result of sympathetic vasocon- striction of many vascular beds, in addition to that of the skin. The renin–angiotensin II–aldosterone system also is activated by the low Pa, and the increased levels of angiotensin II contribute to peripheral vasoconstriction. The increased levels of aldosterone increase Na+ reab- sorption, total body Na+ content, and ECF volume, perpetuating the cycle of edema formation. TREATMENT. Treatment involves two strategies: (1) to increase contractility of the myocardial cells by admin- istering a positive inotropic agent such as digoxin and (2) to reduce total body
4—Cardiovascular Physiology • 187 ■ Compliance is the relationship between volume and pressure: The higher the compliance of a blood vessel, the greater the volume contained at a given pressure. Veins have high compliance and hold large volumes of blood (the unstressed volume) at low pressure. Arteries have low compliance and hold small volumes of blood (the stressed volume) at high pressure. ■ The cardiac action potential is initiated in the SA node, which depolarizes spontaneously. The action potential spreads in a specific sequence throughout the myocardium via a specialized conducting system. Conduction is rapid, except through the AV node, where slow conduction ensures ample time for ventricular filling prior to contraction. ■ In atria and ventricles, the upstroke of the action potential is the result of an inward Na+ current. The action potential in the atria and ventricles exhibits a plateau, which is the result of an inward Ca2+ current. This plateau accounts for the action poten- tial’s long duration and long refractory period. ■ In the SA node, the upstroke of the action potential is the result of an inward Ca2+ current. The SA node exhibits slow, spontaneous depolarization during phase 4, which brings the cells to threshold to fire action potentials. Slow depolarization is the result of an inward Na+ current (If). ■ Excitation-contraction coupling in myocardial cells is similar to that in skeletal muscle. In myocardial cells, however, Ca2+ entering the cell during the plateau of the action potential serves as a trigger for the release of more Ca2+ from the sarcoplasmic reticulum. Ca2+ then binds to troponin C to allow actin-myosin interaction and cross-bridge formation. ■ Inotropism or contractility is the ability of the myo- cardial cell to develop tension at a given cell length: Intracellular [Ca2+] determines the degree of inotro- pism, with positive inotropic agents increasing intracellular [Ca2+] and contractility. ■ Myocardial cells and the myocardium exhibit a length-tension relationship based on the degree of overlap of contractile elements. The Frank-Starling law of the heart describes this relationship between cardiac output and end-diastolic volume. End- diastolic volume reflects venous return. Therefore cardiac output is determined by venous return, and in the steady state, cardiac output and venous return are equal. ■ Pa is the product of cardiac output and TPR. Pa is carefully monitored and maintained at a normal value of 100 mm Hg. The baroreceptor reflex is a fast, neural mechanism that detects changes in Pa Challenge Yourself Answer each question with a word, phrase, sentence, or numerical solution. When a list of possible answers is supplied with the question, one, more than one, or none of the choices may be correct. Correct answers are provided at the end of the book. 1 What are the units of hemodynamic resistance? 2 If heart rate is 75 beats/min, what is the R-R interval in units of milliseconds? 3 What is the correct order of the following events: Ca2+ binding to troponin C, tension, Ca2+ release from sarcoplasmic reticulum, ventricular action potential, Ca2+ accumulation by sarcoplasmic reticulum? 4 If heart rate is 85 beats/min, end-diastolic volume is 150 mL, and stroke volume is 75 mL, what is the ejection fraction? 5 Which portion of the cardiac cycle has the lower ventricular volume: atrial systole or isovolumetric ventricular relaxation? 6 According to the cardiac and vascular function curves, an increase in blood volume leads to _______ right atrial pressure and _______ cardiac output. 7 If cardiac output is 5.2 L/min, heart rate is 76 beats/min, and end-diastolic volume is 145 mL, what is the end-systolic volume? and orchestrates changes in sympathetic and para- sympathetic outflow to the heart and blood vessels to restore Pa back to normal. The renin–angiotensin II–aldosterone system is a slower, hormonal mecha- nism that detects changes in Pa and, via aldosterone, restores Pa to normal through changes in blood volume. ■ The exchange of fluid across capillary walls is deter- mined by the balance of Starling forces. The net Starling pressure determines whether there will be filtration out of the capillary or absorption into the capillary. If filtration of fluid exceeds the ability of the lymphatics to return it to the circulation, then edema occurs. ■ The blood flow to the organ systems is a variable percentage of the cardiac output. Blood flow is determined by arteriolar resistance, which can be altered by vasodilator metabolites or by sympathetic innervation.Www.Medicalstudyzone.com
188 • Physiology 8 In a capillary, if Pc is 35 mm Hg, πc is 25 mm Hg, Pi is 2 mm Hg, and πi is 1 mm Hg, is there net absorption or filtration, and what is the magnitude of the driving force? 9 When a person moves quickly from a lying to a standing position, which of the following decrease(s): venous return, cardiac output, arterial pressure (Pa)? 10 What is the name of the volume contained in the left ventricle immediately before it contracts? 11 Which of the following produce(s) an increase in contractility: decreased heart rate, increased phosphorylation of phospholamban, increased action potential duration? 12 During which phase of the ventricular action potential, phase 0 or phase 4, is inward current greater than outward current? 13 Which term best applies to the ARP of the ventricular action potential: automaticity, excitability, conduction velocity, maximum diastolic potential? 14 If, simultaneously, there is an increased rate of phase 4 depolarization and hyperpolarization of the threshold potential, will there be an increase, decrease, or no change in heart rate? 15 Among the responses that occur following hemorrhage, which of the following increase(s): unstressed volume, heart rate, resistance of cutaneous vascular beds, firing rate of carotid sinus nerves, angiotensin II levels? 16 In the myogenic mechanism of autoregulation, according to the law of Laplace, does an increase in pressure lead to an increase, decrease, or no change in the radius of the blood vessel? 17 Of the following, which circulation receives the highest percentage of the cardiac output: renal, pulmonary, coronary, skeletal muscle during intense exercise, skin during intense exercise? 18 Which of the following cause(s) an increase in stroke volume from the left ventricle: increased contractility, decrease in end-diastolic volume, increase in aortic pressure? 19 During which portion(s) of the cardiac cycle is the aortic valve open: atrial systole, rapid ventricular ejection, diastasis? 20 According to the cardiac and vascular function curves, an increase in TPR leads to _______ venous return and _______ cardiac output. 21 Which situation is associated with the higher efficiency of myocardial oxygen consumption: increased cardiac output secondary to increased heart rate or decreased cardiac output secondary to increased aortic pressure? 22 Three resistors, each with a value of 10, are arranged in parallel. How much does total resistance change if a fourth resistor with a value of 10 is added in parallel? 23 Blood vessel “A” has a cross-sectional area of 1 cm2, and blood vessel “B” has a cross-sectional area of 10 cm2. If blood flow through the two vessels is the same, in which vessel is velocity of blood flow higher? 24 Where am I? For each item in the following list, give its correct location in the cardiovascular system. The location may be anatomic, a graph or portion of a graph, an equation, or a concept. Dicrotic notch β1 receptors Lmax Radius to the fourth power Phospholamban Negative dromotropic effect Pulse pressure Normal automaticity Ejection fraction 25 During which portions(s) of the cardiac cycle is the mitral valve closed: atrial systole, rapid ventricular ejection, isovolumetric ventricular relaxation, diastasis? 26 During exercise, which of the following decrease(s): heart rate, venous return, stroke volume, diameter of splanchnic arterioles, TPR? 27 According to the ventricular pressure-volume loop, an increase in afterload produces an increase in which of the following: end-diastolic volume, end-diastolic pressure, end-systolic volume, stroke volume? 28 Which of the following is/are mediated by an increase in ICa: sympathetic effect to increase heart rate, parasympathetic effect to decrease heart rate, sympathetic effect to increase contractility, parasympathetic effect to decrease conduction velocity in AV node?Www.Medicalstudyzone.com
189 CHAPTER 5 Respiratory Physiology Structure of the Respiratory System, 189 Lung Volumes and Capacities, 191 Mechanics of Breathing, 197 Gas Exchange, 209 Oxygen Transport in Blood, 216 Carbon Dioxide Transport in Blood, 223 Ventilation/Perfusion Relationships, 225 Control of Breathing, 231 Integrative Functions, 235 Hypoxemia and Hypoxia, 239 Summary, 241 Challenge Yourself, 242 The function of the respiratory system is the exchange of oxygen and carbon dioxide between the environ- ment and the cells of the body. Fresh air is brought into the lungs during the inspiratory phase of the breath- ing cycle, oxygen and carbon dioxide are exchanged between inspired air and pulmonary capillary blood, and the air is then expired. STRUCTURE OF THE RESPIRATORY SYSTEM Airways The respiratory system includes the lungs and a series of airways that connect the lungs to the external envi- ronment. The structures of the respiratory system are subdivided into a conducting zone (or conducting airways), which brings air into and out of the lungs, and a respiratory zone lined with alveoli, where gas exchange occurs. The functions of the conducting and respiratory zones differ, and the structures lining them also differ (Fig. 5.1). Conducting Zone The conducting zone includes the nose, nasopharynx, larynx, trachea, bronchi, bron- chioles, and terminal bronchioles. These structures function to bring air into and out of the respiratory zone for gas exchange and to warm, humidify, and filter the air before it reaches the critical gas exchange region. The progressively bifurcating airways are referred to by their generation number. The trachea, which is the zeroth generation, is the main conducting airway. The trachea divides into the right and left mainstem bronchi (the first generation), which divide into two smaller bronchi, which divide again. Ultimately, there are 23 such divisions into increasingly smaller airways, culminating in the airways of the 23rd generation. The conducting airways are lined with mucus-secreting and ciliated cells that function to remove inhaled particles. Although large particles usually are filtered out in the nose, small particles may enter the airways, where they are captured by mucus, which is then swept upward by the rhythmic beating of the cilia. The walls of the conducting airways contain smooth muscle. This smooth muscle has both sympathetic and parasympathetic innervations, which have opposite effects on airway diameter: (1) Sympathetic adrenergic neurons activate β2 receptors on bronchial smooth muscle, which leads to relaxation and dilation of the airways. In addition, andWww.Medicalstudyzone.com
190 • Physiology alveoli occasionally bud off their walls. The alveolar ducts are completely lined with alveoli, but they contain no cilia and little smooth muscle. The alveolar ducts terminate in alveolar sacs, which also are lined with alveoli. The alveoli are pouchlike evaginations of the walls of the respiratory bronchioles, the alveolar ducts, and the alveolar sacs. Each lung has a total of approximately 300 million alveoli. The diameter of each alveolus is approximately 200 micrometers (μm). Exchange of oxygen (O2) and carbon dioxide (CO2) between alveolar gas and pulmonary capillary blood can occur rapidly and efficiently across the alveoli because alveolar walls are thin and have a large surface area for diffusion. The alveolar walls are rimmed with elastic fibers and lined with epithelial cells, called type I and type II pneumocytes (or alveolar cells). Type II pneumocytes synthesize pulmonary surfactant (necessary for reduc- tion of surface tension of alveoli) and have regenerative capacity for the type I and type II pneumocytes. The alveoli contain phagocytic cells called alveolar macrophages. Alveolar macrophages keep the alveoli free of dust and debris because the alveoli have no cilia what is more important, these β2 receptors are activated by circulating epinephrine released from the adrenal medulla and by β2-adrenergic agonists such as isopro- terenol. (2) Parasympathetic cholinergic neurons acti- vate muscarinic receptors, which leads to contraction and constriction of the airways. Changes in diameter of the conducting airways result in changes in their resistance, which produce changes in air flow. Thus the effects of the autonomic nervous system on airway diameter have predictable effects on airway resistance and air flow. The most notable effects are those of β2-adrenergic agonists (e.g., epinephrine, isoproterenol, albuterol), which are used to dilate the airways in the treatment of asthma. Respiratory Zone The respiratory zone includes the structures that are lined with alveoli and therefore participate in gas exchange: the respiratory bronchioles, alveolar ducts, and alveolar sacs. The respiratory bronchioles are transitional structures. Like the conducting airways, they have cilia and smooth muscle, but they also are considered part of the gas exchange region because Trachea CONDUCTING ZONE RESPIRATORY ZONE Bronchi Bronchioles Respiratory bronchioles Alveolar ducts Alveolar sacs CiliaNumber Smooth Muscle Yes1 Yes Yes 4 8 2 Yes Yes– Yes Some– Some No– Some No6 108 No Cartilage Yes Patchy No No No No Fig. 5.1 Structure of the airways. The number of the various structures is reported for two lungs.Www.Medicalstudyzone.com
5—Respiratory Physiology • 191 (RV), which is approximately 1200 mL and cannot be measured by spirometry. Lung Capacities In addition to these lung volumes, there are several lung capacities; each lung capacity includes two or more lung volumes. The inspiratory capacity (IC) is composed of the tidal volume plus the inspiratory reserve volume and is approximately 3500 mL (500 mL + 3000 mL). The functional residual capacity (FRC) is composed of the expiratory reserve volume (ERV) plus the RV, or approximately 2400 mL (1200 mL + 1200 mL). FRC is the volume remaining in the lungs after a normal tidal volume is expired and can be thought of as the equilibrium volume of the lungs. The vital capacity (VC) is composed of the IC plus the expiratory reserve volume, or approximately 4700 mL (3500 mL + 1200 mL). Vital capacity is the volume that can be expired after maximal inspiration. Its value increases with body size, male gender, and physical conditioning and decreases with age. Finally, as the terminology suggests, the total lung capacity (TLC) includes all of the lung volumes: It is the vital capacity plus the RV, or 5900 mL (4700 mL + 1200 mL). Because RV cannot be measured by spirometry, lung capacities that include the RV also cannot be measured by spirometry (i.e., FRC and TLC). Of the lung capaci- ties not measurable by spirometry, the FRC (the volume remaining in the lungs after a normal expiration) is of greatest interest because it is the resting or equilibrium volume of the lungs. Two methods are used to measure FRC: helium dilution and the body plethysmograph. ♦ In the helium dilution method, the subject breathes a known amount of helium, which has been added to the spirometer. Because helium is insoluble in blood, after a few breaths the helium concentration in the lungs becomes equal to that in the spirometer, which can be measured. The amount of helium that was added to the spirometer and its concentration in the lungs are used to “back-calculate” the lung volume. If this measurement is made after a normal tidal volume is expired, the lung volume being calculated is the FRC. ♦ The body plethysmograph employs a variant of Boyle’s law, which states that for gases at constant temperature, gas pressure multiplied by gas volume is constant (P × V = constant). Therefore if volume increases, pressure must decrease, and if volume decreases, pressure must increase. To measure FRC, the subject sits in a large airtight box called a ple- thysmograph. After expiring a normal tidal volume, the mouthpiece to the subject’s airway is closed. The subject then attempts to breathe. As the subject tries to perform this function. Macrophages fill with debris and migrate to the bronchioles, where the beating cilia carry debris to the upper airways and the pharynx, where it can be swallowed or expectorated. Pulmonary Blood Flow Pulmonary blood flow is the cardiac output of the right heart. It is ejected from the right ventricle and delivered to the lungs via the pulmonary artery (see Chapter 4, Fig. 4.1). The pulmonary arteries branch into increas- ingly smaller arteries and travel with the bronchi toward the respiratory zones. The smallest arteries divide into arterioles and then into the pulmonary capillaries, which form dense networks around the alveoli. Because of gravitational effects, pulmonary blood flow is not distributed evenly in the lungs. When a person is standing, blood flow is lowest at the apex (top) of the lungs and highest at the base (bottom) of the lungs. When the person is supine (lying down), these gravitational effects disappear. The physiologic significance of regional variations in blood flow is discussed later in the chapter. As in other organs, regulation of pulmonary blood flow is accomplished by altering the resistance of the pulmonary arterioles. Changes in pulmonary arteriolar resistance are controlled by local factors, mainly O2. Bronchial circulation is the blood supply to the conducting airways (which do not participate in gas exchange) and is a very small fraction of the total pulmonary blood flow. LUNG VOLUMES AND CAPACITIES Lung Volumes Static volumes of the lung are measured with a spirom- eter (Table 5.1). Typically, the subject is sitting and breathes into and out of the spirometer, displacing a bell. The volume displaced is recorded on calibrated paper (Fig. 5.2). First, the subject is asked to breathe quietly. Normal, quiet breathing involves inspiration and expiration of a tidal volume (VT). Normal tidal volume is approxi- mately 500 mL and includes the volume of air that fills the alveoli plus the volume of air that fills the airways. Next, the subject is asked to take a maximal inspi- ration, followed by a maximal expiration. With this maneuver, additional lung volumes are revealed. The additional volume that can be inspired above tidal volume is called the inspiratory reserve volume, which is approximately 3000 mL. The additional volume that can be expired below tidal volume is
TABLE 5.1 Abbreviations and Normal Values Associated With Respiratory Physiology Abbreviation Meaning Normal Value P Gas pressure or partial pressure Q̇ Blood flow V Gas volume V̇ Gas flow rate F Fractional concentration of gas A Alveolar gas a Arterial blood V Venous blood E Expired gas I Inspired gas L Transpulmonary TM Transmural Arterial Blood PaO2 Partial pressure of O2 in arterial blood 100 mm Hg PaCO2 Partial pressure of CO2 in arterial blood 40 mm Hg Mixed Venous Blood PVO2 Partial pressure of O2 in mixed venous blood 40 mm Hg PVCO2 Partial pressure of CO2 in mixed venous blood 46 mm Hg Inspired Air PIO2 Partial pressure of O2 in dry inspired air 160 mm Hg (sea level) PICO2 Partial pressure of CO2 in dry inspired air 0 mm Hg Alveolar Air PAO2 Partial pressure of O2 in alveolar air 100 mm Hg PACO2 Partial pressure of CO2 in alveolar air 40 mm Hg Respiratory Volumes and Rates TLC Total lung capacity 6.0 L FRC Functional residual capacity 2.4 L VC Vital capacity 4.7 L VT Tidal volume 0.5 L V̇A Alveolar ventilation — — Breathing rate 15 breaths/min VD Physiologic dead space 0.15 L FVC Forced vital capacity 4.7 L FEV1 Volume of forced vital capacity expired in 1 second — Constants PB Atmospheric (barometric) pressure 760 mm Hg (sea level) PH2O Water vapor pressure 47 mm Hg (37°C) STPD Standard temperature, pressure, dry 273 K, 760 mm Hg BTPS Body temperature, pressure, saturated 310 K, 760 mm Hg, 47 mm Hg — Solubility of O2 in blood 0.003 mL O2/100 mL blood per mm Hg — Solubility of CO2 in blood 0.07 mL CO2/100 mL blood per mm Hg Other Values — Hemoglobin concentration 15 g/100 mL blood — O2-binding capacity of hemoglobin 1.34 mL O2/g hemoglobin V̇O2 O2 consumption 250 mL/min V̇CO2 CO2 production 200 mL/min R Respiratory exchange quotient (CO2 production/O2 consumption) 0.8Www.Medicalstudyzone.com
5—Respiratory Physiology • 193 exchange (“already been there, done that”). The next air to enter the alveoli is fresh air from the inspired tidal volume (350 mL), which will undergo gas exchange. The rest of the tidal volume (150 mL) does not make it to the alveoli but remains in the conducting airways; this air will not participate in gas exchange and will be the first air expired. (A related point arises from this discussion: The first air expired is dead space air that has not undergone gas exchange. To sample alveolar air, one must sample end-expiratory air.) Physiologic Dead Space The concept of physiologic dead space is more abstract than the concept of anatomic dead space. By definition, the physiologic dead space is the total volume of the lungs that does not participate in gas exchange. Physio- logic dead space includes the anatomic dead space of the conducting airways plus a functional dead space in the alveoli. The functional dead space can be thought of as ventilated alveoli that do not participate in gas exchange. The most important reason that alveoli do not partici- pate in gas exchange is a mismatch of ventilation and perfusion, or so-called ventilation/perfusion defect, in which ventilated alveoli are not perfused by pulmonary capillary blood. In normal persons, the physiologic dead space is nearly equal to the anatomic dead space. In other words, alveolar ventilation and perfusion (blood flow) are normally well matched and functional dead space is small. In certain pathologic situations, however, the physiologic dead space can become larger than the anatomic dead space, suggesting a ventilation/perfusion to inspire, the volume in the subject’s lungs increases and the pressure in his or her lungs decreases. Simultaneously, the volume in the box decreases, and the pressure in the box increases. The increase in pressure in the box can be measured and, from it, the preinspiratory volume in the lungs can be calculated, which is the FRC. Dead Space Dead space is the volume of the airways and lungs that does not participate in gas exchange. Dead space is a general term that refers to both the anatomic dead space of the conducting airways and a functional, or physiologic, dead space. Anatomic Dead Space The anatomic dead space is the volume of the con- ducting airways including the nose (and/or mouth), trachea, bronchi, and bronchioles. It does not include the respiratory bronchioles and alveoli. The volume of the conducting airways is approximately 150 mL. Thus for example, when a tidal volume of 500 mL is inspired, the entire volume does not reach the alveoli for gas exchange; 150 mL fills the conducting airways (the anatomic dead space, where no gas exchange occurs), and 350 mL fills the alveoli. Figure 5.3 shows that at the end of expiration the conducting airways are filled with alveolar air; that is, they are filled with air that has already been in the alveoli and exchanged gases with pulmonary capillary blood. With the inspiration of the next tidal volume, this alveolar air is first to enter the alveoli, although it will not undergo further gas Lung volumes Lung capacities Inspiratory reserve volume (3000 mL) Tidal volume (500 mL) Expiratory reserve volume (1200 mL) Residual volume (1200 mL) Inspiratory capacity Functional residual capacity Total lung capacity Vital capacity Fig. 5.2 Lung volumes and capacities. Measurements of lung volumes and capacities are made by spirometry. Residual volume cannot be measured by spirometry.Www.Medicalstudyzone.com
194 • Physiology V Physiologic dead space mLD = ( ) V Tidal volume mLT = ( ) Pa Pco of arterial blood mm HgCO2 2= ( ) P Pco of mixed expired air mm HgECO2 2= ( ) In words, the equation states that the volume of the physiologic dead space is the tidal volume (volume inspired with a single breath) multiplied by a fraction. The fraction represents the dilution of alveolar PCO2 by dead space air (which contributes no CO2). To better appreciate the equation and its application, consider two extreme examples. In the first example, assume that physiologic dead space is zero; in the second example, assume that physiologic dead space is equal to the entire tidal volume. In the first example, in which dead space is zero, the PCO2 of expired air (PECO2) will be the same as the PCO2 of alveolar gas (PACO2) and arterial blood (PaCO2) because there is no “wasted” ventilation: The fraction in the equation is equal to zero, and thus the calculated value of VD is zero. In the second example, in which dead space is equal to the entire tidal volume, there is no gas exchange: Therefore PECO2 will be zero, the fraction will be 1.0, and VD will be equal to VT. Ventilation Rates Ventilation rate is the volume of air moved into and out of the lungs per unit time. Ventilation rate can be expressed either as the minute ventilation, which is the total rate of air movement into and out of the lungs, or defect. The ratio of physiologic dead space to tidal volume provides an estimate of how much ventilation is “wasted” (either in the conducting airways or in nonperfused alveoli). The volume of the physiologic dead space is esti- mated with the following method, which is based on the measurement of the partial pressure of CO2 (PCO2) of mixed expired air (PECO2) and the following three assumptions: (1) All of the CO2 in expired air comes from exchange of CO2 in functioning (ventilated and per- fused) alveoli; (2) there is essentially no CO2 in inspired air; and (3) the physiologic dead space (nonfunctioning alveoli and airways) neither exchanges nor contributes any CO2. If physiologic dead space is zero, then PECO2 will be equal to alveolar PCO2 (PACO2). However, if a physiologic dead space is present, then PECO2 will be “diluted” by dead space air and PECO2 will be less than PACO2 by a dilution factor. Therefore, by compar- ing PECO2 with PACO2, the dilution factor (i.e., volume of the physiologic dead space) can be measured. A potential problem in measuring physiologic dead space is that alveolar air cannot be sampled directly. This problem can be overcome, however, because alveolar air normally equilibrates with pulmonary capillary blood (which becomes systemic arterial blood). Thus the PCO2 of systemic arterial blood (PaCO2) is equal to the PCO2 of alveolar air (PACO2). Using this assump- tion, the volume of physiologic dead space is calculated by the following equation: V V Pa P Pa D T ECO CO CO = × −2 2 2 where 150 Tidal volume = 500 mL Conducting airways End-expiration Alveoli Alveolar air from previous breath Inspire one VT Inspired air that fills conducting airways End-inspiration Inspired air that participates in gas exchange Alveolar air from previous breath Anatomic dead space 350 Fig. 5.3 Anatomic dead space. One third of each tidal volume (VT) fills the anatomic dead space.Www.Medicalstudyzone.com