Table Of Content

CONTENTS P A R T I CHAPTER 14: The Cardiac Pump 000 CELLULAR PHYSIOLOGY • 000 Thom W. Rooke, M.D., and CHAPTER 1: Homeostasis and Cellular Signaling 000 Harvey V. Sparks, Jr., M.D. Patricia J. Gallagher, Ph.D., and CHAPTER 15: The Systemic Circulation 000 George A. Tanner, Ph.D. Thom W. Rooke, M.D., and CHAPTER 2: The Cell Membrane, Membrane Transport, and the Harvey V. Sparks, Jr., M.D. Resting Membrane Potential 000 CHAPTER 16: The Microcirculation and the Stephen A. Kempson, Ph.D. Lymphatic System 000 CHAPTER 3: The Action Potential, Synaptic Transmission, and H. Glenn Bohlen, Ph.D. Maintenance of Nerve Function 000 CHAPTER 17: Special Circulations 000 Cynthia J. Forehand, Ph.D. H. Glenn Bohlen, Ph.D. CHAPTER 18: Control Mechanisms in Circulatory Function 000 P A R T I I Thom W. Rooke, M.D., and NEUROPHYSIOLOGY • 000 Harvey V. Sparks, Jr., M.D. CHAPTER 4: Sensory Physiology 000 Richard A. Meiss, Ph.D. P A R T V CHAPTER 5: The Motor System 000 RESPIRATORY PHYSIOLOGY • 000 John C. Kincaid, M.D. CHAPTER 19: Ventilation and the Mechanics of Breathing 000 CHAPTER 6: The Autonomic Nervous System 000 Rodney A. Rhoades, Ph.D. John C. Kincaid, M.D. CHAPTER 20: Pulmonary Circulation and CHAPTER 7: Integrative Functions of the Nervous System 000 Ventilation-Perfusion Ratio 000 Cynthia J. Forehand, Ph.D. Rodney A. Rhoades, Ph.D. CHAPTER 21: Gas Transfer and Transport 000 P A R T I I I Rodney A. Rhoades, Ph.D. MUSCLE PHYSIOLOGY • 000 CHAPTER 22: The Control of Ventilation 000 CHAPTER 8: Contractile Properties of Muscle Cells 000 Rodney A. Rhoades, Ph.D. Richard A. Meiss, Ph.D. CHAPTER 9: Skeletal Muscle and Smooth Muscle 000 P A R T V I Richard A. Meiss, Ph.D. CHAPTER 10: Cardiac Muscle 000 RENAL PHYSIOLOGY AND BODY FLUIDS • 000 Richard A. Meiss, Ph.D. CHAPTER 23: Kidney Function 000 George A. Tanner, Ph.D. P A R T I V CHAPTER 24: The Regulation of Fluid and BLOOD AND CARDIOVASCULAR PHYSIOLOGY • 000 Electrolyte Balance 000 CHAPTER 11: Blood Components, Immunity, and Hemostasis 000 George A. Tanner, Ph.D. Denis English, Ph.D. CHAPTER 25: Acid-Base Balance 000 CHAPTER 12: An Overview of the Circulation and George A. Tanner, Ph.D. Hemodynamics 000 Thom W. Rooke, M.D., and P A R T V I I Harvey V. Sparks, Jr., M.D. GASTROINTESTINAL PHYSIOLOGY • 000 CHAPTER 13: The Electrical Activity of the Heart 000 CHAPTER 26: Neurogastroenterology and Gastrointestinal Thom W. Rooke, M.D., and Motility 000 Harvey V. Sparks, Jr., M.D. Jackie D. Wood, Ph.D. ix x Contents CHAPTER 27: Gastrointestinal Secretion, Digestion, and CHAPTER 34: The Adrenal Gland 000 Absorption 000 Robert V. Considine, Ph.D. Patrick Tso, Ph.D. CHAPTER 35: The Endocrine Pancreas 000 CHAPTER 28: The Physiology of the Liver 000 Daniel E. Peavy, Ph.D. Patrick Tso, Ph.D., and James McGill, M.D. CHAPTER 36: Endocrine Regulation of Calcium, Phosphate, and Bone Metabolism 000 P A R T V I I I Daniel E. Peavy, Ph.D. TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY • 000 P A R T X CHAPTER 29: The Regulation of Body Temperature 000 REPRODUCTIVE PHYSIOLOGY • 000 C. Bruce Wenger, M.D., Ph.D. CHAPTER 37: The Male Reproductive System 000 CHAPTER 30: Exercise Physiology 000 Paul F. Terranova, Ph.D. Alon Harris, Ph.D., and Bruce E. Martin, Ph.D. CHAPTER 38: The Female Reproductive System 000 Paul F. Terranova, Ph.D. P A R T I X CHAPTER 39: Fertilization, Pregnancy, and Fetal ENDOCRINE PHYSIOLOGY • 000 Development 000 CHAPTER 31: Endocrine Control Mechanisms 000 Paul F. Terranova, Ph.D. Daniel E. Peavy, Ph.D. CHAPTER 32: The Hypothalamus and the Pituitary Gland 000 Robert V. Considine, Ph.D. Appendix A: Answers to Review Questions 000 CHAPTER 33: The Thyroid Gland 000 Appendix B: Common Abbreviations in Physiology 000 Robert V. Considine, Ph.D. Normal Blood, Plasma, or Serum Values inside front cover PREFACE The goal of this second edition of Medical Physiology is to ogy. Special chapters on the blood and the liver are in- provide a clear, accurate, and up-to-date introduction to cluded. Chapters on acid-base regulation, temperature reg- medical physiology for medical students and students in ulation, and exercise discuss these complex, integrated the allied health sciences. Physiology, the study of normal functions. The order of presentation of topics follows that function, is key to understanding pathophysiology and of most United States medical school courses in physiol- pharmacology and is essential to the everyday practice of ogy. After the first two chapters, the other chapters can be clinical medicine. read in any order, and some chapters may be skipped if the subjects are taught in other courses (e.g., neurobiology or Level. The level of the book is meant to be midway be- biochemistry). tween an oversimplified review book and an encyclopedic Material on pathophysiology is included throughout textbook of physiology. Each chapter is written by medical the book. This not only reinforces fundamental physiolog- school faculty members who have had many years of ex- ical principles but also demonstrates the relevance of phys- perience teaching physiology and who are experts in their iology to an understanding of numerous medically impor- field. They have selected material that is important for tant conditions. medical students to know and have presented this material in a concise, uncomplicated, and understandable fashion. Pedagogy. This second edition incorporates many fea- We have purposely avoided discussion of research labora- tures that should aid the student in his or her study of phys- tory methods or historical material because most medical iology: students are too busy to be burdened by such information. • Chapter outline. The outline at the beginning of each We have also avoided topics that are unsettled, recogniz- chapter gives a preview of the chapter and is a useful ing that new research constantly provides fresh insights study aid. and sometimes challenges old ideas. • Key concepts. Each chapter starts with a short list of key concepts that the student should understand after Key Changes. Many changes have been instituted in reading the chapter. this second edition. All chapters were rewritten, in some • Text. The text is easy to read, and topics are developed cases by new contributors, and most illustrations have logically. Difficult concepts are explained clearly, often been redrawn. The new illustrations are clearer and make with the help of figures. Minutiae or esoteric topics are better use of color. An effort has also been made to insti- avoided. tute more conceptual illustrations, rather than including • Topic headings. Second-level topic headings are active more graphs and tables of data. These conceptual dia- full-sentence statements. For example, instead of head- grams help students understand the general underpinnings ing a section “Homeostasis,” the heading is “Homeosta- of physiology. Another key change is the book’s size: It is sis is the maintenance of steady states in the body by co- more compact because of deletions of extraneous material ordinated physiological mechanisms.” In this way, the and shortening of some of the sections, most notably the key idea in a section is immediately obvious. gastrointestinal physiology section. We also overhauled • Boldfacing. Key terms are boldfaced upon their first ap- many of the features in the book. Each chapter now con- pearance in a chapter. tains a list of key concepts. The clinical focus boxes have • Illustrations and tables. The figures have been selected been updated; they are more practical and less research- to illustrate important concepts. The illustrations often oriented. Each chapter includes a case study, with ques- show interrelationships between different variables or tions and answers. All of the review questions at the end components of a system. Many of the figures are flow of each chapter are now of the USMLE type. Lists of com- diagrams, so that students can appreciate the sequence mon abbreviations in physiology and of normal blood val- of events that follow when a factor changes. Tables of- ues have been added. ten provide useful summaries of material explained in more detail in the text. Content. This book begins with a discussion of basic • Clinical focus boxes. Each chapter contains one or two physiological concepts, such as homeostasis and cell sig- clinical focus boxes that illustrate the relevance of the naling, in Chapter 1. Chapter 2 covers the cell membrane, physiology discussed in the chapter to an understand- membrane transport, and the cell membrane potential. ing of medicine. Most of the remaining chapters discuss the different organ • Case studies. Each section concludes with a set of case systems: nervous, muscle, cardiovascular, respiratory, re- studies, one for each chapter, with questions and an- nal, gastrointestinal, endocrine, and reproductive physiol- swers. These case studies help to reinforce how an un- v vi Preface derstanding of physiology is important in dealing with front cover provides a more complete and easily accessi- clinical conditions. ble reference. • Review questions and answers. Students can use the re- • Index. A complete index allows the student to easily view questions at the end of each chapter to test whether look up material in the text. they have mastered the material. These USMLE-type questions should help students prepare for the Step 1 Design. The design of this second edition has been com- examination. Answers to the questions are provided at pletely overhauled. The new design makes navigating the the end of the book and include explanations as to why text easier. Likewise, the design highlights the pedagogical the choices are correct or incorrect. features, making them easier to find and use. • Suggested readings. Each chapter provides a short list We thank the contributors for their patience and for fol- of recent review articles, monographs, book chapters, lowing directions so that we could achieve a textbook of classic papers, or Web sites where students can obtain reasonably uniform style. Dr. James McGill was kind additional information. enough to write the clinical focus boxes and case studies for • Abbreviations and normal values. This second edition Chapters 26 and 27. We thank Marlene Brown for her sec- includes a table of common abbreviations in physiology retarial assistance, Betsy Dilernia for her critical editing of and a table of normal blood, plasma, or serum values. All each chapter, and Kathleen Scogna, our development edi- abbreviations are defined when first used in the text, but tor, without whose encouragement and support this revised the table of abbreviations in the appendix serves as a use- edition would not have been possible. ful reminder of abbreviations commonly used in physiology and medicine. Normal values for blood are also Rodney A. Rhoades, Ph.D. embedded in the text, but the table on the inside of the George A. Tanner, Ph.D. CONTRIBUTORS H. Glenn Bohlen, Ph.D. Richard A. Meiss, Ph.D. Professor of Physiology and Biophysics Professor of Obstetrics and Gynecology and Indiana University School of Medicine Physiology and Biophysics Indianapolis, Indiana Indiana University School of Medicine Indianapolis, Indiana Robert V. Considine, Ph.D. Assistant Professor of Medicine and Physiology and Biophysics Daniel E. Peavy, Ph.D. Indiana University School of Medicine Associate Professor of Physiology and Biophysics Indianapolis, Indiana Indiana University School of Medicine Indianapolis, Indiana Denis English, Ph.D. Director, Bone Marrow Transplant Laboratory Rodney A. Rhoades, Ph.D. Methodist Hospital of Indiana Professor and Chairman Indianapolis, Indiana Department of Physiology and Biophysics Indiana University School of Medicine Cynthia J. Forehand, Ph.D. Indianapolis, Indiana Associate Professor of Anatomy/Neurobiology University of Vermont College of Medicine Thom W. Rooke, M.D. Burlington, Vermont Director, Vascular Medicine Section Vascular Center Patricia J. Gallagher, Ph.D. Mayo Clinic Assistant Professor of Physiology Rochester, Minnesota Indiana University School of Medicine Indianapolis, Indiana Harvey V. Sparks, Jr., M.D. University Distinguished Professor Alon Harris, Ph.D. Michigan State University Associate Professor of Ophthalmology and East Lansing, Michigan Physiology and Biophysics Indiana University School of Medicine George A. Tanner, Ph.D. Indianapolis, Indiana Professor of Physiology and Biophysics Indiana University School of Medicine Stephen A. Kempson, Ph.D. Indianapolis, Indiana Professor of Physiology and Biophysics Indiana University School of Medicine Paul F. Terranova, Ph.D. Indianapolis, Indiana Director, Center for Reproductive Sciences University of Kansas Medical Center John C. Kincaid, M.D. Kansas City, Kansas Associate Professor of Neurology and Physiology and Biophysics Indiana University School of Medicine Patrick Tso, Ph.D. Indianapolis, Indiana Professor of Pathology University of Cincinnati School of Medicine Bruce E. Martin, Ph.D. Cincinnati, Ohio Associate Professor of Physiology Indiana University School of Medicine C. Bruce Wenger, M.D., Ph.D. Indianapolis, Indiana Research Pharmacologist, Military Ergonomics Division USARIEM James McGill, M.D. Natick, Massachusetts Assistant Professor of Medicine Indiana University School of Medicine Jackie D. Wood, Ph.D. Indianapolis, Indiana Professor and Chairman, Department of Physiology Ohio State University College of Medicine Columbus, Ohio vii PART I Cellular Physiology C H A P T E R Homeostasis and Cellular Signaling Patricia J. Gallagher, Ph.D. George A. Tanner, Ph.D. 1 CHAPTE R O U T L I N E ■ THE BASIS OF PHYSIOLOGICAL REGULATION ■ SECOND MESSENGER SYSTEMS AND ■ MODES OF COMMUNICATION AND SIGNALING INTRACELLULAR SIGNALING PATHWAYS ■ THE MOLECULAR BASIS OF CELLULAR SIGNALING ■ INTRACELLULAR RECEPTORS AND HORMONE ■ SIGNAL TRANSDUCTION BY PLASMA MEMBRANE SIGNALING RECEPTORS K E Y C O N C E P T S 1. Physiology is the study of the functions of living organisms 7. Different modes of cell communication differ in terms of and how they are regulated and integrated. distance and speed. 2. A stable internal environment is necessary for normal cell 8. Chemical signaling molecules (first messengers) provide function and survival of the organism. the major means of intercellular communication; they in- 3. Homeostasis is the maintenance of steady states in the clude ions, gases, small peptides, protein hormones, body by coordinated physiological mechanisms. metabolites, and steroids. 4. Negative and positive feedback are used to modulate the 9. Receptors are the receivers and transmitters of signaling body’s responses to changes in the environment. molecules; they are located either on the plasma mem- 5. Steady state and equilibrium are distinct conditions. brane or within the cell. Steady state is a condition that does not change over time, 10. Second messengers are important for amplification of the while equilibrium represents a balance between opposing signal received by plasma membrane receptors. forces. 11. Steroid and thyroid hormone receptors are intracellular 6. Cellular communication is essential to integrate and coor- receptors that participate in the regulation of gene ex- dinate the systems of the body so they can participate in pression. different functions. hysiology is the study of processes and functions in living distribution of ions across cell membranes is described in ther- Porganisms. It is a broad field that encompasses many dis- modynamic terms, muscle contraction is analyzed in terms of ciplines and has strong roots in physics, chemistry, and math- forces and velocities, and regulation in the body is described ematics. Physiologists assume that the same chemical and in terms of control systems theory. Because the functions of physical laws that apply to the inanimate world govern living systems are carried out by their constituent structures, processes in the body. They attempt to describe functions in knowledge of structure from gross anatomy to the molecular chemical, physical, or engineering terms. For example, the level is germane to an understanding of physiology. 1 2 PART I CELLULAR PHYSIOLOGY The scope of physiology ranges from the activities or External environment functions of individual molecules and cells to the interac- tion of our bodies with the external world. In recent years, we have seen many advances in our understanding of phys- Lungs iological processes at the molecular and cellular levels. In higher organisms, changes in cell function always occur in Alimentary the context of a whole organism, and different tissues and tract organs obviously affect one another. The independent ac- Kidneys tivity of an organism requires the coordination of function at all levels, from molecular and cellular to the organism as a whole. An important part of physiology is understanding Internal environment how different parts of the body are controlled, how they interact, and how they adapt to changing conditions. For a person to remain healthy, physiological conditions in the body must be kept at optimal levels and closely regulated. Regulation requires effective communication be- Body cells tween cells and tissues. This chapter discusses several topics related to regulation and communication: the internal environment, homeostasis of extracellular fluid, intracellu- Skin lar homeostasis, negative and positive feedback, feedforward control, compartments, steady state and equilibrium, intercellular and intracellular communication, nervous and endocrine systems control, cell membrane transduction, The living cells of our body, surrounded and important signal transduction cascades. FIGURE 1.1 by an internal environment (extracellular fluid), communicate with the external world through this medium. Exchanges of matter and energy between the body and THE BASIS OF PHYSIOLOGICAL REGULATION the external environment (indicated by arrows) occur via the gastrointestinal tract, kidneys, lungs, and skin (including the special- Our bodies are made up of incredibly complex and delicate ized sensory organs). materials, and we are constantly subjected to all kinds of disturbances, yet we keep going for a lifetime. It is clear that conditions and processes in the body must be closely maintain a relatively constant internal environment. A controlled and regulated, i.e., kept at appropriate values. good example is the ability of warm-blooded animals to live Below we consider, in broad terms, physiological regula- in different climates. Over a wide range of external temper- tion in the body. atures, core temperature in mammals is maintained constant by both physiological and behavioral mechanisms. This stability has a clear survival value. A Stable Internal Environment Is Essential for Normal Cell Function Homeostasis Is the Maintenance of The nineteenth-century French physiologist Claude Steady States in the Body by Bernard was the first to formulate the concept of the inter- Coordinated Physiological Mechanisms nal environment (milieu intérieur). He pointed out that an external environment surrounds multicellular organisms (air The key to maintaining stability of the internal environ- or water), but the cells live in a liquid internal environment ment is the presence of regulatory mechanisms in the body. (extracellular fluid). Most body cells are not directly ex- In the first half of the twentieth century, the American posed to the external world but, rather, interact with it physiologist Walter B. Cannon introduced a concept de- through the internal environment, which is continuously scribing this capacity for self-regulation: homeostasis, the renewed by the circulating blood (Fig. 1.1). maintenance of steady states in the body by coordinated For optimal cell, tissue, and organ function in animals, physiological mechanisms. several conditions in the internal environment must be The concept of homeostasis is helpful in understanding maintained within narrow limits. These include but are not and analyzing conditions in the body. The existence of limited to (1) oxygen and carbon dioxide tensions, (2) con- steady conditions is evidence of regulatory mechanisms in centrations of glucose and other metabolites, (3) osmotic the body that maintain stability. To function optimally un- pressure, (4) concentrations of hydrogen, potassium, cal- der a variety of conditions, the body must sense departures cium, and magnesium ions, and (5) temperature. Depar- from normal and must engage mechanisms for restoring tures from optimal conditions may result in disordered conditions to normal. Departures from normal may be in the functions, disease, or death. direction of too little or too much, so mechanisms exist for Bernard stated that “stability of the internal environment opposing changes in either direction. For example, if blood is the primary condition for a free and independent exis- glucose concentration is too low, the hormone glucagon, tence.” He recognized that an animal’s independence from from alpha cells of the pancreas, and epinephrine, from the changing external conditions is related to its capacity to adrenal medulla, will increase it. If blood glucose concentra- CHAPTER 1 Homeostasis and Cellular Signaling 3 tion is too high, insulin from the beta cells of the pancreas water within cells. Cells can regulate their ionic strength by will lower it by enhancing the cellular uptake, storage, and maintaining the proper mixture of ions and un-ionized metabolism of glucose. Behavioral responses also contribute molecules (e.g., organic osmolytes, such as sorbitol). to the maintenance of homeostasis. For example, a low Many cells use calcium as an intracellular signal or “mes- blood glucose concentration stimulates feeding centers in senger” for enzyme activation, and, therefore, must possess 2⫹ the brain, driving the animal to seek food. mechanisms for regulating cytosolic [Ca ]. Such funda- Homeostatic regulation of a physiological variable often mental activities as muscle contraction, the secretion of involves several cooperating mechanisms activated at the neurotransmitters, hormones, and digestive enzymes, and same time or in succession. The more important a variable, the opening or closing of ion channels are mediated via 2⫹ 2⫹ the more numerous and complicated are the mechanisms transient changes in cytosolic [Ca ]. Cytosolic [Ca ] in ⫺7 that keep it at the desired value. Disease or death is often resting cells is low, about 10 M, and far below extracel- 2⫹ 2⫹ the result of dysfunction of homeostatic mechanisms. lular fluid [Ca ] (about 2.5 mM). Cytosolic [Ca ] is reg- The effectiveness of homeostatic mechanisms varies ulated by the binding of calcium to intracellular proteins, over a person’s lifetime. Some homeostatic mechanisms are transport is regulated by adenosine triphosphate (ATP)-de- not fully developed at the time of birth. For example, a pendent calcium pumps in mitochondria and other or- newborn infant cannot concentrate urine as well as an adult ganelles (e.g., sarcoplasmic reticulum in muscle), and the and is, therefore, less able to tolerate water deprivation. extrusion of calcium is regulated via cell membrane ⫹ 2⫹ Homeostatic mechanisms gradually become less efficient Na /Ca exchangers and calcium pumps. Toxins or di- as people age. For example, older adults are less able to tol- minished ATP production can lead to an abnormally ele- 2⫹ 2⫹ erate stresses, such as exercise or changing weather, than vated cytosolic [Ca ]. A high cytosolic [Ca ] activates are younger adults. many enzyme pathways, some of which have detrimental effects and may cause cell death. Intracellular Homeostasis Is Essential for Normal Cell Function Negative Feedback Promotes Stability; Feedforward Control Anticipates Change The term homeostasis has traditionally been applied to the internal environment—the extracellular fluid that bathes our Engineers have long recognized that stable conditions can be tissues—but it can also be applied to conditions within achieved by negative-feedback control systems (Fig. 1.2). cells. In fact, the ultimate goal of maintaining a constant in- Feedback is a flow of information along a closed loop. The ternal environment is to promote intracellular homeostasis, components of a simple negative-feedback control system and toward this end, conditions in the cytosol are closely include a regulated variable, sensor (or detector), controller regulated. (or comparator), and effector. Each component controls the The many biochemical reactions within a cell must be next component. Various disturbances may arise within or tightly regulated to provide metabolic energy and proper rates of synthesis and breakdown of cellular constituents. Metabolic reactions within cells are catalyzed by enzymes Feedforward Feedforward path and are therefore subject to several factors that regulate or controller influence enzyme activity. • First, the final product of the reactions may inhibit the Command Command catalytic activity of enzymes, end-product inhibition. End-product inhibition is an example of negative-feed- Feedback back control (see below). controller Disturbance • Second, intracellular regulatory proteins, such as the Set calcium-binding protein calmodulin, may control en- point Effector zyme activity. • Third, enzymes may be controlled by covalent modifi- Regulated cation, such as phosphorylation or dephosphorylation. variable • Fourth, the ionic environment within cells, including ⫹ hydrogen ion concentration ([H ]), ionic strength, and Feedback loop Sensor calcium ion concentration, influences the structure and activity of enzymes. Hydrogen ion concentration or pH affects the electrical Elements of negative feedback and feedfor- FIGURE 1.2 charge of protein molecules and, hence, their configuration ward control systems (red). In a negative- feedback control system, information flows along a closed loop. and binding properties. pH affects chemical reactions in The regulated variable is sensed, and information about its level is cells and the organization of structural proteins. Cells reg- fed back to a feedback controller, which compares it to a desired ulate their pH via mechanisms for buffering intracellular ⫹ value (set point). If there is a difference, an error signal is gener- hydrogen ions and by extruding H into the extracellular ated, which drives the effector to bring the regulated variable fluid (see Chapter 25). closer to the desired value. A feedforward controller generates The structure and activity of cellular proteins are also af- commands without directly sensing the regulated variable, al- fected by ionic strength. Cytosolic ionic strength depends though it may sense a disturbance. Feedforward controllers often on the total number and charge of ions per unit volume of operate through feedback controllers. 4 PART I CELLULAR PHYSIOLOGY outside the system and cause undesired changes in the regu- dioxide tensions hardly change during all but exhausting ex- lated variable. With negative feedback, a regulated variable ercise. One explanation for this remarkable behavior is that is sensed, information is fed back to the controller, and the exercise simultaneously produces a centrally generated feed- effector acts to oppose change (hence, the term negative). forward signal to the active muscles and the respiratory and A familiar example of a negative-feedback control system cardiovascular systems; feedforward control, together with is the thermostatic control of room temperature. Room tem- feedback information generated as a consequence of in- perature (regulated variable) is subjected to disturbances. For creased movement and muscle activity, adjusts the heart, example, on a cold day, room temperature falls. A ther- blood vessels, and respiratory muscles. In addition, control mometer (sensor) in the thermostat (controller) detects the system function can adapt over a period of time. Past experi- room temperature. The thermostat is set for a certain tem- ence and learning can change the control system’s output so perature (set point). The controller compares the actual tem- that it behaves more efficiently or appropriately. perature (feedback signal) to the set point temperature, and Although homeostatic control mechanisms usually act an error signal is generated if the room temperature falls be- for the good of the body, they are sometimes deficient, in- low the set temperature. The error signal activates the fur- appropriate, or excessive. Many diseases, such as cancer, nace (effector). The resulting change in room temperature is diabetes, and hypertension, develop because of a defective monitored, and when the temperature rises sufficiently, the control mechanism. Homeostatic mechanisms may also re- furnace is turned off. Such a negative-feedback system allows sult in inappropriate actions, such as autoimmune diseases, some fluctuation in room temperature, but the components in which the immune system attacks the body’s own tissue. act together to maintain the set temperature. Effective com- Scar formation is one of the most effective homeostatic munication between the sensor and effector is important in mechanisms of healing, but it is excessive in many chronic keeping these oscillations to a minimum. diseases, such as pulmonary fibrosis, hepatic cirrhosis, and Similar negative-feedback systems maintain homeostasis renal interstitial disease. in the body. One example is the system that regulates arterial blood pressure (see Chapter 18). This system’s sensors Positive Feedback Promotes a (arterial baroreceptors) are located in the carotid sinuses Change in One Direction and aortic arch. Changes in stretch of the walls of the carotid sinus and aorta, which follow from changes in With positive feedback, a variable is sensed and action is blood pressure, stimulate these sensors. Afferent nerve taken to reinforce a change of the variable. Positive feed- fibers transmit impulses to control centers in the medulla back does not lead to stability or regulation, but to the oblongata. Efferent nerve fibers send impulses from the opposite—a progressive change in one direction. One medullary centers to the system’s effectors, the heart and example of positive feedback in a physiological process is blood vessels. The output of blood by the heart and the re- the upstroke of the action potential in nerve and muscle sistance to blood flow are altered in an appropriate direc- (Fig. 1.3). Depolarization of the cell membrane to a value tion to maintain blood pressure, as measured at the sensors, greater than threshold leads to an increase in sodium ⫹ ⫹ within a given range of values. This negative-feedback con- (Na ) permeability. Positively charged Na ions rush ⫹ trol system compensates for any disturbance that affects into the cell through membrane Na channels and cause blood pressure, such as changing body position, exercise, further membrane depolarization; this leads to a further ⫹ ⫹ anxiety, or hemorrhage. Nerves accomplish continuous increase in Na permeability and more Na entry. This rapid communication between the feedback elements. Var- snowballing event, which occurs in a fraction of a mil- ious hormones are also involved in regulating blood pressure, but their effects are generally slower and last longer. Feedforward control is another strategy for regulating Depolarization of systems in the body, particularly when a change with time nerve or muscle is desired. In this case, a command signal is generated, membrane which specifies the target or goal. The moment-to-moment operation of the controller is “open loop”; that is, the regulated variable itself is not sensed. Feedforward control mechanisms often sense a disturbance and can, therefore, take corrective action that anticipates change. For example, heart rate and breathing increase even before a person has begun to exercise. Feedforward control usually acts in combination with ⫹ negative-feedback systems. One example is picking up a Entry of Increase in Na ⫹ Na into cell permeability pencil. The movements of the arm, hand, and fingers are di- rected by the cerebral cortex (feedforward controller); the movements are smooth, and forces are appropriate only in part because of the feedback of visual information and sensory information from receptors in the joints and muscles. Another example of this combination occurs during exercise. Respiratory and cardiovascular adjustments closely match A positive-feedback cycle involved in the FIGURE 1.3 muscular activity, so that arterial blood oxygen and carbon upstroke of an action potential. CHAPTER 1 Homeostasis and Cellular Signaling 5 lisecond, leads to an actual reversal of membrane poten- at the blood capillary level. Even within cells there is com- tial and an electrical signal (action potential) conducted partmentalization. The interiors of organelles are separated along the nerve or muscle fiber membrane. The process is from the cytosol by membranes, which restrict enzymes and ⫹ stopped by inactivation (closure) of the Na channels. substrates to structures such as mitochondria and lysosomes Another example of positive feedback occurs during the and allow for the fine regulation of enzymatic reactions and follicular phase of the menstrual cycle. The female sex hor- a greater variety of metabolic processes. mone estrogen stimulates the release of luteinizing hor- When two compartments are in equilibrium, opposing mone, which in turn causes further estrogen synthesis by forces are balanced, and there is no net transfer of a partic- the ovaries. This positive feedback culminates in ovulation. ular substance or energy from one compartment to the A third example is calcium-induced calcium release, other. Equilibrium occurs if sufficient time for exchange has which occurs with each heartbeat. Depolarization of the been allowed and if no physical or chemical driving force cardiac muscle plasma membrane leads to a small influx of would favor net movement in one direction or the other. calcium through membrane calcium channels. This leads to For example, in the lung, oxygen in alveolar spaces diffuses an explosive release of calcium from the muscle’s sarcoplas- into pulmonary capillary blood until the same oxygen ten- mic reticulum, which rapidly increases the cytosolic cal- sion is attained in both compartments. Osmotic equilib- cium level and activates the contractile machinery. Many rium between cells and extracellular fluid is normally pres- other examples are described in this textbook. ent in the body because of the high water permeability of Positive feedback, if unchecked, can lead to a vicious cy- most cell membranes. An equilibrium condition, if undis- cle and dangerous situations. For example, a heart may be turbed, remains stable. No energy expenditure is required so weakened by disease that it cannot provide adequate to maintain an equilibrium state. blood flow to the muscle tissue of the heart. This leads to a Equilibrium and steady state are sometimes confused further reduction in cardiac pumping ability, even less with each other. A steady state is simply a condition that coronary blood flow, and further deterioration of cardiac does not change with time. It indicates that the amount or function. The physician’s task is sometimes to interrupt or concentration of a substance in a compartment is constant. “open” such a positive-feedback loop. In a steady state, there is no net gain or net loss of a substance in a compartment. Steady state and equilibrium both suggest stable conditions, but a steady state does not nec- Steady State and Equilibrium Are Separate Ideas essarily indicate an equilibrium condition, and energy ex- Physiology often involves the study of exchanges of matter penditure may be required to maintain a steady state. For ⫹ or energy between different defined spaces or compart- example, in most body cells, there is a steady state for Na ⫹ ments, separated by some type of limiting structure or ions; the amounts of Na entering and leaving cells per unit ⫹ membrane. The whole body can be divided into two major time are equal. But intracellular and extracellular Na ion compartments: extracellular fluid and intracellular fluid. concentrations are far from equilibrium. Extracellular ⫹ ⫹ ⫹ These two compartments are separated by cell plasma mem- [Na ] is much higher than intracellular [Na ], and Na branes. The extracellular fluid consists of all the body fluids tends to move into cells down concentration and electrical outside of cells and includes the interstitial fluid, lymph, gradients. The cell continuously uses metabolic energy to ⫹ blood plasma, and specialized fluids, such as cerebrospinal pump Na out of the cell to maintain the cell in a steady ⫹ fluid. It constitutes the internal environment of the body. state with respect to Na ions. In living systems, conditions Ordinary extracellular fluid is subdivided into interstitial are often displaced from equilibrium by the constant ex- fluid—lymph and plasma; these fluid compartments are sep- penditure of metabolic energy. arated by the endothelium, which lines the blood vessels. Figure 1.4 illustrates the distinctions between steady Materials are exchanged between these two compartments state and equilibrium. In Figure 1.4A, the fluid level in the Models of the concepts of steady state and (Modified from Riggs DS. The Mathematical Approach to Physio- FIGURE 1.4 equilibrium. A, B, and C, Depiction of a logical Problems. Cambridge, MA: MIT Press, 1970;169.) steady state. In C, compartments X and Y are in equilibrium.