Physiology PDF

98761_FM 10/05/10 8:28 PM Page i Physiology 98761_FM 10/05/10 8:28 PM Page ii 98761_FM 10/05/10 8:28 PM Page iii Physiology Linda S. Costanzo, Ph.D. Professor of Physiology and Biophysics Medical College of Virgin...

98761_FM 10/05/10 8:28 PM Page i Physiology 98761_FM 10/05/10 8:28 PM Page ii 98761_FM 10/05/10 8:28 PM Page iii Physiology Linda S. Costanzo, Ph.D. Professor of Physiology and Biophysics Medical College of Virginia Virginia Commonwealth University Richmond, Virginia 98761_FM 13/05/10 3:38 PM Page iv Acquisitions Editor: Crystal Taylor Product Manager: Stacey L. Sebring Designer: Holly Reid McLaughlin Compositor: MPS Limited, A Macmillan Company Copyright © 2011 Lippincott Williams & Wilkins Two Commerce Square 2001 Market Street Philadelphia, PA 19103 All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner. The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein. This publication contains information relating to general principles of medical care that should not be construed as specific instructions for individual patients. Manufacturers’ product information and package inserts should be reviewed for current infor- mation, including contraindications, dosages, and precautions. Printed in China First Edition, 1995 Second Edition, 1998 Third Edition, 2003 Fourth Edition, 2007 Library of Congress Cataloging-in-Publication Data Costanzo, Linda S., 1947- Physiology/Linda S. Costanzo. —5th ed. p. ; cm. —(Board review series) Includes bibliographical references and index. ISBN 978-0-7817-9876-1 (alk. paper) 1. Human physiology—Examinations, questions, etc. I. Title. II. Series: Board review series. [DNLM: 1. Physiological Phenomena—Examination Questions. 2. Physiology—Examination Questions. QT 18.2 C838p 2011] QP40.C67 2011 612’.0076—dc22 2010018984 The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320. International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: http://www.LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST. 1 2 3 4 5 6 7 8 9 10 98761_FM 10/05/10 8:28 PM Page v For Richard And for Dan and Rebecca 98761_FM 10/05/10 8:28 PM Page vi 98761_FM 10/05/10 8:28 PM Page vii Preface The subject matter of physiology is the foundation of the practice of medicine, and a firm grasp of its principles is essential for the physician. This book is intended to aid the student preparing for the United States Medical Licensing Examination (USMLE) Step 1. It is a concise review of key physiologic principles and is intended to help the student recall material taught during the first and second years of medical school. It is not intended to substitute for comprehensive textbooks or for course syllabi, although the student may find it a useful adjunct to physiology and pathophysiology courses. The material is organized by organ system into seven chapters. The first chapter reviews general principles of cellular physiology. The remaining six chapters review the major organ systems—neurophysiology, cardiovascular, respiratory, renal and acid–base, gastrointestinal, and endocrine physiology. Difficult concepts are explained stepwise, concisely, and clearly, with appropriate illustrative examples and sample problems. Numerous clinical correlations are included so that the student can understand physiology in relation to medicine. An integrative approach is used, when possible, to demonstrate how the organ systems work together to maintain homeostasis. More than 130 full-color illustrations and flow diagrams and more than 50 tables help the student visualize the material quickly and aid in long-term retention. The inside front cover contains “Key Physiology Topics for USMLE Step 1.” The inside back cover contains “Key Physiology Equations for USMLE Step 1.” Questions reflecting the content and format of USMLE Step 1 are included at the end of each chapter and in a Comprehensive Examination at the end of the book. These questions, many with clinical relevance, require problem-solving skills rather than straight recall. Clear, concise explanations accompany the questions and guide the student through the correct steps of reasoning. The questions can be used as a pretest to identify areas of weakness or as a post test to determine mastery. Special attention should be given to the Comprehensive Examination, because its questions integrate several areas of physiology and related concepts of pathophysiology and pharmacology. New to this edition: Addition of new full-color figures Updated organization and text Expanded coverage of cellular, respiratory, renal, gastrointestinal, and endocrine physiology Increased emphasis on pathophysiology Best of luck in your preparation for USMLE Step 1! Linda S. Costanzo, Ph.D. Chapter 3 vii 98761_FM 10/05/10 8:28 PM Page viii 98761_FM 10/05/10 8:28 PM Page ix Acknowledgments It has been a pleasure to be a part of the Board Review Series and to work with the staff at Lippincott Williams & Wilkins. Crystal Taylor and Stacey Sebring provided expert edi- torial assistance. Matthew Chansky again served as illustrator, revising and colorizing existing figures and creating new ones. My sincere thanks to students in the School of Medicine at Virginia Commonwealth University/Medical College of Virginia, who have provided so many helpful suggestions for BRS Physiology. Thanks also to the many students from other medical schools who have taken the time to write to me about their experiences with this book. Linda S. Costanzo, Ph.D. ix 98761_FM 10/05/10 8:28 PM Page x 98761_FM 10/05/10 8:28 PM Page xi Contents Preface vii Acknowledgments ix 1. CELL PHYSIOLOGY 1 I. Cell Membranes 1 II. Transport Across Cell Membranes 2 III. Osmosis 5 IV. Diffusion Potential, Resting Membrane Potential, and Action Potential 7 V. Neuromuscular and Synaptic Transmission 12 VI. Skeletal Muscle 16 VII. Smooth Muscle 20 VIII. Comparison of Skeletal Muscle, Smooth Muscle, and Cardiac Muscle 22 Review Test 23 2. NEUROPHYSIOLOGY 31 I. Autonomic Nervous System 31 II. Sensory Systems 35 III. Motor Systems 47 IV. Higher Functions of the Cerebral Cortex 53 V. Blood–Brain Barrier and Cerebrospinal Fluid 54 VI. Temperature Regulation 55 Review Test 57 3. CARDIOVASCULAR PHYSIOLOGY 64 I. Circuitry of the Cardiovascular System 64 II. Hemodynamics 64 III. Cardiac Electrophysiology 69 IV. Cardiac Muscle and Cardiac Output 74 Chapter xi 98761_FM 10/05/10 8:28 PM Page xii xii Contents V. Cardiac Cycle 83 VI. Regulation of Arterial Pressure 85 VII. Microcirculation and Lymph 89 VIII. Special Circulations 92 IX. Integrative Functions of the Cardiovascular System: Gravity, Exercise, and Hemorrhage 95 Review Test 100 4. RESPIRATORY PHYSIOLOGY 113 I. Lung Volumes and Capacities 113 II. Mechanics of Breathing 115 III. Gas Exchange 122 IV. Oxygen Transport 123 V. CO2 Transport 128 VI. Pulmonary Circulation 129 VII. V/Q Defects 131 VIII. Control of Breathing 132 IX. Integrated Responses of the Respiratory System 134 Review Test 136 5. RENAL AND ACID–BASE PHYSIOLOGY 144 I. Body Fluids 144 II. Renal Clearance, Renal Blood Flow, and Glomerular Filtration Rate 148 III. Reabsorption and Secretion 152 IV. NaCl Regulation 155 V. K⫹ Regulation 159 VI. Renal Regulation of Urea, Phosphate, Calcium, and Magnesium 162 VII. Concentration and Dilution of Urine 163 VIII. Renal Hormones 168 IX. Acid–Base Balance 168 X. Diuretics 177 XI. Integrative Examples 177 Review Test 180 6. GASTROINTESTINAL PHYSIOLOGY 190 I. Structure and Innervation of the Gastrointestinal Tract 190 II. Regulatory Substances in the Gastrointestinal Tract 191 III. Gastrointestinal Motility 195 IV. Gastrointestinal Secretion 199 V. Digestion and Absorption 209 VI. Liver Physiology 214 Review Test 216 98761_FM 10/05/10 8:28 PM Page xiii Contents xiii 7. ENDOCRINE PHYSIOLOGY 222 I. Overview of Hormones 222 II. Cell Mechanisms and Second Messengers 224 III. Pituitary Gland (Hypophysis) 227 IV. Thyroid Gland 232 V. Adrenal Cortex and Adrenal Medulla 235 VI. Endocrine Pancreas—Glucagon and Insulin 242 VII. Calcium Metabolism (Parathyroid Hormone, Vitamin D, Calcitonin) 245 VIII. Sexual Differentiation 249 IX. Male Reproduction 250 X. Female Reproduction 253 Review Test 257 Comprehensive Examination 265 Index 287 98761_FM 10/05/10 8:28 PM Page xiv 98761_Ch01 5/7/10 6:38 PM Page 1 chapter 1 Cell Physiology I. CELL MEMBRANES are composed primarily of phospholipids and proteins. A. Lipid bilayer 1. Phospholipids have a glycerol backbone, which is the hydrophilic (water-soluble) head, and two fatty acid tails, which are hydrophobic (water-insoluble). The hydrophobic tails face each other and form a bilayer. 2. Lipid-soluble substances (e.g., O2, CO2, steroid hormones) cross cell membranes because they can dissolve in the hydrophobic lipid bilayer. 3. Water-soluble substances (e.g., Na+, Cl–, glucose, H2O) cannot dissolve in the lipid of the membrane, but may cross through water-filled channels, or pores, or may be transport- ed by carriers. B. Proteins 1. Integral proteins are anchored to, and imbedded in, the cell membrane through hydrophobic interactions. may span the cell membrane. include ion channels, transport proteins, receptors, and guanosine 5′-triphosphate (GTP)-binding proteins (G proteins). 2. Peripheral proteins are not imbedded in the cell membrane. are not covalently bound to membrane components. are loosely attached to the cell membrane by electrostatic interactions. C. Intercellular connections 1. Tight junctions (zonula occludens) are the attachments between cells (often epithelial cells). may be an intercellular pathway for solutes, depending on the size, charge, and char- acteristics of the tight junction. may be “tight” (impermeable), as in the renal distal tubule, or “leaky” (permeable), as in the renal proximal tubule and gallbladder. 2. Gap junctions are the attachments between cells that permit intercellular communication. for example, permit current flow and electrical coupling between myocardial cells. 1 98761_Ch01 5/7/10 6:38 PM Page 2 2 Board Review Series: Physiology t a b l e 1-1 Characteristics of Different Types of Transport Electrochemical Carrier- Metabolic Na+ Inhibition of Type Gradient Mediated Energy Gradient Na+–K+ Pump Simple diffusion Downhill No No No — Facilitated diffusion Downhill Yes No No — Primary active transport Uphill Yes Yes — Inhibits (if Na+– K+ pump) Cotransport Uphill* Yes Indirect Yes, same direction Inhibits Countertransport Uphill* Yes Indirect Yes, opposite direction Inhibits *One or more solutes are transported uphill; Na+ is transported downhill. II. TRANSPORT ACROSS CELL MEMBRANES (TABLE 1.1) A. Simple diffusion 1. Characteristics of simple diffusion is the only form of transport that is not carrier-mediated. occurs down an electrochemical gradient (“downhill”). does not require metabolic energy and therefore is passive. 2. Diffusion can be measured using the following equation: J ⴝ ⴚPA (C1 ⴚ C2 ) where: J = flux (flow) (mmol/sec) P = permeability (cm/sec) A = area (cm2) C1 = concentration1 (mmol/L) C2 = concentration2 (mmol/L) 3. Sample calculation for diffusion The urea concentration of blood is 10 mg/100 mL. The urea concentration of prox- imal tubular fluid is 20 mg/100 mL. If the permeability to urea is 1 × 10–5 cm/ sec and the surface area is 100 cm2, what are the magnitude and direction of the urea flux? ⎛ 1 × 10−5 cm ⎞ 2 ⎛ 20 mg 10 mg ⎞ Flux = ⎜ ⎟ (100 cm ) ⎜ − ⎟ ⎝ sec ⎠ ⎝ 100 mL 100 mL ⎠ ⎛ 1 × 10−5 cm ⎞ 2 ⎛ 10 mg ⎞ =⎜ ⎟ (100 cm ) ⎜ ⎟ ⎝ sec ⎠ ⎝ 100 mL ⎠ ⎛ 1 × 10−5 cm ⎞ 2 ⎛ 0.1 mg ⎞ =⎜ ⎟ (100 cm ) ⎜ 3 ⎟ ⎝ sec ⎠ ⎝ cm ⎠ en to blood (high to low concentration) = 1 × 10−4 mg/sec from lume Note: The minus sign preceding the diffusion equation indicates that the direction of flux, or flow, is from high to low concentration. It can be ignored if the higher concen- tration is called C1 and the lower concentration is called C2. Also note: 1 mL = 1 cm3. 98761_Ch01 5/7/10 6:38 PM Page 3 Chapter 1 Cell Physiology 3 4. Permeability is the P in the equation for diffusion. describes the ease with which a solute diffuses through a membrane. depends on the characteristics of the solute and the membrane. a. Factors that increase permeability: ↑ Oil/water partition coefficient of the solute increases solubility in the lipid of the membrane. ↓ Radius (size) of the solute increases the diffusion coefficient and speed of diffusion. ↓ Membrane thickness decreases the diffusion distance. b. Small hydrophobic solutes (e.g., O2) have the highest permeabilities in lipid membranes. c. Hydrophilic solutes (e.g., Na+) must cross cell membranes through water-filled chan- nels, or pores. If the solute is an ion (is charged), then its flux will depend on both the concentration difference and the potential difference across the membrane. B. Carrier-mediated transport includes facilitated diffusion and primary and secondary active transport. The characteristics of carrier-mediated transport are: 1. Stereospecificity. For example, D-glucose (the natural isomer) is transported by facilitat- ed diffusion, but the L-isomer is not. Simple diffusion, in contrast, would not distinguish between the two isomers because it does not involve a carrier. 2. Saturation. The transport rate increases as the concentration of the solute increases, until the carriers are saturated. The transport maximum (Tm) is analogous to the maximum velocity (Vmax) in enzyme kinetics. 3. Competition. Structurally related solutes compete for transport sites on carrier mole- cules. For example, galactose is a competitive inhibitor of glucose transport in the small intestine. C. Facilitated diffusion 1. Characteristics of facilitated diffusion occurs down an electrochemical gradient (“downhill”), similar to simple diffusion. does not require metabolic energy and therefore is passive. is more rapid than simple diffusion. is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition. 2. Example of facilitated diffusion Glucose transport in muscle and adipose cells is “downhill,” is carrier-mediated, and is inhibited by sugars such as galactose; therefore, it is categorized as facilitated diffu- sion. In diabetes mellitus, glucose uptake by muscle and adipose cells is impaired because the carriers for facilitated diffusion of glucose require insulin. D. Primary active transport 1. Characteristics of primary active transport occurs against an electrochemical gradient (“uphill”). requires direct input of metabolic energy in the form of adenosine triphosphate (ATP) and therefore is active. is carrier-mediated and therefore exhibits stereospecificity, saturation, and competition. 2. Examples of primary active transport a. Na+,K+-ATPase (or Na+–K+ pump) in cell membranes transports Na+ from intracellular to extracellular fluid and K+ from extracellular to intracellular fluid; it maintains low intracellular [Na+] and high intracellular [K+]. 98761_Ch01 5/7/10 6:38 PM Page 4 4 Board Review Series: Physiology Both Na+ and K+ are transported against their electrochemical gradients. Energy is provided from the terminal phosphate bond of ATP. The usual stoichiometry is 3 Na+/2 K+. Specific inhibitors of Na+,K+-ATPase are the cardiac glycoside drugs ouabain and digitalis. b. Ca2+-ATPase (or Ca2+ pump) in the sarcoplasmic reticulum (SR) or cell membranes transports Ca2+ against an electrochemical gradient. Sarcoplasmic and endoplasmic reticulum Ca2+-ATPase is called SERCA. c. H+,K+-ATPase (or proton pump) in gastric parietal cells transports H+ into the lumen of the stomach against its electrochemical gradient. It is inhibited by proton pump inhibitors, such as omeprazole. E. Secondary active transport 1. Characteristics of secondary active transport a. The transport of two or more solutes is coupled. b. One of the solutes (usually Na+) is transported “downhill” and provides energy for the “uphill” transport of the other solute(s). c. Metabolic energy is not provided directly, but indirectly from the Na+ gradient that is maintained across cell membranes. Thus, inhibition of Na+,K+-ATPase will decrease transport of Na+ out of the cell, decrease the transmembrane Na+ gradient, and even- tually inhibit secondary active transport. d. If the solutes move in the same direction across the cell membrane, it is called cotrans- port, or symport. Examples are Na+–glucose cotransport in the small intestine and Na+–K+–2Cl– cotrans- port in the renal thick ascending limb. e. If the solutes move in opposite directions across the cell membranes, it is called counter- transport, exchange, or antiport. Examples are Na+–Ca2+ exchange and Na+–H+ exchange. 2. Example of Na+–glucose cotransport (Figure 1-1) a. The carrier for Na+–glucose cotransport is located in the luminal membrane of intes- tinal mucosal and renal proximal tubule cells. b. Glucose is transported “uphill”; Na+ is transported “downhill.” c. Energy is derived from the “downhill” movement of Na+. The inwardly directed Na+ gradient is maintained by the Na+–K+ pump on the basolateral (blood side) mem- brane. Poisoning the Na+–K+ pump decreases the transmembrane Na+ gradient and consequently inhibits Na+–glucose cotransport. Lumen Intestinal or Blood proximal tubule cell Na+ Na+ Na+ Na+ Glucose K+ Na+ Secondary Primary FIGURE 1-1 Na+–glucose cotransport (symport) active active in intestinal or proximal tubule epithelial cell. 98761_Ch01 5/7/10 6:38 PM Page 5 Chapter 1 Cell Physiology 5 Secondary active Na+ Ca2+ Ca2+ Ca2+ Na+ Na+ Na+ K+ Primary FIGURE 1-2 Na+–Ca+ countertransport (antiport). active 3. Example of Na+–Ca2+ countertransport or exchange (Figure 1-2) a. Many cell membranes contain a Na+–Ca2+ exchanger that transports Ca2+ “uphill” from low intracellular [Ca2+] to high extracellular [Ca2+]. Ca2+ and Na+ move in oppo- site directions across the cell membrane. b. The energy is derived from the “downhill” movement of Na+. As with cotransport, the inwardly directed Na+ gradient is maintained by the Na+–K+ pump. Poisoning the Na+–K+ pump therefore inhibits Na+–Ca2+ exchange. III. OSMOSIS A. Osmolarity is the concentration of osmotically active particles in a solution. is a colligative property that can be measured by freezing point depression. can be calculated using the following equation: Osmolarity ⴝ g ⴛ C where: Osmolarity = concentration of particles (osm/L) g = number of particles in solution (osm/mol) [e.g., gNaCl = 2; gglucose = 1] C = concentration (mol/L) Two solutions that have the same calculated osmolarity are isosmotic. If two solutions have different calculated osmolarities, the solution with the higher osmolarity is hyper- osmotic and the solution with the lower osmolarity is hyposmotic. Sample calculation: What is the osmolarity of a 1 M NaCl solution? Osmolarity = g × C = 2 osm mol × 1 M = 2 osm L B. Osmosis and osmotic pressure Osmosis is the flow of water across a semipermeable membrane from a solution with low solute concentration to a solution with high solute concentration. 1. Example of osmosis (Figure 1-3) a. Solutions 1 and 2 are separated by a semipermeable membrane. Solution 1 contains a solute that is too large to cross the membrane. Solution 2 is pure water. The pres- ence of the solute in solution 1 produces an osmotic pressure. 98761_Ch01 5/7/10 6:38 PM Page 6 6 Board Review Series: Physiology Semipermeable membrane Time Water flows by osmosis from 2 1 1 2 1 2 FIGURE 1-3 Osmosis of H2O across a semipermeable membrane. b. The osmotic pressure difference across the membrane causes water to flow from solution 2 (which has no solute and the lower osmotic pressure) to solution 1 (which has the solute and the higher osmotic pressure). c. With time, the volume of solution 1 increases and the volume of solution 2 decreases. 2. Calculating osmotic pressure (van’t Hoff’s law) a. The osmotic pressure of solution 1 (see Figure 1-3) can be calculated by van’t Hoff’s law, which states that osmotic pressure depends on the concentration of osmotically active particles. The concentration of particles is converted to pressure according to the fol- lowing equation: o ⴝ g ⴛ C ⴛ RT where: π = osmotic pressure (mm Hg or atm) g = number of particles in solution (osm/mol) C = concentration (mol/L) R = gas constant (0.082 L—atm/mol—K) T = absolute temperature (K) b. The osmotic pressure increases when the solute concentration increases. A solution of 1 M CaCl2 has a higher osmotic pressure than a solution of 1 M KCl because the con- centration of particles is higher. c. The higher the osmotic pressure of a solution, the greater the water flow into it. d. Two solutions having the same effective osmotic pressure are isotonic because no water flows across a semipermeable membrane separating them. If two solutions sep- arated by a semipermeable membrane have different effective osmotic pressures, the solution with the higher effective osmotic pressure is hypertonic and the solution with the lower effective osmotic pressure is hypotonic. Water flows from the hypotonic to the hypertonic solution. e. Colloidosmotic pressure, or oncotic pressure, is the osmotic pressure created by pro- teins (e.g., plasma proteins). 3. Reflection coefficient (σ) is a number between zero and one that describes the ease with which a solute perme- ates a membrane. a. If the reflection coefficient is one, the solute is impermeable. Therefore, it is retained in the original solution, it creates an osmotic pressure, and it causes water flow. Serum albumin (a large solute) has a reflection coefficient of nearly one. b. If the reflection coefficient is zero, the solute is completely permeable. Therefore, it will not exert any osmotic effect, and it will not cause water flow. Urea (a small solute) has a reflection coefficient of close to zero and it is, therefore, an ineffective osmole. 4. Calculating effective osmotic pressure Effective osmotic pressure is the osmotic pressure (calculated by van’t Hoff’s law) mul- tiplied by the reflection coefficient. 98761_Ch01 5/7/10 6:38 PM Page 7 Chapter 1 Cell Physiology 7 If the reflection coefficient is one, the solute will exert maximal effective osmotic pres- sure. If the reflection coefficient is zero, the solute will exert no osmotic pressure. IV. DIFFUSION POTENTIAL, RESTING MEMBRANE POTENTIAL, AND ACTION POTENTIAL A. Ion channels are integral proteins that span the membrane and, when open, permit the passage of certain ions. 1. Ion channels are selective; they permit the passage of some ions, but not others. Selectivity is based on the size of the channel and the distribution of charges that line it. For example, a small channel lined with negatively charged groups will be selective for small cations and exclude large solutes and anions. Conversely, a small channel lined with positively charged groups will be selective for small anions and exclude large solutes and cations. 2. Ion channels may be open or closed. When the channel is open, the ion(s) for which it is selective can flow through. When the channel is closed, ions cannot flow through. 3. The conductance of a channel depends on the probability that the channel is open. The higher the probability that a channel is open, the higher the conductance, or permeability. Opening and closing of channels are controlled by gates. a. Voltage-gated channels are opened or closed by changes in membrane potential. The activation gate of the Na+ channel in nerve is opened by depolarization; when open, the nerve membrane is permeable to Na+ (e.g., during the upstroke of the nerve action potential). The inactivation gate of the Na+ channel in nerve is closed by depolarization; when closed, the nerve membrane is impermeable to Na+ (e.g., during the repolarization phase of the nerve action potential). b. Ligand-gated channels are opened or closed by hormones, second messengers, or neurotransmitters. For example, the nicotinic receptor for acetylcholine (ACh) at the motor end plate is an ion channel that opens when ACh binds to it. When open, it is permeable to Na+ and K+, causing the motor end plate to depolarize. B. Diffusion and equilibrium potentials A diffusion potential is the potential difference generated across a membrane because of a concentration difference of an ion. A diffusion potential can be generated only if the membrane is permeable to the ion. The size of the diffusion potential depends on the size of the concentration gradient. The sign of the diffusion potential depends on whether the diffusing ion is positively or negatively charged. Diffusion potentials are created by the diffusion of very few ions and, therefore, do not result in changes in concentration of the diffusing ions. The equilibrium potential is the diffusion potential that exactly balances (opposes) the tendency for diffusion caused by a concentration difference. At electrochemical equilib- rium, the chemical and electrical driving forces that act on an ion are equal and oppo- site, and no more net diffusion of the ion occurs. 1. Example of a Na+ diffusion potential (Figure 1-4) a. Two solutions of NaCl are separated by a membrane that is permeable to Na+ but not to Cl–. The NaCl concentration of solution 1 is higher than that of solution 2. 98761_Ch01 5/7/10 6:38 PM Page 8 8 Board Review Series: Physiology Na+-selective membrane 1 2 1 2 Na+ Na+ Na+ – + Na+ – + – + Cl– Cl– – + Cl– Cl– FIGURE 1-4 Generation of a Na+ diffusion potential across a Na+-selective membrane. b. Because the membrane is permeable to Na+, Na+ will diffuse from solution 1 to solu- tion 2 down its concentration gradient. Cl– is impermeable and therefore will not accompany Na+. c. As a result, a diffusion potential will develop and solution 1 will become negative with respect to solution 2. d. Eventually, the potential difference will become large enough to oppose further net diffusion of Na+. The potential difference that exactly counterbalances the diffusion of Na+ down its concentration gradient is the Na+ equilibrium potential. At electrochemi- cal equilibrium, the chemical and electrical driving forces on Na+ are equal and oppo- site, and there is no net diffusion of Na+. 2. Example of a Cl– diffusion potential (Figure 1-5) a. Two solutions identical to those shown in Figure 1-4 are now separated by a mem- brane that is permeable to Cl– rather than to Na+. b. Cl– will diffuse from solution 1 to solution 2 down its concentration gradient. Na+ is impermeable and therefore will not accompany Cl–. c. A diffusion potential will be established such that solution 1 will become positive with respect to solution 2. The potential difference that exactly counterbalances the diffu- sion of Cl– down its concentration gradient is the Cl– equilibrium potential. At electro- chemical equilibrium, the chemical and electrical driving forces on Cl– are equal and opposite, and there is no net diffusion of Cl–. 3. Using the Nernst equation to calculate equilibrium potentials a. The Nernst equation is used to calculate the equilibrium potential at a given con- centration difference of a permeable ion across a cell membrane. It tells us what potential would exactly balance the tendency for diffusion down the concentra- tion gradient; in other words, at what potential would the ion be at electrochemical equilibrium? RT [ Ci ] E ⴝ ⴚ2.3 log10 zF [ Ce ] Cl–-selective membrane 1 2 1 2 Na+ Na+ + – Na+ + – Na+ + – + – Cl– Cl– Cl– Cl– FIGURE 1-5 Generation of a Cl– diffusion potential across a Cl– -selective membrane. 98761_Ch01 5/7/10 6:38 PM Page 9 Chapter 1 Cell Physiology 9 where: E = equilibrium potential (mV) RT 2.3 = 60 mV at 37ºC zF z = charge on the ion (+1 for Na+; +2 for Ca2+; –1 for Cl–) Ci = intracellular concentration (mM) Ce = extracellular concentration (mM) b. Sample calculation with the Nernst equation If the intracellular [Na+] is 15 mM and the extracellular [Na+] is 150 mM, what is the equilibrium potential for Na+? −60 mV ⎡⎣Ci ⎤⎦ ENa = + log10 z ⎡⎣Ce ⎤⎦ −60 mV 15 mM = log10 +1 150 mM = −60 mV log10 0.1 = +60 mV Note: You need not remember which concentration goes in the numerator. Because it is a log function, perform the calculation either way to get the absolute value of 60 mV. Then use an “intuitive approach” to determine the correct sign. (Intuitive approach: The [Na+] is higher in extracellular fluid than in intracellular fluid, so Na+ ions will diffuse from extra- cellular to intracellular, making the inside of the cell positive [i.e., +60 mV at equilibrium].) c. Approximate values for equilibrium potentials in nerve and muscle ENa+ +65 mV ECa2+ +120 mV EK+ –85 mV ECl– –85 mV C. Resting membrane potential is expressed as the measured potential difference across the cell membrane in milli- volts (mV). is, by convention, expressed as the intracellular potential relative to the extracellular potential. Thus, a resting membrane potential of –70 mV means 70 mV, cell negative. 1. The resting membrane potential is established by diffusion potentials that result from con- centration differences of permeant ions. 2. Each permeable ion attempts to drive the membrane potential toward its equilibrium potential. Ions with the highest permeabilities, or conductances, will make the greatest contribu- tions to the resting membrane potential, and those with the lowest permeabilities will make little or no contribution. 3. For example, the resting membrane potential of nerve is –70 mV, which is close to the cal- culated K+ equilibrium potential of –85 mV, but far from the calculated Na+ equilibrium potential of +65 mV. At rest, the nerve membrane is far more permeable to K+ than to Na+. 4. The Na+–K+ pump contributes only indirectly to the resting membrane potential by main- taining, across the cell membrane, the Na+ and K+ concentration gradients that then pro- duce diffusion potentials. The direct electrogenic contribution of the pump (3 Na+ pumped out of the cell for every 2 K+ pumped into the cell) is small. D. Action potentials 1. Definitions a. Depolarization makes the membrane potential less negative (the cell interior becomes less negative). 98761_Ch01 5/7/10 6:38 PM Page 10 10 Board Review Series: Physiology Absolute Relative refractory refractory period period +65 mV Na+ equilibrium potential Action potential Voltage or conductance 0 mV Na+ conductance K+ conductance –70 mV Resting membrane potential –85 mV K+ equilibrium potential 1.0 2.0 Time (msec) FIGURE 1-6 Nerve action potential and associated changes in Na+ and K+ conductance. b. Hyperpolarization makes the membrane potential more negative (the cell interior becomes more negative). c. Inward current is the flow of positive charge into the cell. Inward current depolarizes the membrane potential. d. Outward current is the flow of positive charge out of the cell. Outward current hyperpo- larizes the membrane potential. e. Action potential is a property of excitable cells (i.e., nerve, muscle) that consists of a rapid depolarization, or upstroke, followed by repolarization of the membrane potential. Action potentials have stereotypical size and shape, are propagating, and are all-or-none. f. Threshold is the membrane potential at which the action potential is inevitable. At threshold potential, net inward current becomes larger than net outward current. The resulting depolarization becomes self-sustaining and gives rise to the upstroke of the action potential. If net inward current is less than net outward current, no action potential will occur (i.e., all-or-none response). 2. Ionic basis of the nerve action potential (Figure 1-6) a. Resting membrane potential is approximately –70 mV, cell negative. is the result of the high resting conductance to K+, which drives the membrane potential toward the K+ equilibrium potential. At rest, the Na+ channels are closed and Na+ conductance is low. b. Upstroke of the action potential (1) Inward current depolarizes the membrane potential to threshold. (2) Depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance of the membrane promptly increases. (3) The Na+ conductance becomes higher than the K+ conductance, and the mem- brane potential is driven toward (but does not quite reach) the Na+ equilibrium potential of +65 mV. Thus, the rapid depolarization during the upstroke is caused by an inward Na+ current. 98761_Ch01 5/7/10 6:38 PM Page 11 Chapter 1 Cell Physiology 11 (4) The overshoot is the brief portion at the peak of the action potential when the membrane potential is positive. (5) Tetrodotoxin (TTX) and lidocaine block these voltage-sensitive Na+ channels and abolish action potentials. c. Repolarization of the action potential (1) Depolarization also closes the inactivation gates of the Na+ channel (but more slowly than it opens the activation gates). Closure of the inactivation gates results in clo- sure of the Na+ channels, and the Na+ conductance returns toward zero. (2) Depolarization slowly opens K+ channels and increases K+ conductance to even higher levels than at rest. (3) The combined effect of closing the Na+ channels and greater opening of the K+ chan- nels makes the K+ conductance higher than the Na+ conductance, and the mem- brane potential is repolarized. Thus, repolarization is caused by an outward K+ current. d. Undershoot (hyperpolarizing afterpotential) The K+ conductance remains higher than at rest for some time after closure of the Na+ channels. During this period, the membrane potential is driven very close to the K+ equilibrium potential. 3. Refractory periods (see Figure 1-6) a. Absolute refractory period is the period during which another action potential cannot be elicited, no matter how large the stimulus. coincides with almost the entire duration of the action potential. Explanation: Recall that the inactivation gates of the Na+ channel are closed when the membrane potential is depolarized. They remain closed until repolarization occurs. No action potential can occur until the inactivation gates open. b. Relative refractory period begins at the end of the absolute refractory period and continues until the membrane potential returns to the resting level. An action potential can be elicited during this period only if a larger than usual inward current is provided. Explanation: The K+ conductance is higher than at rest, and the membrane potential is closer to the K+ equilibrium potential and, therefore, farther from threshold; more inward current is required to bring the membrane to threshold. c. Accommodation occurs when the cell membrane is held at a depolarized level such that the threshold potential is passed without firing an action potential. occurs because depolarization closes inactivation gates on the Na+ channels. is demonstrated in hyperkalemia, in which skeletal muscle membranes are depolarized by the high serum K+ concentration. Although the membrane potential is closer to threshold, action potentials do not occur because inactivation gates on Na+ channels are closed by depolarization, causing muscle weakness. 4. Propagation of action potentials (Figure 1-7) occurs by the spread of local currents to adjacent areas of membrane, which are then depolarized to threshold and generate action potentials. Conduction velocity is increased by: a. ↑ fiber size. Increasing the diameter of a nerve fiber results in decreased internal resist- ance; thus, conduction velocity down the nerve is faster. b. Myelination. Myelin acts as an insulator around nerve axons and increases conduc- tion velocity. Myelinated nerves exhibit saltatory conduction because action potentials can be generated only at the nodes of Ranvier, where there are gaps in the myelin sheath (Figure 1-8). 98761_Ch01 5/7/10 6:38 PM Page 12 12 Board Review Series: Physiology + + + + – + + + + – – – – + – – – – FIGURE 1-7 Unmyelinated axon showing spread of depolarization by local current flow. Box shows active zone where action potential has reversed the polarity. Myelin sheath Node of Ranvier FIGURE 1-8 Myelinated axon. Action potentials can occur at nodes of Ranvier. V. NEUROMUSCULAR AND SYNAPTIC TRANSMISSION A. General characteristics of chemical synapses 1. An action potential in the presynaptic cell causes depolarization of the presynaptic terminal. 2. As a result of the depolarization, Ca2+ enters the presynaptic terminal, causing release of neurotransmitter into the synaptic cleft. 3. Neurotransmitter diffuses across the synaptic cleft and combines with receptors on the postsynaptic cell membrane, causing a change in its permeability to ions and, conse- quently, a change in its membrane potential. 4. Inhibitory neurotransmitters hyperpolarize the postsynaptic membrane; excitatory neuro- transmitters depolarize the postsynaptic membrane. B. Neuromuscular junction (Figure 1-9 and Table 1.2) is the synapse between axons of motoneurons and skeletal muscle. The neurotransmitter released from the presynaptic terminal is ACh, and the postsy- naptic membrane contains a nicotinic receptor. 1. Synthesis and storage of ACh in the presynaptic terminal Choline acetyltransferase catalyzes the formation of ACh from acetyl coenzyme A (CoA) and choline in the presynaptic terminal. ACh is stored in synaptic vesicles with ATP and proteoglycan for later release. AChR Action potential in nerve 3 Action potential in muscle ACh 1 5 Na+ K+ Ca2+ 2 4 Motoneuron Muscle FIGURE 1-9 Neuromuscular junction. ACh = acetylcholine; AChR = acetylcholine receptor. 98761_Ch01 5/7/10 6:38 PM Page 13 Chapter 1 Cell Physiology 13 t a b l e 1-2 Agents Affecting Neuromuscular Transmission Example Action Effect on Neuromuscular Transmission Botulinus toxin Blocks release of ACh from presynaptic Total blockade terminals Curare Competes with ACh for receptors on motor Decreases size of EPP; maximal doses produce end plate paralysis of respiratory muscles and death Neostigmine Inhibits acetylcholinesterase Prolongs and enhances action of ACh at muscle end plate Hemicholinium Blocks reuptake of choline into Depletes ACh stores from presynaptic terminal presynaptic terminal ACh = acetylcholine; EPP = end plate potential. 2. Depolarization of the presynaptic terminal and Ca2+ uptake Action potentials are conducted down the motoneuron. Depolarization of the presy- naptic terminal opens Ca2+ channels. When Ca2+ permeability increases, Ca2+ rushes into the presynaptic terminal down its electrochemical gradient. 3. Ca2+ uptake causes release of ACh into the synaptic cleft The synaptic vesicles fuse with the plasma membrane and empty their contents into the cleft by exocytosis. 4. Diffusion of ACh to the postsynaptic membrane (muscle end plate) and binding of ACh to nicotinic receptors The nicotinic ACh receptor is also a Na+ and K+ ion channel. Binding of ACh to α subunits of the receptor causes a conformational change that opens the central core of the channel and increases its conductance to Na+ and K+. These are examples of ligand-gated channels. 5. End plate potential (EPP) in the postsynaptic membrane Because the channels opened by ACh conduct both Na+ and K+ ions, the postsynaptic membrane potential is depolarized to a value halfway between the Na+ and K+ equi- librium potentials (approximately 0 mV). The contents of one synaptic vesicle (one quantum) produce a miniature end plate potential (MEPP), the smallest possible EPP. MEPPs summate to produce a full-fledged EPP. The EPP is not an action potential, but simply a depolarization of the specialized muscle end plate. 6. Depolarization of adjacent muscle membrane to threshold Once the end plate region is depolarized, local currents cause depolarization and action potentials in the adjacent muscle tissue. Action potentials in the muscle are followed by contraction. 7. Degradation of Ach The EPP is transient because ACh is degraded to acetyl CoA and choline by acetyl- cholinesterase (AChE) on the muscle end plate. One-half of the choline is taken back into the presynaptic ending by Na+–choline cotransport and used to synthesize new ACh. AChE inhibitors (neostigmine) block the degradation of ACh, prolong its action at the muscle end plate, and increase the size of the EPP. Hemicholinium blocks choline reuptake and depletes the presynaptic endings of ACh stores. 98761_Ch01 5/7/10 6:38 PM Page 14 14 Board Review Series: Physiology 8. Disease—myasthenia gravis is caused by the presence of antibodies to the ACh receptor. is characterized by skeletal muscle weakness and fatigability resulting from a reduced number of ACh receptors on the muscle end plate. The size of the EPP is reduced; therefore, it is more difficult to depolarize the muscle membrane to threshold and to produce action potentials. Treatment with AChE inhibitors (e.g., neostigmine) prevents the degradation of ACh and prolongs the action of ACh at the muscle end plate, partially compensating for the reduced number of receptors. C. Synaptic transmission 1. Types of arrangements a. One-to-one synapses (such as those found at the neuromuscular junction) An action potential in the presynaptic element (the motor nerve) produces an action potential in the postsynaptic element (the muscle). b. Many-to-one synapses (such as those found on spinal motoneurons) An action potential in a single presynaptic cell is insufficient to produce an action potential in the postsynaptic cell. Instead, many cells synapse on the postsynaptic cell to depolarize it to threshold. The presynaptic input may be excitatory or inhibitory. 2. Input to synapses The postsynaptic cell integrates excitatory and inhibitory inputs. When the sum of the input brings the membrane potential of the postsynaptic cell to threshold, it fires an action potential. a. Excitatory postsynaptic potentials (EPSPs) are inputs that depolarize the postsynaptic cell, bringing it closer to threshold and closer to firing an action potential. are caused by opening of channels that are permeable to Na+ and K+, similar to the ACh channels. The membrane potential depolarizes to a value halfway between the equilibrium potentials for Na+ and K+ (approximately 0 mV). Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin. b. Inhibitory postsynaptic potentials (IPSPs) are inputs that hyperpolarize the postsynaptic cell, moving it away from threshold and farther from firing an action potential. are caused by opening Cl– channels. The membrane potential is hyperpolarized toward the Cl– equilibrium potential (–90 mV). Inhibitory neurotransmitters are γ-aminobutyric acid (GABA) and glycine. 3. Summation at synapses a. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously. Together, they produce greater depolarization. b. Temporal summation occurs when two excitatory inputs arrive at a postsynaptic neuron in rapid succession. Because the resulting postsynaptic depolarizations overlap in time, they add in stepwise fashion. c. Facilitation, augmentation, and post-tetanic potentiation occur after tetanic stimulation of the presynaptic neuron. In each of these, depolarization of the postsynaptic neu- ron is greater than expected because greater than normal amounts of neurotrans- mitter are released, possibly because of the accumulation of Ca2+ in the presynaptic terminal. Long-term potentiation (memory) involves new protein synthesis. 98761_Ch01 5/7/10 6:38 PM Page 15 Chapter 1 Cell Physiology 15 Tyrosine tyrosine hydroxylase L-dopa dopa decarboxylase Dopamine dopamine β-hydroxylase Norepinephrine phenylethanolamine-N-methyltransferase (S-adenosylmethionine) Epinephrine FIGURE 1-10 Synthetic pathway for dopamine, norepi- nephrine, and epinephrine. 4. Neurotransmitters a. ACh (see V B) b. Norepinephrine, epinephrine, and dopamine (Figure 1-10) (1) Norepinephrine is the primary transmitter released from postganglionic sympathetic neurons. is synthesized in the nerve terminal and released into the synapse to bind with ` or a receptors on the postsynaptic membrane. is removed from the synapse by reuptake or is metabolized in the presynaptic terminal by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The metabolites are: (a) 3,4-Dihydroxymandelic acid (DOMA) (b) Normetanephrine (NMN) (c) 3-Methoxy-4-hydroxyphenylglycol (MOPEG) (d) 3-Methoxy-4-hydroxymandelic acid, or vanillylmandelic acid (VMA) In pheochromocytoma, a tumor of the adrenal medulla that secretes cate- cholamines, urinary excretion of VMA is increased. (2) Epinephrine is synthesized from norepinephrine by the action of phenylethanolamine-N- methyltransferase. is secreted, along with norepinephrine, from the adrenal medulla. (3) Dopamine is prominent in midbrain neurons. is released from the hypothalamus and inhibits prolactin secretion; in this context it is called prolactin-inhibiting factor (PIF). is metabolized by MAO and COMT. (a) D1 receptors activate adenylate cyclase via a Gs protein. (b) D2 receptors inhibit adenylate cyclase via a Gi protein. (c) Parkinson’s disease involves degeneration of dopaminergic neurons that use the D2 receptors. (d) Schizophrenia involves increased levels of D2 receptors. 98761_Ch01 5/7/10 6:38 PM Page 16 16 Board Review Series: Physiology c. Serotonin is present in high concentrations in the brain stem. is formed from tryptophan. is converted to melatonin in the pineal gland. d. Histamine is formed from histidine. is present in the neurons of the hypothalamus. e. Glutamate is the most prevalent excitatory neurotransmitter in the brain. There are four subtypes of glutamate receptors. Three subtypes are ionotropic receptors (ligand-gated ion channels) including the NMDA (N-methyl-D-aspartate) receptor. One subtype is a metabotropic receptor, which is coupled to ion channels via a hetero- trimeric G protein. f. GABA is an inhibitory neurotransmitter. is synthesized from glutamate by glutamate decarboxylase. has two types of receptors: (1) The GABAA receptor increases Cl– conductance and is the site of action of benzodi- azepines and barbiturates. (2) The GABAB receptor increases K+ conductance. g. Glycine is an inhibitory neurotransmitter found primarily in the spinal cord and brain stem. increases Cl– conductance. h. Nitric oxide (NO) is a short-acting inhibitory neurotransmitter in the gastrointestinal tract, blood ves- sels, and the central nervous system. is synthesized in presynaptic nerve terminals, where NO synthase converts arginine to citrulline and NO. is a permeant gas that diffuses from the presynaptic terminal to its target cell. also functions in signal transduction of guanylyl cyclase in a variety of tissues, including vascular smooth muscle. VI. SKELETAL MUSCLE A. Muscle structure and filaments (Figure 1-11) Each muscle fiber is multinucleate and behaves as a single unit. It contains bundles of myofibrils, surrounded by SR and invaginated by transverse tubules (T tubules). Each myofibril contains interdigitating thick and thin filaments arranged longitudinally in sarcomeres. Repeating units of sarcomeres account for the unique banding pattern in striated muscle. A sarcomere runs from Z line to Z line. 1. Thick filaments are present in the A band in the center of the sarcomere. contain myosin. 98761_Ch01 5/7/10 6:38 PM Page 17 Chapter 1 Cell Physiology 17 A Motoneuron Muscle Sarcomere I band I band Thin filament Thick filament Myofibril Z line M line Z line H band A band B Transverse tubules Sarcolemmal membrane Terminal cisternae Sarcoplasmic reticulum FIGURE 1-11 Structure of the sarcomere in skeletal muscle. A. Arrangement of thick and thin filaments. B. Transverse tubules and sarcoplasmic reticulum. a. Myosin has six polypeptide chains, including one pair of heavy chains and two pairs of light chains. b. Each myosin molecule has two “heads” attached to a single “tail.” The myosin heads bind ATP and actin, and are involved in cross-bridge formation. 2. Thin filaments are anchored at the Z lines. are present in the I bands. interdigitate with the thick filaments in a portion of the A band. contain actin, tropomyosin, and troponin. a. Troponin is the regulatory protein that permits cross-bridge formation when it binds Ca2+. b. Troponin is a complex of three globular proteins: Troponin T (“T” for tropomyosin) attaches the troponin complex to tropomyosin. Troponin I (“I” for inhibition) inhibits the interaction of actin and myosin. Troponin C (“C” for Ca2+) is the Ca2+-binding protein that, when bound to Ca2+, permits the interaction of actin and myosin. 98761_Ch01 5/7/10 6:38 PM Page 18 18 Board Review Series: Physiology 3. T tubules are an extensive tubular network, open to the extracellular space, that carry the depo- larization from the sarcolemmal membrane to the cell interior. are located at the junctions of A bands and I bands. contain a voltage-sensitive protein called the dihydropyridine receptor; depolarization causes a conformational change in the dihydropyridine receptor. 4. SR is the internal tubular structure that is the site of Ca2+ storage and release for excitation–contraction coupling. has terminal cisternae that make intimate contact with the T tubules in a triad arrangement. membrane contains Ca2+-ATPase (Ca2+ pump), which transports Ca2+ from intracellular fluid into the SR interior, keeping intracellular [Ca2+] low. contains Ca2+ bound loosely to calsequestrin. contains a Ca2+ release channel called the ryanodine receptor. B. Steps in excitation–contraction coupling in skeletal muscle (Figures 1-12 and 1-13) 1. Action potentials in the muscle cell membrane initiate depolarization of the T tubules. 2. Depolarization of the T tubules causes a conformational change in its dihydropyridine receptor, which opens Ca2+ release channels (ryanodine receptors) in the nearby SR, causing release of Ca2+ from the SR into the intracellular fluid. 3. Intracellular [Ca2+] increases. Actin filament – + Myosin head Myosin filament A – + – + ADP ATP D B – + ADP Pi C FIGURE 1-12 Cross-bridge cycle. Myosin “walks” toward the plus end of actin to produce shortening and force- generation. ADP = adenosine diphosphate; ATP = adenosine triphosphate; Pi = inorganic phosphate. 98761_Ch01 5/7/10 6:38 PM Page 19 Chapter 1 Cell Physiology 19 Action potential Intracellular [Ca2+] Response Twitch tension FIGURE 1-13 Relationship of the action potential, the increase in intracellular [Ca2+], and muscle contraction Time in skeletal muscle. 4. Ca2+ binds to troponin C on the thin filaments, causing a conformational change in tro- ponin that moves tropomyosin out of the way. The cross-bridge cycle begins (see Figure 1-12): a. At first, no ATP is bound to myosin (A), and myosin is tightly attached to actin. In rapid- ly contracting muscle, this stage is brief. In the absence of ATP, this state is permanent (i.e., rigor). b. ATP then binds to myosin (B), producing a conformational change in myosin that caus- es myosin to be released from actin. c. Myosin is displaced toward the plus end of actin. There is hydrolysis of ATP to ADP and inorganic phosphate (Pi). ADP remains attached to myosin (C). d. Myosin attaches to a new site on actin, which constitutes the power (force-generating) stroke (D). ADP is then released, returning myosin to its rigor state. e. The cycle repeats as long as Ca2+ is bound to troponin C. Each cross-bridge cycle “walks” myosin further along the actin filament. 5. Relaxation occurs when Ca2+ is reaccumulated by the SR Ca2+-ATPase (SERCA). Intracellular Ca2+ concentration decreases, Ca2+ is released from troponin C, and tropomyosin again blocks the myosin-binding site on actin. As long as intracellular Ca2+ concentration is low, cross-bridge cycling cannot occur. 6. Mechanism of tetanus. A single action potential causes the release of a standard amount of Ca2+ from the SR and produces a single twitch. However, if the muscle is stimulated repeat- edly, more Ca2+ is released from the SR and there is a cumulative increase in intracellular [Ca2+], extending the time for cross-bridge cycling. The muscle does not relax (tetanus). C. Length–tension and force–velocity relationships in muscle Isometric contractions are measured when length is held constant. Muscle length (preload) is fixed, the muscle is stimulated to contract, and the developed tension is measured. There is no shortening. Isotonic contractions are measured when load is held constant. The load against which the muscle contracts (afterload) is fixed, the muscle is stimulated to contract, and shorten- ing is measured. 1. Length–tension relationship (Figure 1-14) measures tension developed during isometric contractions when the muscle is set to fixed lengths (preload). a. Passive tension is the tension developed by stretching the muscle to different lengths. b. Total tension is the tension developed when the muscle is stimulated to contract at dif- ferent lengths. c. Active tension is the difference between total tension and passive tension. 98761_Ch01 5/7/10 6:38 PM Page 20 20 Board Review Series: Physiology Total Tension Passive Length at maximum cross-bridge Active overlap Muscle length FIGURE 1-14 Length–tension relationship in skeletal muscle. Active tension represents the active force developed from contraction of the mus- cle. It can be explained by the cross-bridge cycle model. Active tension is proportional to the number of cross-bridges formed. Tension will be max- imum when there is maximum overlap of thick and thin filaments. When the mus- cle is stretched to greater lengths, the number of cross-bridges is reduced because there is less overlap. When muscle length is decreased, the thin filaments collide and tension is reduced. 2. Force–velocity relationship (Figure 1-15) measures the velocity of shortening of isotonic contractions when the muscle is chal- lenged with different afterloads (the load against which the muscle must contract). The velocity of shortening decreases as the afterload increases. VII. SMOOTH MUSCLE has thick and thin filaments that are not arranged in sarcomeres; therefore, they appear homogeneous rather than striated. A. Types of smooth muscle 1. Multi-unit smooth muscle is present in the iris, ciliary muscle of the lens, and vas deferens. behaves as separate motor units. Initial velocity of shortening Afterload FIGURE 1-15 Force–velocity relationship in skeletal muscle. 98761_Ch01 5/7/10 6:38 PM Page 21 Chapter 1 Cell Physiology 21 has little or no electrical coupling between cells. is densely innervated; contraction is controlled by neural innervation (e.g., autonomic nervous system). 2. Unitary (single-unit) smooth muscle is the most common type and is present in the uterus, gastrointestinal tract, ureter, and bladder. is spontaneously active (exhibits slow waves) and exhibits “pacemaker” activity (see Chapter 6 III A), which is modulated by hormones and neurotransmitters. has a high degree of electrical coupling between cells and, therefore, permits coordi- nated contraction of the organ (e.g., bladder). 3. Vascular smooth muscle has properties of both multi-unit and single-unit smooth muscle. B. Steps in excitation–contraction coupling in smooth muscle (Figure 1-16) The mechanism of excitation–contraction coupling is different from that in skeletal muscle. Hormones or neurotransmitters Depolarization Hormones or IP3 neurotransmitters Opens voltage-gated Ca2+ release Open ligand-gated Ca2+ channels from SR Ca2+ channels [Ca2+] Ca2+-calmodulin (CaM) myosin-light-chain kinase Phosphorylation of myosin light chains Myosin ATPase Myosin~P + actin Cross-bridge cycling FIGURE 1-16 Sequence of events in con- Tension traction of smooth muscle. 98761_Ch01 5/7/10 6:38 PM Page 22 22 Board Review Series: Physiology There is no troponin; instead, Ca2+ regulates myosin on the thick filaments. 1. Depolarization of the cell membrane opens voltage-gated Ca2+ channels and Ca2+ flows into the cell down its electrochemical gradient, increasing the intracellular [Ca2+]. Hormones and neurotransmitters may open ligand-gated Ca2+ channels in the cell mem- brane. They also directly release Ca2+ from the SR through inositol 1,4,5-triphosphate (IP3)-gated Ca2+ channels. 2. Intracellular [Ca2+] increases. 3. Ca2+ binds to calmodulin. The Ca2+–calmodulin complex binds to and activates myosin light-chain kinase. When activated, myosin light-chain kinase phosphorylates myosin and allows it to bind to actin, thus initiating cross-bridge cycling. The amount of ten- sion produced is proportional to the intracellular Ca2+ concentration. 4. A decrease in intracellular [Ca2+] produces relaxation. VIII. COMPARISON OF SKELETAL MUSCLE, SMOOTH MUSCLE, AND CARDIAC MUSCLE Table 1-3 compares the ionic basis for the action potential and mechanism of contrac- tion in skeletal muscle, smooth muscle, and cardiac muscle. Cardiac muscle is discussed in Chapter 3. t a b l e 1-3 Comparison of Skeletal, Smooth, and Cardiac Muscle Feature Skeletal Muscle Smooth Muscle Cardiac Muscle Appearance Striated No striations Striated Upstroke of action potential Inward Na+ current Inward Ca2+ current Inward Ca2+ current (SA node) Inward Na+ current (atria, ventricles, Purkinje fibers) Plateau No No No (SA node) Yes (atria, ventricles, Purkinje fibers; due to inward Ca2+ current) Duration of action potential ~1 msec ~10 msec 150 msec (SA node, atria) 250–300 msec (ventricles and Purkinje fibers) Excitation–contraction Action potential Action potential opens Inward Ca2+ current during coupling → T tubules voltage-gated Ca2+ plateau of action potential channels in cell membrane Ca2+ released from Ca2+-induced Ca2+ release from SR nearby SR ↑ [Ca2+]i Hormones and transmitters ↑ [Ca2+]i open IP3 – gated Ca2+ channels in SR Molecular basis for Ca2+–troponin C Ca2+–calmodulin ↑ myosin Ca2+–troponin C contraction light-chain kinase IP3 = inositol 1,4,5-triphosphate; SA = sinoatrial; SR = sarcoplasmic reticulum. 98761_Ch01 5/7/10 6:38 PM Page 23 Review Test 1. Which of the following characteristics is uptake of Ca2+ into the presynaptic shared by simple and facilitated diffusion of nerve terminal glucose? (B) uptake of Ca2+ into the presynaptic ter- (A) Occurs down an electrochemical gradient minal; release of acetylcholine (ACh); (B) Is saturable depolarization of the muscle end plate (C) Requires metabolic energy (C) release of ACh; action potential in the (D) Is inhibited by the presence of galactose motor nerve; action potential in the (E) Requires a Na+ gradient muscle (D) uptake of Ca2+ into the motor end plate; 2. During the upstroke of the nerve action action potential in the motor end plate; potential action potential in the muscle (E) release of ACh; action potential in the (A) there is net outward current and the cell muscle end plate; action potential in the interior becomes more negative muscle (B) there is net outward current and the cell interior becomes less negative (C) there is net inward current and the cell 5. Which characteristic or component is interior becomes more negative shared by skeletal muscle and smooth muscle? (D) there is net inw