Medical Physiology

Temperature Regulation PART 8 and Exercise Physiology CHAPTER The Regulation of 29 Body Temperature* 29 C. Bruce Wenger, Ph.D. CHAPTER OUTLINE ■ BODY TEMPERATURES AND HEAT TRANSFER IN ■ THERMOREGULATORY RESPONSES DURING THE BODY EXERCISE ■ THE BALANCE BETWEEN HEAT PRODUCTION AND ■ HEAT ACCLIMATIZATION HEAT LOSS ■ RESPONSES TO COLD ■ HEAT DISSIPATION ■ CLINICAL ASPECTS OF THERMOREGULATION ■ THERMOREGULATORY CONTROL KEY CONCEPTS 1. The body is divided into an inner core and an outer shell; 6. The control of thermoregulatory responses is accom- temperature is relatively uniform in the core and is regu- plished through reflex signals generated in the CNS ac- lated within narrow limits, while shell temperature is per- cording to the level of the thermoregulatory set point, as mitted to vary. well as signals from temperature-sensitive CNS neurons 2. The body produces heat through metabolic processes and and nerve endings elsewhere, chiefly in the skin. The re- exchanges energy with the environment as mechanical sponse of sweat glands and superficial blood vessels to work and heat; it is in thermal balance when the sum of these signals is modified by local skin temperature. metabolic energy production plus energy gain from the en- 7. Acclimatization to heat can dramatically increase the vironment equals energy loss to the environment. body’s ability to dissipate heat, maintain cardiovascular 3. In humans, the chief physiological thermoregulatory re- homeostasis in hot temperatures, and conserve salt while sponses are the secretion of sweat, which removes heat from sweating profusely. Acclimatization to cold has only mod- the skin as it evaporates; the control of skin blood flow, which est effects, depending on how the acclimatization was pro- governs the flow of heat to the skin from the rest of the body; duced, and may include increased tissue insulation and and increasing metabolic heat production in the cold. variable metabolic responses. 4. The thermoregulatory set point (the setting of the body’s 8. Adverse systemic effects of excessive heat stress include “thermostat”) varies cyclically with the circadian rhythm circulatory instability, fluid-electrolyte imbalance, exer- and the menstrual cycle, and is elevated during fever. tional heat injury, and heatstroke. Exertional heat injury 5. Core and whole-body skin temperatures govern the reflex and heatstroke involve organ and tissue injury produced in control of physiological thermoregulatory responses, several ways, some of which are not well understood. The which are graded according to disturbances in the body’s primary adverse systemic effect of excessive cold stress is thermal state. hypothermia. *The views, opinions, and findings contained in this chapter are those of the author and should not be construed as official Department of the Army position, policy, or decision unless so designated by other official documentation. Approved for public release; distribution unlimited. 527

528 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY umans, like other mammals, are homeotherms, or Cold also can injure tissues. As a water-based solution Hwarm-blooded animals, and regulate their internal freezes, ice crystals consisting of pure water form, so that all body temperatures within a narrow range near 37
C, in dissolved substances in the solution are left in the unfrozen spite of wide variations in environmental temperature liquid. Therefore, as more ice forms, the remaining liquid be- (Fig. 29.1). Internal body temperatures of poikilotherms, or comes more and more concentrated. Freezing damages cells cold-blooded animals, by contrast, are governed by envi- through two mechanisms. Ice crystals probably injure the ronmental temperature. The range of temperatures that liv- cell mechanically. In addition, the increase in solute concen- ing cells and tissues can tolerate without harm extends from tration of the cytoplasm as ice forms denatures the proteins just above freezing to nearly 45
C—far wider than the lim- by removing their water of hydration, increasing the ionic its within which homeotherms regulate body temperature. strength of the cytoplasm, and causing other changes in the What biological advantage do homeotherms gain by main- physicochemical environment in the cytoplasm. taining a stable body temperature? As we shall see, tissue Second, temperature changes profoundly alter biologi- temperature is important for two reasons. cal function through specific effects on such specialized First, temperature extremes injure tissue directly. High functions as electrical properties and fluidity of cell mem- temperatures alter the configuration and overall structure of branes, and through a general effect on most chemical re- protein molecules, even though the sequence of amino action rates. In the physiological temperature range, most acids is unchanged. Such alteration of protein structure is reaction rates vary approximately as an exponential func- called denaturation. A familiar example of denaturation by tion of temperature (T); increasing T by 10
C increases the heat is the coagulation of albumin in the white of a cooked reaction rate by a factor of 2 to 3. For any particular reac- egg. Since the biological activity of a protein molecule de- tion, the ratio of the rates at two temperatures 10
C apart is pends on its configuration and charge distribution, denatu- called the Q 10 for that reaction, and the effect of tempera- ration inactivates a cell’s proteins and injures or kills the ture on reaction rate is called the Q 10 effect. The notion of cell. Injury occurs at tissue temperatures higher than about Q 10 may be generalized to apply to a group of reactions 45
C, which is also the point at which heating the skin be- that have some measurable overall effect (such as O 2 con- comes painful. The severity of injury depends on the tem- sumption) in common and are, thus, thought of as com- perature to which the tissue is heated and how long the prising a physiological process. The Q 10 effect is clinically heating lasts. important in managing patients who have high fevers and are receiving fluid and nutrition intravenously. A com- monly used rule is that a patient’s fluid and calorie needs are increased 13% above normal for each 1
C of fever. Upper limit of survival? The profound effect of temperature on biochemical re- Temperature action rates is illustrated by the sluggishness of a reptile regulation that comes out of its burrow in the morning chill and be- seriously Heatstroke, impaired brain lesions comes active only after being warmed by the sun. Homeotherms avoid such a dependence of metabolic rate on environmental temperature by regulating their internal Temperature Fever and regulation exercise body temperatures within a narrow range. A drawback of effective in homeothermy is that, in most homeotherms, certain vital fever and Usual range processes cannot function at low levels of body tempera- health of normal at rest ture that poikilotherms tolerate easily. For example, ship- wreck victims immersed in cold water die of respiratory or circulatory failure (through disruption of the electrical ac- tivity of the brainstem or heart) at body temperatures of Temperature regulation about 25
C, even though such a temperature produces no impaired direct tissue injury and fish thrive in the same water. BODY TEMPERATURES AND HEAT TRANSFER Temperature IN THE BODY regulation lost The body is divided into a warm internal core and a cooler Lower limit outer shell (Fig. 29.2). Because the temperature of the shell of survival? is strongly influenced by the environment, its temperature is not regulated within narrow limits as the internal body Rectal temperature ranges in healthy peo- FIGURE 29.1 temperature is, even though thermoregulatory responses ple, patients with fever, and people with impaired or failed thermoregulation. (Modified from Wenger strongly affect the temperature of the shell, especially its CB, Hardy JD. Temperature regulation and exposure to heat and outermost layer, the skin. The thickness of the shell de- cold. In: Lehmann JF, ed. Therapeutic Heat and Cold. 4th Ed. pends on the environment and the body’s need to conserve Baltimore: Williams & Wilkins, 1990;150–178. Based on DuBois heat. In a warm environment, the shell may be less than 1 EF. Fever and the Regulation of Body Temperature. Springfield, cm thick, but in a subject conserving heat in a cold envi- IL: CC Thomas, 1948.) ronment, it may extend several centimeters below the skin.

CHAPTER 29 The Regulation of Body Temperature 529 Thermal Conductivities and Rates TABLE 29.1 of Heat Flow Rate of Heat Flow a Conductivity Material kcal/(sm°C) kcal/hr Watts Copper 0.092 33,120 38,474 Epidermis 0.00005 18 21 Dermis 0.00009 32 38 Fat 0.00004 14 17 Muscle 0.00011 40 46 Oak (across grain) 0.00004 14 17 Glass fiber 0.00001 3.6 4.2 insulation a 2 Values are calculated for slabs 1 m in area and 1 cm thick, with a 1°C temperature difference between the two faces of the slab. which in the cold may include most of the limbs and the more superficial muscles of the neck and trunk—become cooler as they lose heat by conduction to cool overlying skin and, ultimately, to the environment. In this way, these un- derlying tissues, which in the heat were part of the body Distribution of temperatures in the body’s FIGURE 29.2 core, now become part of the shell. In addition to the organs core and shell. A, During exposure to cold. B, In a warm environment. Since the temperatures of the surface and in the trunk and head, the core includes a greater or lesser the thickness of the shell depend on environmental temperature, amount of more superficial tissue—mostly skeletal muscle— the shell is thicker in the cold and thinner in the heat. depending on the body’s thermal state. Because the shell lies between the core and the environ- ment, all heat leaving the body core, except heat lost through the respiratory tract, must pass through the shell The internal body temperature that is regulated is the tem- perature of the vital organs inside the head and trunk, before being given up to the environment. Thus, the shell which, together with a variable amount of other tissue, insulates the core from the environment. In a cool subject, comprise the warm internal core. the skin blood flow is low, so core-to-skin heat transfer is Heat is produced in all tissues of the body but is lost to dominated by conduction; the shell is also thicker, provid- the environment only from tissues in contact with the en- ing more insulation to the core, since heat flow by conduc- vironment—predominantly from the skin and, to a lesser tion varies inversely with the distance the heat must travel. degree, from the respiratory tract. We, therefore, need to Changes in skin blood flow, which directly affect core-to- consider heat transfer within the body, especially heat skin heat transfer by convection, also indirectly affect core- transfer (1) from major sites of heat production to the rest to-skin heat transfer by conduction by changing the thick- of the body, and (2) from the core to the skin. Heat is ness of the shell. In a cool subject, the subcutaneous fat transported within the body by two means: conduction layer contributes to the insulation value of the shell because through the tissues and convection by the blood, a process the fat layer increases the thickness of the shell and because in which flowing blood carries heat from warmer tissues to fat has a conductivity about 0.4 times that of dermis or mus- cooler tissues. cle (see Table 29.1). Thus, fat is a correspondingly better Heat flow by conduction varies directly with the ther- insulator. In a warm subject, however, the shell is relatively mal conductivity of the tissues, the change in temperature thin, and provides little insulation. Furthermore, a warm over the distance the heat travels, and the area (perpendi- subject’s skin blood flow is high, so heat flow from the core cular to the direction of heat flow) through which the to the skin is dominated by convection. In these circum- heat flows. It varies inversely with the distance the heat stances the subcutaneous fat layer, which affects conduc- must travel. As Table 29.1 shows, the tissues are rather tion but not convection, has little effect on heat flow from poor heat conductors. the core to the skin. Heat flow by convection depends on the rate of blood flow and the temperature difference between the tissue and Core Temperature Is Close to the blood supplying the tissue. Because the vessels of the mi- Central Blood Temperature crovasculature have thin walls and, collectively, a large total surface area, the blood comes to the temperature of the sur- Core temperature varies slightly from one site to another rounding tissue before it reaches the capillaries. Changes in depending on such local factors as metabolic rate, blood skin blood flow in a cool environment change the thickness supply, and the temperatures of neighboring tissues. How- of the shell. When skin blood flow is reduced in the cold, the ever, temperatures at different places in the core are all affected skin becomes cooler, and the underlying tissues— close to the temperature of the central blood and tend to

530 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY change together. The notion of a single uniform core tem- quently used. Infrared ear thermometers are convenient perature, although not strictly correct, is a useful approxi- and widely used in the clinic, but temperatures of the tym- mation. The value of 98.6
F often given as the normal level panum and external auditory meatus are loosely related to of body temperature may give the misleading impression more accepted indices of core temperature, and ear tem- that body temperature is regulated so precisely that it is perature in collapsed hyperthermic runners may be 3 to not allowed to deviate even a few tenths of a degree. In 6
C below rectal temperature. fact, 98.6
F is simply the Fahrenheit equivalent of 37
C, and body temperature does vary somewhat (see Fig. 29.1). The effects of heavy exercise and fever are familiar; varia- Skin Temperature Is Important in Heat tion among individuals and such factors as time of day Exchange and Thermoregulatory Control (Fig. 29.3), phase of the menstrual cycle, and acclimatiza- Most heat is exchanged between the body and the envi- tion to heat can also cause differences of up to about 1
C ronment at the skin surface. Skin temperature is much in core temperature at rest. more variable than core temperature; it is affected by ther- To maintain core temperature within a narrow range, moregulatory responses such as skin blood flow and sweat the thermoregulatory system needs continuous informa- secretion, the temperatures of underlying tissues, and en- tion about the level of core temperature. Temperature- vironmental factors such as air temperature, air move- sensitive neurons and nerve endings in the abdominal vis- ment, and thermal radiation. Skin temperature is one of cera, great veins, spinal cord, and, especially, the brain the major factors determining heat exchange with the en- provide this information. We discuss how the thermoreg- vironment. For these reasons, it provides the thermoregu- ulatory system processes and responds to this information latory system with important information about the need later in the chapter. to conserve or dissipate heat. Core temperature should be measured at a site whose Many bare nerve endings just under the skin are sensitive temperature is not biased by environmental temperature. to temperature. Depending on the relation of discharge rate Sites used clinically include the rectum, the mouth and, oc- to temperature, they are classified as either warm or cold re- casionally, the axilla. The rectum is well insulated from the ceptors (see Chapter 4). Cold receptors are about 10 times environment; its temperature is independent of environ- more numerous than warm receptors. Furthermore, as the mental temperature and is a few tenths of 1
C warmer than skin is heated, warm receptors respond with a transient burst arterial blood and other core sites. The tongue is richly sup- of activity and cold receptors respond with a transient sup- plied with blood; oral temperature under the tongue is usu- pression; the reverse happens as the skin is cooled. These ally close to blood temperature (and 0.4 to 0.5
C below transient responses at the beginning of heating or cooling rectal temperature), but cooling the face, neck, or mouth give the central thermoregulatory controller almost imme- can make oral temperature misleadingly low. If a patient diate information about changes in skin temperature and holds his or her upper arm firmly against the chest to close may explain, for example, the intense, brief sensation of be- the axilla, axillary temperature will eventually come rea- ing chilled that occurs during a plunge into cold water. sonably close to core temperature. However, as this may Since skin temperature usually is not uniform over the take 30 minutes or more, axillary temperature is infre- body surface, mean skin temperature ( sk ) is frequently cal- culated from temperatures at several skin sites, usually weighting each temperature according to the fraction of 37.0 body surface area it represents. sk is used to summarize the input to the CNS from temperature-sensitive nerve endings 36.8 in the skin. sk also is commonly used, along with core tem- Core temperature (°C) 36.6 mate the quantity of heat stored in the body, since the di- perature, to calculate a mean body temperature and to esti- rect measurement of shell temperature would be difficult and invasive. 36.4 THE BALANCE BETWEEN HEAT PRODUCTION 36.2 AND HEAT LOSS 36.0 All animals exchange energy with the environment. Some 4:00 AM 8:00 AM Noon 4:00 PM 8:00 PM Midnight energy is exchanged as mechanical work, but most is ex- Time of day changed as heat (Fig. 29.4). Heat is exchanged by conduc- tion, convection, and radiation and as latent heat through Effect of time of day on internal body tem- FIGURE 29.3 evaporation or (rarely) condensation of water. If the sum of perature of healthy resting subjects. (Drawn energy production and energy gain from the environment from data of Mackowiak PA, Wasserman SS, Levine MM. A criti- does not equal energy loss, the extra heat is “stored” in, or cal appraisal of 98.6
F, the upper limit of normal body tempera- lost from, the body. This relationship is summarized in the ture, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992;268:1578–1580; and Stephenson LA, Wenger CB, heat balance equation: O’Donovan BH, et al. Circadian rhythm in sweating and cuta- neous blood flow. Am J Physiol 1984;246:R321–R324.) M  E  R  C  K  W  S (1)

CHAPTER 29 The Regulation of Body Temperature 531 The traditional units for measuring heat are a potential source of confusion, because the word calorie refers to two units differing by a 1,000-fold. The calorie used in chemistry and physics is the quantity of heat that will raise the tem- perature of 1 g of pure water by 1
C; it is also called the small calorie or gram calorie. The Calorie (capital C) used in physiology and nutrition is the quantity of heat that will raise the temperature of 1 kg of pure water by 1
C; it is also called the large calorie, kilogram calorie, or (the usual prac- tice in thermal physiology) the kilocalorie (kcal). Because heat is a form of energy, it is now often measured in joules, the unit of work (1 kcal  4,186 J), and rate of heat pro- duction or heat flow in watts, the unit of power (1 W  1 J/sec). This practice avoids confusing calories and Calories. However, kilocalories are still used widely enough that it is necessary to be familiar with them, and there is a certain ad- vantage to a unit based on water because the body itself is mostly water. Heat Is a By-product of Energy-Requiring Metabolic Processes Metabolic energy is used for active transport via membrane pumps, for energy-requiring chemical reactions, such as the formation of glycogen from glucose and proteins from amino acids, and for muscular work. Most of the metabolic energy used in these processes is converted into heat within the body. This conversion may occur almost immediately, as with energy used for active transport or heat produced as a by-product of muscular activity. Other energy is con- verted to heat only after a delay, as when the energy used Exchange of energy with the environment. FIGURE 29.4 in forming glycogen or protein is released as heat when the This hiker gains heat from the sun by radiation and loses heat by conduction to the ground through the soles of glycogen is converted back into glucose or the protein is his feet, convection into the air, radiation to the ground and sky, converted back into amino acids. and evaporation of water from his skin and respiratory passages. In addition, some of the energy released by his metabolic Metabolic Rate and Sites of Heat Production at Rest. processes is converted into mechanical work, rather than heat, Among subjects of different body size, metabolic rate at since he is walking uphill. rest varies approximately in proportion to body surface area. In a resting and fasting young adult man it is about 45 2 2 W/m (81 W or 70 kcal/hr for 1.8 m body surface area), where M is metabolic rate; E is rate of heat loss by evapora- corresponding to an O 2 consumption of about 240 mL/min. tion; R and C are rates of heat loss by radiation and con- About 70% of energy production at rest occurs in the body vection, respectively; K is the rate of heat loss by conduc- core—trunk viscera and the brain—even though they com- tion; W is rate of energy loss as mechanical work; and S is prise only about 36% of the body mass (Table 29.2). As a rate of heat storage in the body, manifested as changes in by-product of their metabolic processes, these organs pro- tissue temperatures. duce most of the heat needed to maintain heat balance at M is always positive, but the terms on the right side of comfortable environmental temperatures; only in the cold equation 1 represent energy exchange with the environ- must such by-product heat be supplemented by heat pro- ment and storage and may be either positive or negative. duced expressly for thermoregulation. E, R, C, K, and W are positive if they represent energy Factors other than body size that affect metabolism at losses from the body and negative if they represent energy rest include age and sex (Fig. 29.5), and hormones and di- gains. When S  0, the body is in heat balance and body gestion. The ratio of metabolic rate to surface area is high- temperature neither rises nor falls. When the body is not est in infancy and declines with age, most rapidly in child- in heat balance, its mean tissue temperature increases if S hood and adolescence and more slowly thereafter. Children is positive and decreases if S is negative. This situation have high metabolic rates in relation to surface area because commonly lasts only until the body’s responses to the tem- of the energy used to synthesize the fats, proteins, and other perature changes are sufficient to restore balance. How- tissue components needed to sustain growth. Similarly, a ever, if the thermal stress is too great for the thermoregu- woman’s metabolic rate increases during pregnancy to sup- latory system to restore balance, the body will continue to ply the energy needed for the growth of the fetus. However, gain or lose heat until either the stress diminishes suffi- a nonpregnant woman’s metabolic rate is 5 to 10% lower ciently or the animal dies. than that of a man of the same age and surface area, proba-

532 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY Measurement of Metabolic Rate. Because so many fac- Relative Masses and Metabolic Heat tors affect metabolism at rest, metabolic rate is often meas- TABLE 29.2 Production Rates During Rest and Heavy ured under a set of standard conditions to compare it with Exercise established norms. Metabolic rate measured under these % of conditions is called basal metabolic rate (BMR). The com- Heat Production monly accepted conditions for measuring BMR are that the % of person must have fasted for 12 hours; the measurement Body Mass Rest Exercise must be made in the morning after a good night’s sleep, be- ginning after the person has rested quietly for at least 30 Brain 2 16 1 Trunk viscera 34 56 8 minutes; and the air temperature must be comfortable, Muscle and skin 56 18 90 about 25
C (77
F). Basal metabolic rate is “basal” only dur- Other 8 10 1 ing wakefulness, since metabolic rate during sleep is some- what less than BMR. Heat exchange with the environment can be measured directly by using a human calorimeter. In this insulated bly because a higher proportion of the female body is com- chamber, heat can exit only in the air ventilating the cham- posed of fat, a tissue with low metabolism. ber or in water flowing through a heat exchanger in the The catecholamines and thyroxine are the hormones chamber. By measuring the flow of air and water and their that have the greatest effect on metabolic rate. Cate- temperatures as they enter and leave the chamber, one can cholamines cause glycogen to break down into glucose determine the subject’s heat loss by conduction, convec- and stimulate many enzyme systems, increasing cellular tion, and radiation. And by measuring the moisture content metabolism. Hypermetabolism is a clinical feature of of air entering and leaving the chamber, one can determine some cases of pheochromocytoma, a catecholamine-se- heat loss by evaporation. This technique is called direct creting tumor of the adrenal medulla. Thyroxine magni- calorimetry, and though conceptually simple, it is cumber- fies the metabolic response to catecholamines, increases some and costly. protein synthesis, and stimulates oxidation by the mito- Metabolic rate is often estimated by indirect calorime- chondria. The metabolic rate is typically 45% above nor- try, which is based on measuring a person’s rate of O 2 con- mal in hyperthyroidism (but up to 100% above normal in sumption, since virtually all energy available to the body severe cases) and 25% below normal in hypothyroidism depends ultimately on reactions that consume O 2 . Con- (but 45% below normal with complete lack of thyroid suming 1 L of O 2 is associated with releasing 21.1 kJ (5.05 hormone). Other hormones have relatively minor effects kcal) if the fuel is carbohydrate, 19.8 kJ (4.74 kcal) if the on metabolic rate. fuel is fat, and 18.6 kJ (4.46 kcal) if the fuel is protein. An A resting person’s metabolic rate increases 10 to 20% af- average value often used for the metabolism of a mixed ter a meal. This effect of food, called the thermic effect of diet is 20.2 kJ (4.83 kcal) per liter of O 2 . The ratio of CO 2 food (formerly known as specific dynamic action), lasts produced to O 2 consumed in the tissues is called the res- several hours. The effect is greatest after eating protein and piratory quotient (RQ). The RQ is 1.0 for the oxidation of less after carbohydrate and fat; it appears to be associated carbohydrate, 0.71 for the oxidation of fat, and 0.80 for with processing the products of digestion in the liver. the oxidation of protein. In a steady state where CO 2 is ex- haled from the lungs at the same rate it is produced in the tissues, RQ is equal to the respiratory exchange ratio, R (see Chapter 19). One can improve the accuracy of indi- 54 rect calorimetry by also determining R and either estimat- 62 ing the amount of protein oxidized—which usually is 60 52 small compared to fat and carbohydrate—or calculating it 50 58 Basal metabolic rate (W/m 2 ) 52 Males 46 Basal metabolic rate [kcal/(m 2 •hr)] Skeletal Muscle Metabolism and External Work. Even from urinary nitrogen excretion. 48 56 54 44 50 during mild exercise, the muscles are the principal source of 42 48 metabolic heat, and during intense exercise, they may ac- 40 46 count for up to 90%. Moderately intense exercise by a 38 44 42 40 rate of 600 W (in contrast to about 80 W at rest), and in- 34 38 tense activity by a trained athlete, 1,400 W or more. Be- 32 36 Females 36 healthy, but sedentary, young man may require a metabolic 34 30 cause of their high metabolic rate, exercising muscles may 28 be almost 1
C warmer than the core. Blood perfusing these 0 5 1015 20 2530 35 40 45 50 55 60 65 70 75 muscles is warmed and, in turn, warms the rest of the body, Age (yr) raising the core temperature. Muscles convert most of the energy in the fuels they Effects of age and sex on the basal meta- FIGURE 29.5 bolic rate of healthy subjects. Metabolic rate consume into heat rather than mechanical work. During here is expressed as the ratio of energy consumption to body sur- phosphorylation of ADP to form ATP, 58% of the energy face area. released from the fuel is converted into heat, and only

CHAPTER 29 The Regulation of Body Temperature 533 about 42% is captured in the ATP that is formed in the tensity that depends on its temperature, the net heat flow is process. When a muscle contracts, some of the energy in from the warmer to the cooler body. the ATP that was hydrolyzed is converted into heat rather At ordinary tissue and environmental temperatures, vir- than mechanical work. The efficiency at this stage varies tually all thermal radiation is in a region of the infrared enormously; it is zero in isometric muscle contraction, in range where most surfaces, other than polished metals, have which a muscle’s length does not change while it develops emissivities near 1 and emit with a power output near the tension, so that no work is done even though metabolic en- theoretical maximum. However, bodies that are hot enough ergy is required. Finally, some of the mechanical work pro- to glow, such as the sun, emit large amounts of radiation in duced is converted by friction into heat within the body. the visible and near-infrared range, in which light-colored (This is, for example, the fate of all of the mechanical work surfaces have lower emissivities and absorptivities than dark done by the heart in pumping blood.) At best, no more than ones. Therefore, colors of skin and clothing affect heat ex- 25% of the metabolic energy released during exercise is change only in sunlight or bright artificial light. converted into mechanical work outside the body, and the When 1 g of water is converted into vapor at 30
C, it other 75% or more is converted into heat within the body. absorbs 2,425 J (0.58 kcal), the latent heat of evaporation, in the process. Evaporation of water is, thus, an efficient way of losing heat, and it is the body’s only means of los- Convection, Radiation, and Evaporation Are ing heat when the environment is hotter than the skin, as the Main Avenues of Heat Exchange With it usually is when the environment is warmer than 36
C. the Environment Evaporation must then dissipate both the heat produced by metabolic processes and any heat gained from the en- Convection is the transfer of heat resulting from the move- ment of a fluid, either liquid or gas. In thermal physiology, vironment by convection and radiation. Most water evap- the fluid is usually air or water in the environment or blood, orated in the heat comes from sweat, but even in cold tem- in the case of heat transfer inside the body. To illustrate, peratures, the skin loses some water by the evaporation of consider an object immersed in a fluid that is cooler than insensible perspiration, water that diffuses through the the object. Heat passes from the object to the immediately skin rather than being secreted. In equation 1, E is nearly adjacent fluid by conduction. If the fluid is stationary, con- always positive, representing heat loss from the body. duction is the only means by which heat can pass through However, E is negative in the rare circumstances in which the fluid, and over time, the rate of heat flow from the body water vapor gives up heat to the body by condensing on to the fluid will diminish as the fluid nearest the object ap- the skin (as in a steam room). proaches the temperature of the object. In practice, how- ever, fluids are rarely stationary. If the fluid is moving, heat Heat Exchange Is Proportional to Surface Area will still be carried from the object into the fluid by con- and Obeys Biophysical Principles duction, but once the heat has entered the fluid, it will be carried by the movement of the fluid—by convection. The Animals exchange heat with their environment through same fluid movement that carries heat away from the sur- both the skin and the respiratory passages, but only the skin face of the object constantly brings fresh cool fluid to the exchanges heat by radiation. In panting animals, respira- surface, so the object gives up heat to the fluid much more tory heat loss may be large and may be an important means rapidly than if the fluid were stationary. Although conduc- of achieving heat balance. In humans, however, respiratory tion plays a role in this process, convection so dominates heat exchange is usually relatively small and (though hy- the overall heat transfer that we refer to the heat transfer as perthermic subjects may hyperventilate) is not predomi- if it were entirely convection. Therefore, the conduction nantly under thermoregulatory control. Therefore, we do term (K) in the heat balance equation is restricted to heat not consider it further here. flow between the body and other solid objects, and it usu- Convective heat exchange between the skin and the en- ally represents only a small part of the total heat exchange vironment is proportional to the difference between skin with the environment. and ambient air temperatures, as expressed by this equation: Every surface emits energy as electromagnetic radiation, C  h c
A
( sk  T a )(2) with a power output proportional to the area of the surface, the fourth power of its absolute temperature (i.e., measured where A is the body surface area, sk and T a are mean skin from absolute zero), and the emissivity (e) of the surface, a and ambient temperatures, and h c is the convective heat number between 0 and 1 that depends on the nature of the transfer coefficient. surface and the wavelength of the radiation. (In this discus- The value of h c includes the effects of the factors other sion, the term surface is broadly defined, so that a flame and than temperature and surface area that influence convective the sky, for example, are surfaces.) Such radiation, called heat exchange. For the whole body, air movement is the thermal radiation, has a characteristic distribution of power most important of these factors, and convective heat ex- as a function of wavelength, which depends on the temper- change (and, thus, h c ) varies approximately as the square ature of the surface. The emissivity of any surface is equal root of the air speed, except when air movement is slight to the absorptivity—the fraction of incident radiant energy (Fig. 29.6). Other factors that affect h c include the direc- the surface absorbs. (For this reason, an ideal emitter, with tion of air movement and the curvature of the skin surface. an emissivity of 1, is called a black body.) If two bodies ex- As the radius of curvature decreases, h c increases, so the change heat by thermal radiation, radiation travels in both hands and fingers are effective in convective heat exchange directions, but since each body emits radiation with an in- disproportionately to their surface area.

534 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY 35 Water vapor, like heat, is carried away by moving air, so geometric factors and air movement affect E and h e in the same way they affect C and h c . If the skin is completely wet, 70 30 60 the water vapor pressure at the skin surface is the saturation water vapor pressure at the temperature of the skin Convective heat transfer coefficient h c [W/(m 2 •°C)] 20 50 h e [W/(m 2 •torr)] Evaporative heat transfer coefficient mental conditions. This condition is described as: (5) (Fig. 29.7), and evaporative heat loss is E max , the maximum 25 possible for the prevailing skin temperature and environ- E max  h e
A
(P sk,sat  P a ) 40 where P sk,sat is the saturation water vapor pressure at skin temperature. When the skin is not completely wet, it is im- 15 practical to measure P sk , the actual average water vapor 30 pressure at the skin surface. Therefore, a coefficient called 10 skin wettedness (w) is defined as the ratio E/E max , with 0  w 20  1. Skin wettedness depends on the hydration of the epi- dermis and the fraction of the skin surface that is wet. We 5 10 can now rewrite equation 4 as: E  h e
A
w
(P sk,sat  P a )(6) 0 0 012345 Wettedness depends on the balance between secretion Air speed (m/sec) and evaporation of sweat. If secretion exceeds evaporation, sweat accumulates on the skin and spreads out to wet more Dependence of convection and evaporation FIGURE 29.6 of the space between neighboring sweat glands, increasing on air movement. This figure shows the con- wettedness and E; if evaporation exceeds secretion, the re- vective heat transfer coefficient, h c (left), and the evaporative heat verse occurs. If sweat rate exceeds E max , once wettedness transfer coefficient, h e (right) for a standing human as a function of air speed. The convective and evaporative heat transfer coeffi- becomes 1, the excess sweat drips from the body, since it cients are related by the equation h e  h c
2.2
C/torr. The hori- cannot evaporate. zontal axis can be converted into English units by using the rela- Note that P a , on which evaporation from the skin di- tion 5 m/sec  16.4 ft/sec  11.2 miles/hr. rectly depends, is proportional to the actual moisture con- tent in the air. By contrast, the more familiar quantity rela- tive humidity (rh) is the ratio between the actual moisture Radiative heat exchange is proportional to the differ- content in the air and the maximum moisture content pos- ence between the fourth powers of the absolute tempera- sible at the temperature of the air. It is important to recog- tures of the skin and of the radiant environment (T r) and to 4 4 the emissivity of the skin (e sk): R ∝ e sk
( sk  T r ). How- ever, if T r is close enough to sk that sk  T r is much smaller than the absolute temperature of the skin, R is nearly pro- 100 portional to e sk
( sk  T r). Some parts of the body surface 90 (e.g., the inner surfaces of the thighs and arms) exchange heat by radiation with other parts of the body surface, so 80 the body exchanges heat with the environment as if it had an area smaller than its actual surface area. This smaller 70 area, called the effective radiating surface area (A r), de- 60 pends on the body’s posture, and it is closest to the actual surface area in a spread-eagle position and least in a curled- Saturation vapor pressure (torr) 50 up position. Radiative heat exchange can be represented by the equation 40  30 R  h r
e sk
A r
(T sk  T r )(3) where h r is the radiant heat transfer coefficient, 6.43 W/ 20 2 (m 
C) at 28
C. 10 Evaporative heat loss from the skin to the environment is proportional to the difference between the water vapor 0 pressure at the skin surface and the water vapor pressure in 01020304050 the ambient air. These relations are summarized as: Temperature (°C) E  h e
A
(P sk  P a )(4) Saturation vapor pressure of water as a func- FIGURE 29.7 tion of temperature. For any given tempera- where P sk is the water vapor pressure at the skin surface, P a ture, the water vapor pressure is at its saturation value when the air is the ambient water vapor pressure, and h e is the evapora- is “saturated” with water vapor (i.e., holds the maximum amount tive heat transfer coefficient. possible at that temperature). At 37
C, PH 2 O equals 47 torr.

CHAPTER 29 The Regulation of Body Temperature 535 nize that rh is only indirectly related to evaporation from the skin. For example, in a cold environment, P a will be low 38 Rectal 38 enough that sweat can easily evaporate from the skin even 36 36 if rh equals 100%, since the skin is warm and P sk,sat , which Temperature ( C) 34 Skin 34 depends on the temperature of the skin, will be much Men greater than P a . 32 Women 32 30 30 Heat Storage Is a Change in the 70 60 Heat Content of the Body Total men 55 60 50 The rate of heat storage is the difference between heat pro- Total women 45 duction and net heat loss (equation 1). (In the unusual cir- 50 cumstances in which there is a net heat gain from the envi- 40 ronment, such as during immersion in a hot bath, storage is Heat loss (W/m 2 ) 40 35 the sum of heat production and net heat gain.) It can be de- Dry (R+C), 30 termined experimentally from simultaneous measurements 30 men 25 Heat loss [kcal/(m 2 of metabolism by indirect calorimetry and heat gain or loss 20 Dry (R+C), 20 by direct calorimetry. Storage of heat in the tissues changes women 15 their temperature, and the amount of heat stored is the 10 10 product of body mass, the body’s mean specific heat, and a 5 hr)] suitable mean body temperature (T b ). The body’s mean C) 0 E, men E, women 0 specific heat depends on its composition, especially the proportion of fat, and is about 3.55 kJ/(kg
C) [0.85 50 40 kcal/(kg
C)]. Empirical relations of T b to core temperature 40 35 (T c ) and T sk , determined in calorimetric studies, depend on Conductance, men 30 ambient temperature, with T b varying from 0.65
T c  Conductance (W/m 2 30 Conductance, women 25 Conductance [kcal/(m 2 0.35
sk in the cold to 0.9
T c  0.1
T sk in the heat. 20 The shift from cold to heat in the relative weighting of T c 20 15 and T sk reflects the accompanying change in the thickness 10 10 of the shell (see Fig. 29.2). 5 hr 0 0 23 24 25 26 27 28 29 30 31 32 33 34 35 36 C)] Calorimeter temperature ( C) HEAT DISSIPATION Heat dissipation. These graphs show the av- Figure 29.8 shows rectal and mean skin temperatures, heat FIGURE 29.8 erage values of rectal and mean skin tempera- losses, and calculated core-to-skin (shell) conductances for tures, heat loss, and core-to-skin thermal conductance for nude nude resting men and women at the end of 2-hour exposures resting men and women near steady state after 2 hours at different in a calorimeter to ambient temperatures of 23 to 36
C. Shell environmental temperatures in a calorimeter. (All energy ex- conductance represents the sum of heat transfer by two par- change quantities in this figure have been divided by body surface allel modes: conduction through the tissues of the shell, and area to remove the effect of individual body size.) Total heat loss convection by the blood. It is calculated by dividing heat is the sum of dry heat loss, by radiation (R) and convection (C), flow through the skin (HF sk ) (i.e., total heat loss from the and evaporative heat loss (E). Dry heat loss is proportional to the difference between skin temperature and calorimeter temperature body less heat loss through the respiratory tract) by the dif- and decreases with increasing calorimeter temperature. (Based on ference between core and mean skin temperatures: data from Hardy JD, DuBois EF. Differences between men and  women in their response to heat and cold. Proc Natl Acad Sci U C  HF sk /(T c  T sk )(7)  S A 1940;26:389–398.) where C is shell conductance and T c and T sk are core and mean skin temperatures. From 23 to 28
C, conductance is minimal because the and, thus, R and C. As equations 2 to 4 show, C, R, and E all skin is vasoconstricted and its blood flow is low. The mini- depend on skin temperature, which, in turn, depends partly mal level of conductance attainable depends largely on the on skin blood flow. E depends also, through skin wetted- thickness of the subcutaneous fat layer, and the women’s ness, on sweat secretion. Therefore, all these modes of heat thicker layer allows them to attain a lower conductance exchange are partly under physiological control. than men. At about 28
C, conductance begins to increase, and above 30
C, conductance continues to increase and The Evaporation of Sweat Can sweating begins. Dissipate Large Amounts of Heat For these subjects, 28 to 30
C is the zone of ther- moneutrality, the range of comfortable environmental In Figure 29.8, evaporative heat loss is nearly independent 2 temperatures in which thermal balance is maintained with- of ambient temperature below 30
C and is 9 to 10 W/m , 2 out either shivering or sweating. In this zone, heat balance corresponding to evaporation of about 13 to 15 g/(m h), is maintained entirely by controlling conductance and T sk of which about half is moisture lost in breathing and half is

536 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY insensible perspiration. This evaporation occurs independ- temperature until it reaches the skin, reaches skin tempera- ent of thermoregulatory control. As the ambient tempera- ture as it passes through the skin, and then stays at skin ture increases, the body depends more and more on the temperature until it returns to the core, we can compute the evaporation of sweat to achieve heat balance. rate of heat flow (HF b ) as a result of convection by the The two histological types of sweat glands are eccrine blood as and apocrine. In northern Europeans, apocrine glands are found mostly in the axilla and pigmented skin, such as the HF b  SkBF
(T c  T sk )
3.85 kJ/(L
C) (8) lips, but they are more widely distributed in some other where SkBF is the rate of skin blood flow, expressed in L/sec populations. Eccrine sweat is essentially a dilute electrolyte rather than the usual L/min to simplify computing HF in W solution, but apocrine sweat also contains fatty material. (i.e., J/sec); and 3.85 kJ/(L
C) [0.92 kcal/(L
C)] is the vol- Eccrine sweat glands, the dominant type in all human pop- ume-specific heat of blood. Conductance as a result of con- ulations, are more important in human thermoregulation vection by the blood (C b ) is calculated as: and number about 2,500,000. They are controlled through postganglionic sympathetic nerves that release acetyl- C b  HF b /(T c  T sk )  SkBF
3.85 kJ/(L
C) (9) choline (ACh) rather than norepinephrine. A healthy man Of course, heat continues to flow by conduction unacclimatized to heat can secrete up to 1.5 L/hr of sweat. through the tissues of the shell, so total conductance is the Although the number of functional sweat glands is fixed be- sum of conductance as a result of convection by the blood, fore the age of 3, the secretory capacity of the individual plus that result from conduction through the tissues. Total glands can change, especially with endurance exercise heat flow is given by training and heat acclimatization; men well acclimatized to heat can attain peak sweat rates greater than 2.5 L/hr. Such HF  (C b  C 0 )
(T c  T sk ) (10) rates cannot be maintained, however; the maximum daily in which C 0 is thermal conductance of the tissues when skin sweat output is probably about 15 L. blood flow is minimal and, thus, is predominantly due to The sodium concentration of eccrine sweat ranges from conduction through the tissues. less than 5 to 60 mmol/L (versus 135 to 145 mmol/L in The assumptions made in deriving equation 8 are some- plasma). In producing sweat that is hypotonic to plasma, what artificial and represent the conditions for maximum the glands reabsorb sodium from the sweat duct by active efficiency of heat transfer by the blood. In practice, blood transport. As sweat rate increases, the rate at which the exchanges heat also with the tissues through which it glands reabsorb sodium increases more slowly, so that passes on its way to and from the skin. Heat exchange with sodium concentration in the sweat increases. The sodium these other tissues is greatest when skin blood flow is low; concentration of sweat is affected also by heat acclimatiza- in such cases, heat flow to the skin may be much less than tion and by the action of mineralocorticoids. predicted by equation 8, as discussed further below. How- ever, equation 8 is a reasonable approximation in a warm subject with moderate to high skin blood flow. Although Skin Circulation Is Important in Heat Transfer measuring whole-body SkBF directly is not possible, it is believed to reach several liters per minute during heavy ex- Heat produced in the body must be delivered to the skin surface to be eliminated. When skin blood flow is minimal, ercise in the heat. The maximum obtainable is estimated to 2 shell conductance is typically 5 to 9 W/
C per m of body be nearly 8 L/min. If SkBF  1.89 L/min (0.0315 L/sec), ac- surface. For a lean resting subject with a surface area of 1.8 cording to equation 9, skin blood flow contributes about 121 W/
C to the conductance of the shell. If conduction 2 m , minimal whole body conductance of 16 W/
C [i.e., 8.9 through the tissues contributes 16 W/
C, total shell con- 2 2 W/(
C  m )
1.8 m ] and a metabolic heat production of ductance is 137 W/
C, and if T c  38.5
C and T sk  35
C, 80 W, the temperature difference between the core and the this will produce a core-to-skin heat transfer of 480 W, the skin must be 5
C (i.e., 80 W  16 W/
C) for the heat pro- heat production in our earlier example of moderate exer- duced to be conducted to the surface. In a cool environ- cise. Therefore, even a moderate rate of skin blood flow can ment, T sk may easily be low enough for this to occur. How- have a dramatic effect on heat transfer. ever, in an ambient temperature of 33
C, T sk is typically When a person is not sweating, raising skin blood flow about 35
C, and without an increase in conductance, core brings skin temperature nearer to blood temperature and temperature would have to rise to 40
C—a high, although lowering skin blood flow brings skin temperature nearer to not yet dangerous, level—for the heat to be conducted to ambient temperature. Under such conditions, the body can the skin. If the rate of heat production were increased to control dry (convective and radiative) heat loss by varying 480 W by moderate exercise, the temperature difference skin blood flow and, thus, skin temperature. Once sweating between core and skin would have to rise to 30
C—and begins, skin blood flow continues to increase as the person core temperature to well beyond lethal levels—to allow all becomes warmer. In these conditions, however, the ten- the heat produced to be conducted to the skin. In the latter dency of an increase in skin blood flow to warm the skin is circumstances, the conductance of the shell must increase approximately balanced by the tendency of an increase in greatly for the body to reestablish thermal balance and sweating to cool the skin. Therefore, after sweating has be- continue to regulate its temperature. This is accomplished gun, further increases in skin blood flow usually cause little by increasing the skin blood flow. change in skin temperature or dry heat exchange and serve primarily to deliver to the skin the heat that is being removed Effectiveness of Skin Blood Flow in Heat Transfer. As- by the evaporation of sweat. Skin blood flow and sweating suming that blood on its way to the skin remains at core work in tandem to dissipate heat under such conditions.

CHAPTER 29 The Regulation of Body Temperature 537 Sympathetic Control of Skin Circulation. Blood flow in through the use of shelter, space heating, air conditioning, human skin is under dual vasomotor control. In most of the and clothing—enables humans to live in the most extreme skin, the vasodilation that occurs during heat exposure de- climates in the world, but it does not provide fine control pends on sympathetic nerve signals that cause the blood of body heat balance. In contrast, physiological ther- vessels to dilate, and this vasodilation can be prevented or moregulation is capable of fairly precise adjustments of reversed by regional nerve block. Because it depends on the heat balance but is effective only within a relatively narrow action of nerve signals, such vasodilation is sometimes re- range of environmental temperatures. ferred to as active vasodilation. Active vasodilation occurs in almost all the skin, except in so-called acral regions— hands, feet, lips, ears, and nose. In skin areas where active Behavioral Thermoregulation Is Governed vasodilation occurs, vasoconstrictor activity is minimal at by Thermal Sensation and Comfort thermoneutral temperatures, and active vasodilation during Sensory information about body temperatures is an essen- heat exposure does not begin until close to the onset of tial part of both behavioral and physiological thermoregu- sweating. Therefore, skin blood flow in these areas is not lation. The distinguishing feature of behavioral thermoreg- much affected by small temperature changes within the ulation is the involvement of consciously directed efforts to thermoneutral range. regulate body temperature. Thermal discomfort provides The neurotransmitter or other vasoactive substance re- the necessary motivation for thermoregulatory behavior, sponsible for active vasodilation in human skin has not and behavioral thermoregulation acts to reduce both the been identified. Active vasodilation operates in tandem discomfort and the physiological strain imposed by a with sweating in the heat, and is impaired or absent in an- stressful thermal environment. For this reason, the zone of hidrotic ectodermal dysplasia, a congenital disorder in thermoneutrality is characterized by both thermal comfort which sweat glands are sparse or absent. For these reasons, and the absence of shivering and sweating. the existence of a mechanism linking active vasodilation to Warmth and cold on the skin are felt as either comfort- the sweat glands has long been suspected, but never estab- able or uncomfortable, depending on whether they de- lished. Earlier suggestions that active vasodilation is crease or increase the physiological strain—a shower tem- cholinergic or is caused by the release of bradykinin from perature that feels pleasant after strenuous exercise may be activated sweat glands have not gained general acceptance. uncomfortably chilly on a cold winter morning. The pro- More recently, however, nerve endings containing both cessing of thermal information in behavioral thermoregula- ACh and vasoactive peptides have been found near eccrine tion is not as well understood as it is in physiological ther- sweat glands in human skin, suggesting that active vasodi- moregulation. However, perceptions of thermal sensation lation may be mediated by a vasoactive cotransmitter that and comfort respond much more quickly than core tem- is released along with ACh from the endings of nerves that perature or physiological thermoregulatory responses to innervate sweat glands. changes in environmental temperature and, thus, appear to Reflex vasoconstriction, occurring in response to cold anticipate changes in the body’s thermal state. Such an an- and as part of certain nonthermal reflexes such as barore- ticipatory feature would be advantageous, since it would re- flexes, is mediated primarily through adrenergic sympa- duce the need for frequent small behavioral adjustments. thetic fibers distributed widely over most of the skin. Re- ducing the flow of impulses in these nerves allows the blood vessels to dilate. In the acral regions and superficial Physiological Thermoregulation Operates veins (whose role in heat transfer is discussed below), vaso- Through Graded Control of Heat-Production constrictor fibers are the predominant vasomotor innerva- and Heat-Loss Responses tion, and the vasodilation that occurs during heat exposure Familiar inanimate control systems, such as most refrigera- is largely a result of the withdrawal of vasoconstrictor ac- tors and heating and air-conditioning systems, operate at tivity. Blood flow in these skin regions is sensitive to small only two levels: on and off. In a steam heating system, for temperature changes even in the thermoneutral range, and example, when the indoor temperature falls below the de- may be responsible for “fine-tuning” heat loss to maintain sired level, the thermostat turns on the burner under the heat balance in this range. boiler; when the temperature is restored to the desired level, the thermostat turns the burner off. Rather than operating at only two levels, most physiological control systems produce THERMOREGULATORY CONTROL a graded response according to the size of the disturbance In discussions of control systems, the words “regulation” in the regulated variable. In many instances, changes in the and “regulate” have meanings distinct from those of the controlled variables are proportional to displacements of the word “control” (see Chapter 1). The variable that a control regulated variable from some threshold value; such control system acts to maintain within narrow limits (e.g., temper- systems are called proportional control systems. ature) is called the regulated variable, and the quantities it The control of heat-dissipating responses is an example controls to accomplish this (e.g., sweating rate, skin blood of a proportional control system. Figure 29.9 shows how re- flow, metabolic rate, and thermoregulatory behavior) are flex control of two heat-dissipating responses, sweating and called controlled variables. skin blood flow, depends on body core temperature and Humans have two distinct subsystems for regulating mean skin temperature. Each response has a core tempera- body temperature: behavioral thermoregulation and physi- ture threshold—a temperature at which the response starts ological thermoregulation. Behavioral thermoregulation— to increase—and this threshold depends on mean skin tem-

538 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY 1.5 20 Back sweat rate [mg/(cm 2 •min)] 0.5 1 – – Forearm blood flow [mL/(100mL•min)] 10 5 – – 15 T sk  35.5°C T sk  30.3°C T sk  33.9°C T sk  27.9°C 0 0 36 37 38 39 36 37 38 39 Core temperature (°C) Core temperature (°C) Control of heat-dissipating responses. These MN, Gonzalez RR, Drolet LL, et al. Heat exchange during upper- FIGURE 29.9 graphs show the relations of back (scapular) and lower-body exercise. J Appl Physiol 1984;57:1050–1054. Right: sweat rate (left) and forearm blood flow (right) to core temperature Modified from Wenger CB, Roberts MF, Stolwijk JAJ, et al. Forearm and mean skin temperatures ( sk ). In these experiments, core temper- blood flow during body temperature transients produced by leg exer- ature was increased by exercise. (Left: Based on data from Sawka cise. J Appl Physiol 1975;38:58–63.) perature. At any given skin temperature, the change in each shivering—the centralization of shivering—to help re- response is proportional to the change in core temperature, tain the heat produced during shivering within the body and increasing the skin temperature lowers the threshold core; and the familiar experience of teeth chattering is one level of core temperature and increases the response at any of the earliest signs of shivering. As with heat-dissipating given core temperature. In humans, a change of 1
C in core responses, the control of shivering depends on both core temperature elicits about 9 times as great a thermoregula- and skin temperatures, but the details of its control are not tory response as a 1
C change in mean skin temperature. precisely understood. (Besides its effect on the reflex signals, skin temperature has a local effect that modifies the response of the blood ves- The Central Nervous System Integrates Thermal sels and sweat glands to the reflex signal, discussed later.) Information From the Core and the Skin Cold stress elicits increases in metabolic heat production through shivering and nonshivering thermogenesis. Shiver- Temperature receptors in the body core and skin transmit ing is a rhythmic oscillating tremor of skeletal muscles. The information about their temperatures through afferent primary motor center for shivering lies in the dorsomedial nerves to the brainstem and, especially, the hypothalamus, part of the posterior hypothalamus and is normally inhibited where much of the integration of temperature information by signals of warmth from the preoptic area of the hypo- occurs. The sensitivity of the thermoregulatory system to thalamus. In the cold, these inhibitory signals are with- core temperature enables it to adjust heat production and drawn, and the primary motor center for shivering sends im- heat loss to resist disturbances in core temperature. Sensi- pulses down the brainstem and lateral columns of the spinal tivity to mean skin temperature lets the system respond ap- cord to anterior motor neurons. Although these impulses are propriately to mild heat or cold exposure with little change not rhythmic, they increase muscle tone, thereby increasing in body core temperature, so that changes in body heat as metabolic rate somewhat. Once the tone exceeds a critical a result of changes in environmental temperature take place level, the contraction of one group of muscle fibers stretches almost entirely in the peripheral tissues (see Fig. 29.2). For the muscle spindles in other fiber groups in series with it, example, the skin temperature of someone who enters a hot eliciting contractions from those groups of fibers via the environment may rise and elicit sweating even if there is no stretch reflex, and so on; thus, the rhythmic oscillations that change in core temperature. On the other hand, an increase characterize frank shivering begin. in heat production within the body, as during exercise, elic- Shivering occurs in bursts, and the “shivering pathway” its the appropriate heat-dissipating responses through a rise is inhibited by signals from the cerebral cortex, so that in core temperature. voluntary muscular activity and attention can suppress Core temperature receptors involved in controlling shivering. Since the limbs are part of the shell in the cold, thermoregulatory responses are unevenly distributed and trunk and neck muscles are preferentially recruited for are concentrated in the hypothalamus. In experimental

CHAPTER 29 The Regulation of Body Temperature 539 mammals, temperature changes of only a few tenths of 1
C Although the disturbance in this example is exercise, the in the anterior preoptic area of the hypothalamus elicit same principle applies if the disturbance is a decrease in changes in the thermoregulatory effector responses, and metabolic rate or a change in the environment. However, if this area contains many neurons that increase their firing the disturbance is in the environment, most of the temper- rate in response to either warming or cooling. Thermal re- ature change will be in the skin and shell rather than in the ceptors have been reported elsewhere in the core of labo- core; if the disturbance produces a net loss of heat, the ratory animals, including the heart, pulmonary vessels, and body will restore heat balance by decreasing heat loss and spinal cord, but the thermoregulatory role of core thermal increasing heat production. receptors outside the CNS is unknown. Consider what happens when some disturbance—say, Relation of Controlling Signal to Thermal Integration and an increase in metabolic heat production resulting from ex- Set Point. Both sweating and skin blood flow depend on ercise—upsets the thermal balance. Additional heat is core and skin temperatures in the same way, and changes in stored in the body, and core temperature rises. The central the threshold for sweating are accompanied by similar thermoregulatory controller receives information about changes in the threshold for vasodilation. We may, there- these changes from the thermal receptors and elicits appro- fore, think of the central thermoregulatory controller as priate heat-dissipating responses. Core temperature contin- generating one thermal command signal for the control of ues to rise, and these responses continue to increase until both sweating and skin blood flow (Fig. 29.10). This signal they are sufficient to dissipate heat as fast as it is being pro- is based on the information about core and skin tempera- duced, restoring heat balance and preventing further in- tures that the controller receives and on the thermoregula- creases in body temperatures. In the language of control tory set point—the target level of core temperature, or the theory, the rise in core temperature that elicits heat-dissi- setting of the body’s “thermostat.” In the operation of the pating responses sufficient to reestablish thermal balance thermoregulatory system, it is a reference point that deter- during exercise is an example of a load error. A load error mines the thresholds of all of the thermoregulatory re- is characteristic of any proportional control system that is sponses. Shivering and thermal comfort are affected by resisting the effect of some imposed disturbance or “load.” changes in the set point in the same way as sweating and Thermal comfort and effector signal Hypothalamic Other deep for behavior Cerebral cortex temperature temperatures – T sk T c Effector signal for sweating and vasodilation Sweat glands Thermal Intergration – error of thermal signal signals Skin arterioles Effector Pyrogens signal for vasoconstriction – Exercise training T set and heat acclimatization Superficial veins Biological rhythms Effector signal for heat production Skeletal muscle Control of human thermoregulatory re- the set point (T set ) to generate an error signal, which is integrated FIGURE 29.10 sponses. The plus and minus signs next to the with thermal input from the skin to produce effector signals for inputs to T set indicate that pyrogens raise the set point and heat the thermoregulatory responses. acclimatization lowers it. Core temperature (T c ) is compared with

540 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY skin blood flow. However, our understanding of the con- tion increases skin blood flow, as discussed later.) Second, in trol of shivering is insufficient to say whether it is con- skin regions where active vasodilation occurs, local heating trolled by the same command signal as sweating and skin causes vasodilation (and local cooling causes vasoconstric- blood flow. (Thermal comfort, as we saw earlier, seems not tion) through a direct action on the vessels, independent of to be controlled by the same command signal.) nerve signals. The local vasodilator effect of skin temperature is especially strong above 35
C; and, when the skin is warmer Effect of Nonthermal Inputs on Thermoregulatory than the blood, increased blood flow helps cool the skin and Responses. Each thermoregulatory response may be af- protect it from heat injury, unless this response is impaired by fected by inputs other than body temperatures and factors vascular disease. Local thermal effects on sweat glands paral- that influence the set point. We have already noted that lel those on blood vessels, so local heating potentiates (and voluntary activity affects shivering and certain hormones local cooling diminishes) the local sweat gland response to re- affect metabolic heat production. In addition, nonthermal flex stimulation or ACh, and intense local heating elicits factors may produce a burst of sweating at the beginning sweating directly, even in skin whose sympathetic innerva- of exercise, and emotional effects on sweating and skin tion has been interrupted surgically. blood flow are matters of common experience. Skin blood flow is the thermoregulatory response most influenced by Skin Wettedness and the Sweat Gland Response. Dur- nonthermal factors because of its potential involvement in ing prolonged heat exposure (lasting several hours) with reflexes that function to maintain cardiac output, blood high sweat output, sweating rates gradually decline and the pressure, and tissue O 2 delivery under a variety of distur- response of sweat glands to local cholinergic drugs is re- bances, including heat stress, postural changes, hemor- duced. This reduction of sweat gland responsiveness is rhage, and exercise. sometimes called sweat gland “fatigue.” Wetting the skin makes the stratum corneum swell, mechanically obstruct- ing the sweat gland ducts and causing a reduction in sweat Several Factors May Change the secretion, an effect called hidromeiosis. The glands’ re- Thermoregulatory Set Point sponsiveness can be at least partly restored if air movement Fever elevates core temperature at rest, heat acclimatization increases or humidity is reduced, allowing some of the decreases it, and time of day and (in women) the phase of the sweat on the skin to evaporate. Sweat gland fatigue may in- menstrual cycle change it in a cyclic fashion. Core tempera- volve processes besides hidromeiosis, since prolonged ture at rest varies in an approximately sinusoidal fashion with sweating also causes histological changes, including the time of day. The minimum temperature occurs at night, sev- depletion of glycogen, in the sweat glands. eral hours before awaking, and the maximum, which is 0.5 to 1
C higher, occurs in the late afternoon or evening (see Fig. 29.3). This pattern coincides with patterns of activity THERMOREGULATORY RESPONSES and eating but does not depend on them, and it occurs even DURING EXERCISE during bed rest in fasting subjects. This pattern is an example of a circadian rhythm, a rhythmic pattern in a physiological Intense exercise may increase heat production within the function with a period of about 1 day. During the menstrual body 10-fold or more, requiring large increases in skin cycle, core temperature is at its lowest point just before ovu- blood flow and sweating to reestablish the body’s heat bal- lation; during the next few days, it rises 0.5 to 1
C to a ance. Although hot environments also elicit heat-dissipat- plateau that persists through most of the luteal phase. Each ing responses, exercise ordinarily is responsible for the of these factors—fever, heat acclimatization, the circadian greatest demands on the thermoregulatory system for heat rhythm, and the menstrual cycle—change the core temper- dissipation. Exercise provides an important example of how ature at rest by changing the thermoregulatory set point, the thermoregulatory system responds to a disturbance in producing corresponding changes in the thresholds for all of heat balance. In addition, exercise and thermoregulation the thermoregulatory responses. impose competing demands on the circulatory system be- cause exercise requires large increases in blood flow to ex- ercising muscle, while the thermoregulatory responses to Peripheral Factors Modify the Responses of Skin exercise require increases in skin blood flow. Muscle blood Blood Vessels and Sweat Glands flow during exercise is several times as great as skin blood flow, but the increase in skin blood flow is responsible for The skin is the organ most directly affected by environ- mental temperature. Skin temperature influences heat loss disproportionately large demands on the cardiovascular responses not only through reflex actions (see Fig. 29.9), system, as discussed below. Finally, if the water and elec- but also through direct effects on the skin blood vessels and trolytes lost through sweating are not replaced, the result- sweat glands. ing reduction in plasma volume will eventually create a fur- ther challenge to cardiovascular homeostasis. Skin Temperature and Cutaneous Vascular and Sweat Gland Responses. Local temperature changes act on skin Core Temperature Rises During Exercise, blood vessels in at least two ways. First, local cooling poten- Triggering Heat-Loss Responses tiates (and heating weakens) the constriction of blood vessels in response to nerve signals and vasoconstrictor substances. As previously mentioned, the increased heat production dur- (At very low temperatures, however, cold-induced vasodila- ing exercise causes an increase in core temperature, which in

CHAPTER 29 The Regulation of Body Temperature 541 turn elicits heat-loss responses. Core temperature continues crease substantially (through shivering), when core tem- to rise until heat loss has increased enough to match heat pro- perature is rising early during fever, it need not stay high to duction, and core temperature and the heat-loss responses maintain the fever; in fact, it returns nearly to prefebrile lev- reach new steady-state levels. Since the heat-loss responses els once the fever is established. During exercise, however, are proportional to the increase in core temperature, the in- an increase in heat production not only causes the elevation crease in core temperature at steady state is proportional to in core temperature but is necessary to sustain it. Also, the rate of heat production and, thus, to the metabolic rate. while core temperature is rising during fever, the rate of A change in ambient temperature causes changes in the heat loss is, if anything, lower than it was before the fever levels of sweating and skin blood flow necessary to maintain began. During exercise, however, the heat-dissipating re- any given level of heat dissipation. However, the change in sponses and the rate of heat loss start to increase early and ambient temperature also elicits, via direct and reflex effects continue increasing as core temperature rises. of the accompanying skin temperature changes, altered re- sponses in the right direction. For any given rate of heat pro- duction, there is a certain range of environmental conditions Exercise in the Heat Can Threaten within which an ambient temperature change elicits the nec- Cardiovascular Homeostasis essary changes in heat-dissipating responses almost entirely through the effects of skin temperature changes, with virtu- The rise in core temperature during exercise increases the ally no effect on core temperature. (The limits of this range temperature difference between the core and the skin of environmental conditions depend on the rate of heat pro- somewhat, but not nearly enough to match the increase in duction and such individual factors as skin surface area and metabolic heat production. Therefore, as we saw earlier, state of heat acclimatization.) Within this range, the core skin blood flow must increase to carry all of the heat that is temperature reached during exercise is nearly independent of produced to the skin. In a warm environment, where the ambient temperature; for this reason, it was once believed temperature difference between core and skin is relatively that the increase in core temperature during exercise is small, the necessary increase in skin blood flow may be sev- caused by an increase in the thermoregulatory set point, as eral liters per minute. during fever. As noted, however, the increase in core tem- perature with exercise is an example of a load error rather Impaired Cardiac Filling During Exercise in the Heat. than an increase in set point. The work of providing the skin blood flow required for This difference between fever and exercise is shown in thermoregulation in the heat may impose a heavy burden Figure 29.11. Note that, although heat production may in- on a diseased heart, but in healthy people, the major car- A Fever B Exercise Heat production In warm environment Heat loss Heat production Heat loss In cool Heat production environment Heat loss Sustained Corrected es es error error T c T set signal signal T c T set Rate of Rate of heat storage heat storage Time Time Thermal events during fever and exercise. start of exercise, T c  T set , so that es  0. At steady state, T set has FIGURE 29.11 A, The development of fever. B, The increase not changed but T c has increased and is greater than T set , produc- in core temperature (T c ) during exercise. The error signal is the ing a sustained error signal, which is equal to the load error. (The difference between core temperature (T c) and the set point (T set). error signal, or load error, is here represented with an arrow point- At the start of a fever, T set has risen, so that T set is higher than T c ing downward for T c  T set and with an arrow pointing upward and es is negative. At steady state, T c has risen to equal the new for T c  T set.) (Modified from Stitt JT. Fever versus hyperthermia. level of T set and es is corrected (i.e., it returns to zero.) At the Fed Proc 1979;38:39–43.)

542 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY diovascular burden of heat stress results from impaired ve- nous return. As skin blood flow increases, the dilated vas- cular bed of the skin becomes engorged with large volumes of blood, reducing central blood volume and cardiac filling (Fig. 29.12). Stroke volume is decreased, and a higher heart rate is required to maintain cardiac output. These effects are aggravated by a decrease in plasma volume if the large amounts of salt and water lost in the sweat are not replaced. Since the main cation in sweat is sodium, disproportion- ately much of the body water lost in sweat is at the expense of extracellular fluid, including plasma, although this effect is mitigated if the sweat is dilute. Compensatory Responses During Exercise in the Heat. Several reflex adjustments help maintain cardiac filling, car- diac output, and arterial pressure during exercise and heat stress. The most important of these is constriction of the re- nal and splanchnic vascular beds. A reduction in blood flow through these beds allows a corresponding diversion of cardiac output to the skin and the exercising muscles. In ad- dition, since the splanchnic vascular beds are compliant, a decrease in their blood flow reduces the amount of blood pooled in them (see Fig. 29.12), helping compensate for decreases in central blood volume caused by reduced plasma volume and blood pooling in the skin. The degree of vasoconstriction is graded according to the levels of heat stress and exercise intensity. During stren- uous exercise in the heat, renal and splanchnic blood flows may fall to 20% of their values in a cool resting subject. FIGURE 29.12 Cardiovascular strain and compensatory re- Such intense splanchnic vasoconstriction may produce sponses during heat stress. This figure first mild ischemic injury to the gut, helping explain the intes- shows the effects of skin vasodilation on peripheral pooling of tinal symptoms some athletes experience after endurance blood and the thoracic reservoirs from which the ventricles are events. The cutaneous veins constrict during exercise; since filled; and second, the effects of compensatory vasomotor adjust- most of the vascular volume is in the veins, constriction ments in the splanchnic circulation. The valves on the right rep- makes the cutaneous vascular bed less easily distensible and resent the resistance vessels that control blood flow through the liver/splanchnic, muscle, and skin vascular beds. Arrows show the reduces peripheral pooling. Because of the essential role of direction of the changes during heat stress. (Modified from Row- skin blood flow in thermoregulation during exercise and ell LB. Cardiovascular aspects of human thermoregulation. Circ heat stress, the body preferentially compromises splanch- Res 1983;52:367–379.) nic and renal flow for the sake of cardiovascular homeosta- sis. Above a certain level of cardiovascular strain, however, skin blood flow, too, is compromised. climatization on performance can be dramatic, and accli- HEAT ACCLIMATIZATION matized subjects can easily complete exercise in the heat Prolonged or repeated exposure to stressful environmental that earlier was difficult or impossible. conditions elicits significant physiological changes, called acclimatization, that reduce the resulting strain. (Such Heat Acclimatization Includes Adjustments in changes are often referred to as acclimation when produced Heart Rate, Temperatures, and Sweat Rate in a controlled experimental setting.) Some degree of heat acclimatization occurs either by heat exposure alone or by Cardiovascular adaptations that reduce the heart rate re- regular strenuous exercise, which raises core temperature quired to sustain a given level of activity in the heat appear and provokes heat-loss responses. Indeed, the first summer quickly and reach nearly their full development within 1 heat wave produces enough heat acclimatization that most week. Changes in sweating develop more slowly. After ac- people notice an improvement in their level of energy and climatization, sweating begins earlier and at a lower core general feeling of well-being after a few days. However, the temperature (i.e., the core temperature threshold for sweat- acclimatization response is greater if heat exposure and ex- ing is reduced). The sweat glands become more sensitive to ercise are combined, causing a greater rise of internal tem- cholinergic stimulation, and a given elevation in core tem- perature and more profuse sweating. Evidence of acclimati- perature elicits a higher sweat rate; in addition, the glands be- zation appears in the first few days of combined exercise come resistant to hidromeiosis and fatigue, so higher sweat and heat exposure, and most of the improvement in heat rates can be sustained. These changes reduce the levels of tolerance occurs within 10 days. The effect of heat ac- core and skin temperatures reached during a period of exer-

CHAPTER 29 The Regulation of Body Temperature 543 40 180 1.4 160 1.2 Rectal temperature (°C) 38 Heart rate (beats/min) 120 Sweat rate (L/hr) 0.8 39 1.0 140 100 0.6 37 Unacclimatized 80 0.4 0.2 60 Acclimatized 40 0 01234 01234 0123 4 Time in exercise (hr) Time in exercise (hr) Time in exercise (hr) Heat acclimatization. These graphs show rec- Wenger CB. Human heat acclimatization. In: Pandolf KB, Sawka FIGURE 29.13 tal temperatures, heart rates, and sweat rates MN, Gonzalez RR, eds. Human Performance Physiology and En- during 4 hours’ exercise (bench stepping, 35 W mechanical vironmental Medicine at Terrestrial Extremes. Indianapolis: power) in humid heat (33.9
C dry bulb, 89% relative humidity, Benchmark, 1988;153–197. Based on data from Wyndham CH, 35 torr ambient vapor pressure) on the first and last days of a 2- Strydom NB, Morrison JF, et al. Heat reactions of Caucasians and week program of acclimatizaton to humid heat. (Modified from Bantu in South Africa. J Appl Physiol 1964;19:598–606.) cise in the heat, increase the sweat rate, and enable one to ex- 2). One important consequence of the salt-conserving re- ercise longer. The threshold for cutaneous vasodilation is re- sponse of the sweat glands is that the loss of a given volume duced along with the threshold for sweating, so heat transfer of sweat causes a smaller decrease in the volume of the ex- from the core to the skin is maintained. The lower heart rate tracellular space than if the sodium concentration of the and core temperature and the higher sweat rate are the three sweat is high (Table 29.3). Other consequences are dis- classical signs of heat acclimatization (Fig. 29.13). cussed in Clinical Focus Box 29.1. Heat acclimatization is transient, disappearing in a few weeks if not maintained by repeated heat exposure. The Changes in Fluid and Electrolyte Balance Also components of heat acclimatization are lost in the order in Occur With Heat Acclimatization which they were acquired; the cardiovascular changes de- cay more quickly than the reduction in exercise core tem- During the first week, total body water and, especially, plasma volume increase. These changes likely contribute to perature and sweating changes. the cardiovascular adaptations. Later, the fluid changes seem to diminish or disappear, although the cardiovascular adaptations persist. In an unacclimatized person, sweating RESPONSES TO COLD occurs mostly on the chest and back, but during acclimati- zation, especially in humid heat, the fraction of sweat se- The body maintains core temperature in the cold by mini- creted on the limbs increases to make better use of the skin mizing heat loss and, when this response is insufficient, in- surface for evaporation. An unacclimatized person who is creasing heat production. Reducing shell conductance is sweating profusely can lose large amounts of sodium. With the chief physiological means of heat conservation in hu- acclimatization, the sweat glands become able to conserve mans. Furred or hairy animals also can increase the thick- sodium by secreting sweat with a sodium concentration as ness of their coat and, thus, its insulating properties by low as 5 mmol/L. This effect is mediated through aldos- making the hairs stand on end. This response, called pilo- terone, which is secreted in response to sodium depletion erection, makes a negligible contribution to heat conserva- and to exercise and heat exposure. The sweat glands re- tion in humans, but manifests itself as gooseflesh. spond to aldosterone more slowly than the kidneys, requir- ing several days; unlike the kidneys, the sweat glands do Blood Vessels in the Shell Constrict not escape the influence of aldosterone when sodium bal- to Conserve Heat ance has been restored, but continue to conserve sodium for as long as acclimatization persists. The constriction of cutaneous arterioles reduces skin blood The cell membranes are freely permeable to water, so flow and shell conductance. Constriction of the superficial that any osmotic imbalance between the intracellular and limb veins further improves heat conservation by diverting extracellular compartments is rapidly corrected by the venous blood to the deep limb veins, which lie close to the movement of water across the cell membranes (see Chapter major arteries of the limbs and do not constrict in the cold.

TABLE 29.3 Effect of Sweat Secretion on Body Fluid Compartments and Plasma Sodium Concentration a Extracellular Space Intracellular Space Total Body Water Osmotic Osmotic Osmotic Plasma Volume Content Volume Content Volume Content Osmolality [Na ] Subject Condition (L) (mOsm) (L) (mOsm) (L) (mOsm) (mOsm/kg) (mmol/L) Initial 15 4,350 25 7,250 40 11,600 290 140 A Loss of 5 L of 11.9 3,750 23.1 7,250 35 11,000 314 151 sweat, 120 mOsm/L, 60 mmol Na /L Above condition 13.6 3,750 26.4 7,250 40 11,000 275 132 accompanied by intake of 5 L water B Loss of 5 L of 12.9 4,250 22.1 7,250 35 11,500 329 159 sweat, 20 mOsm/L, 10 mmol Na /L Above condition 14.8 4,250 25.2 7,250 40 11,500 288 139 accompanied by intake of 5 L water a Each subject has total body water of 40 L. The sweat of subject A has a relatively high [Na ] of 60 mmol/L while that of subject B has a relatively low [Na ] of 10 mmol/L. Volumes of the extracellular and intracellular spaces are calculated assuming that water moves between the two spaces as needed to maintain osmotic balance. CLINICAL FOCUS BOX 29.1 Water and Salt Depletion as a Result of Sweating salt, somewhat more than the daily salt intake in a normal Changes in fluid and electrolyte balance are probably the Western diet, and he is becoming salt-depleted. most frequent physiological disturbances associated with Thirst is stimulated by increased osmolality of the extra- sustained exercise and heat stress. Water loss via the cellular fluid, and by decreased plasma volume via a reduc- sweat glands can exceed 1 L/hr for many hours. Salt loss in tion in the activity of the cardiovascular stretch receptors the sweat is variable; however, since sweat is more dilute (see Chapter 18). When sweating is profuse, however, thirst than plasma, sweating always results in an increase in the usually does not elicit enough drinking to replace fluid as osmolality of the fluid remaining in the body, and in- rapidly as it is lost, so that people exercising in the heat tend creased plasma [Na ] and [Cl ], as long as the lost water is to become progressively dehydrated—in some cases losing not replaced. as much as 7 to 8% of body weight—and restore normal Because people who secrete large volumes of sweat fluid balance only during long periods of rest or at meals. usually replace at least some of their losses by drinking Depending on how much of his fluid losses he replaces, water or electrolyte solutions, the final effect on body flu- subject B may either be hypernatremic and dehydrated or ids may vary. In Table 29.3, the second and third condi- be in essentially normal fluid and electrolyte balance. (If he tions (subject A) represent the effects on body fluids of drinks fluid well in excess of his losses, he may become sweat losses alone and combined with replacement by an overhydrated and hyponatremic, but this is an unlikely oc- equal volume of plain water, respectively, for someone currence.) However, subject A, who is somewhat salt de- producing sweat with a [Na ] and [Cl ] in the upper part of pleted, may be very dehydrated and hypernatremic, nor- the normal range. By contrast, the fourth and fifth condi- mally hydrated but hyponatremic, or somewhat dehydrated tions (subject B) represent the corresponding effects for a with plasma [Na ] anywhere in between these two ex- heat-acclimatized person secreting dilute sweat. Compar- tremes. Once subject A replaces all the water lost as sweat, ing the effects on these two individuals, we note: (1) The his extracellular fluid volume will be about 10% below its ini- more dilute the sweat that is secreted, the greater the in- tial value. If he responds to the accompanying reduction in crease in osmolality and plasma [Na ] if no fluid is re- plasma volume by continuing to drink water, he will be- placed; (2) Extracellular fluid volume, a major determinant come even more hyponatremic than shown in Table 29.3. of plasma volume (see Chapter 18), is greater in subject B The disturbances shown in Table 29.3, while physiolog- (secreting dilute sweat) than in subject A (secreting saltier ically significant and useful for illustration, are not likely to sweat), whether or not water is replaced; and (3) Drinking require clinical attention. Greater disturbances, with corre- plain water allowed subject B to maintain plasma sodium spondingly more severe clinical effects, may occur. The and extracellular fluid volume almost unchanged while se- consequences of the various possible disturbances of salt creting 5 L of sweat. In subject A, however, drinking the and water balance can be grouped as effects of decreased same amount of water reduced plasma [Na ] by 8 mmol/L, plasma volume secondary to decreased extracellular fluid and failed to prevent a decrease of almost 10% in extracel- volume, effects of hypernatremia, and effects of hypona- lular fluid volume. In 5 L of sweat, subject A lost 17.5 g of tremia. (continued)

CHAPTER 29 The Regulation of Body Temperature 545 (Many penetrating veins connect the superficial veins to properties. As the blood vessels in the shell constrict, blood the deep veins, so that venous blood from anywhere in the is shifted to the central blood reservoir in the thorax. This limb potentially can return to the heart via either superficial shift produces many of the same effects as an increase in or deep veins.) In the deep veins, cool venous blood re- blood volume, including so-called cold diuresis as the kid- turning to the core can take up heat from the warm blood neys respond to the increased central blood volume. in the adjacent deep limb arteries. Therefore, some of the Once skin blood flow is near minimal, metabolic heat heat contained in the arterial blood as it enters the limbs production increases—almost entirely through shivering takes a “short circuit” back to the core. When the arterial in human adults. Shivering may increase metabolism at rest blood reaches the skin, it is already cooler than the core, so by more than 4-fold—that is, to 350 to 400 W. Although it loses less heat to the skin than it otherwise would. (When it is often stated that shivering diminishes substantially af- the superficial veins dilate in the heat, most venous blood ter several hours and is impaired by exhaustive exercise, returns via superficial veins so as to maximize core-to-skin such effects are not well understood. In most laboratory heat flow.) The transfer of heat from arteries to veins by mammals, chronic cold exposure also causes nonshivering this short circuit is called countercurrent heat exchange. thermogenesis, an increase in metabolic rate that is not This mechanism can cool the blood in the radial artery of a due to muscle activity. Nonshivering thermogenesis ap- cool but comfortable subject to as low as 30
C by the time pears to be elicited through sympathetic stimulation and it reaches the wrist. circulating catecholamines. It occurs in many tissues, espe- As we saw earlier, the shell’s insulating properties increase cially the liver and brown fat, a tissue specialized for non- in the cold as its blood vessels constrict and its thickness in- shivering thermogenesis whose color is imparted by high creases. Furthermore, the shell includes a fair amount of concentrations of iron-containing respiratory enzymes. skeletal muscle in the cold, and although muscle blood flow Brown fat is found in human infants, and nonshivering is believed not to be affected by thermoregulatory reflexes, it thermogenesis is important for their thermoregulation. is reduced by direct cooling. In a cool subject, the resulting The existence of brown fat and nonshivering thermogene- reduction in muscle blood flow adds to the shell’s insulating sis in human adults is controversial, but there is some evi- The circulatory effects of decreased volume are causes symptoms. The development of water intoxication nearly identical to the effects of peripheral pooling of requires either massive overdrinking, or a condition, such blood (see Fig. 29.12), and the combined effects of pe- as the inappropriate secretion of arginine vasopressin, that ripheral pooling and decreased volume will be greater impairs the excretion of free water by the kidneys. Over- than the effects of either alone. These effects include im- drinking sufficient to cause hyponatremia may occur in pa- pairment of cardiac filling and cardiac output, and com- tients with psychiatric disorders or disturbance of the thirst pensatory reflex reductions in renal, splanchnic, and mechanism, or may be done with a mistaken intention of skin blood flow. Impaired cardiac output leads to fatigue preventing or treating dehydration. However, individuals during exertion and decreased exercise tolerance; if skin who secrete copious amounts of sweat with a high sodium blood flow is reduced, heat dissipation will be impaired. concentration, like subject A or people with cystic fibrosis, Exertional rhabdomyolysis, the injury of skeletal mus- may easily lose enough salt to become hyponatremic be- cle fibers, is a frequent result of unaccustomed intense cause of sodium loss. Some healthy young adults who exercise. Myoglobin released from injured skeletal mus- come to medical attention for salt depletion after profuse cle cells appears in the plasma, rapidly enters the sweating are found to have genetic variants of cystic fibro- glomerular filtrate, and is excreted in the urine, produc- sis, which cause these individuals to have salty sweat with- ing myoglobinuria and staining the urine brown if out producing the characteristic digestive and pulmonary enough myoglobin is present. This process may be manifestations of cystic fibrosis. harmless to the kidneys if urine flow is adequate; how- As sodium concentration and osmolality of the extra- ever, a reduction in renal blood flow reduces urine flow, cellular space decrease, water moves from the extracellu- increasing the likelihood that the myoglobin will cause lar space into the cells to maintain osmotic balance across renal tubular injury. the cell membranes. Most of the manifestations of hy- Hypernatremic dehydration is believed to predis- ponatremia are due to the resulting swelling of the brain pose to heatstroke. Dehydration is often accompanied by cells. Mild hyponatremia is characterized by nonspecific both hypernatremia and reduced plasma volume. Hyper- symptoms such as fatigue, confusion, nausea, and natremia impairs the heat-loss responses (sweating and headache, and may be mistaken for heat exhaustion. Se- increased skin blood flow) independently of any accompa- vere hyponatremia can be a life-threatening medical emer- nying reduction in plasma volume and elevates the ther- gency and may include seizures, coma, herniation of the moregulatory set point. Hypernatremic dehydration pro- brainstem (which occurs if the brain swells enough to ex- motes the development of high core temperature in ceed the capacity of the cranium) and death. In the setting multiple ways through the combination of hypernatremia of prolonged exertion in the heat, symptomatic hypona- and reduced plasma volume. tremia is far less common than heat exhaustion, but po- Even in the absence of sodium loss, overdrinking that tentially far more dangerous. Therefore, it is important not exceeds the kidneys’ ability to compensate dilutes all the to treat a presumed case of heat exhaustion with large body’s fluid compartments, producing dilutional hy- amounts of low-sodium fluids without first ruling out hy- ponatremia, which is also called water intoxication if it ponatremia.

546 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY dence for functioning brown fat in the neck and medi- exposed to cold, such as fishermen working with nets in astinum of outdoor workers. cold water. Since the Lewis hunting response increases heat loss from the body somewhat, whether or not it is truly an example of acclimatization to cold is debatable. However, Human Cold Acclimatization Confers a the response is advantageous because it keeps the extremi- Modest Thermoregulatory Advantage ties warmer, more comfortable, and functional and proba- The pattern of human cold acclimatization depends on the bly protects them from cold injury. nature of the cold exposure. It is partly for this reason that the occurrence of cold acclimatization in humans was con- troversial for a long time. Our knowledge of human cold CLINICAL ASPECTS OF THERMOREGULATION acclimatization comes from both laboratory studies and Temperature is important clinically because of the presence studies of populations whose occupation or way of life ex- of fever in many diseases, the effects of many factors on tol- poses them repeatedly to cold temperatures. erance to heat or cold stress, and the effects of heat or cold stress in causing or aggravating certain disorders. Metabolic Changes in Cold Acclimatization. At one time it was believed that humans must acclimatize to cold as lab- oratory mammals do—by increasing their metabolic rate. Fever Enhances Defense Mechanisms There are a few reports of increased basal metabolic rate and, sometimes, thyroid activity in the winter. More often, Fever may be caused by infection or noninfectious condi- however, increased metabolic rate has not been observed in tions (e.g., inflammatory processes such as collagen vascular studies of human cold acclimatization. In fact, several re- diseases, trauma, neoplasms, acute hemolysis, immunologi- ports indicate the opposite response, consisting of a lower cally-mediated disorders). Pyrogens are substances that core temperature threshold for shivering, with a greater fall cause fever and may be either exogenous or endogenous. in core temperature and a smaller metabolic response dur- Exogenous pyrogens are derived from outside the body; ing cold exposure. Such a response would spare metabolic most are microbial products, microbial toxins, or whole mi- energy and might be advantageous in an environment that croorganisms. The best studied of these is the lipopolysac- is not so cold that a blunted metabolic response would al- charide endotoxin of gram-negative bacteria. Exogenous low core temperature to fall to dangerous levels. pyrogens stimulate a variety of cells, especially monocytes and macrophages, to release endogenous pyrogens, Increased Tissue Insulation in Cold Acclimatization. A polypeptides that cause the thermoreceptors in the hypo- lower core-to-skin conductance (i.e., increased insulation thalamus (and perhaps elsewhere in the brain) to alter their by the shell) has often been reported in studies of cold ac- firing rate and input to the central thermoregulatory con- climatization in which a reduction in the metabolic re- troller, raising the thermoregulatory set point. This effect of sponse to cold occurred. This increased insulation is not endogenous pyrogens is mediated by the local synthesis and due to subcutaneous fat (in fact, it has been observed in release of prostaglandin E 2 . Aspirin and other drugs that in- very lean subjects), but apparently results from lower blood hibit the synthesis of prostaglandins also reduce fever. flow in the limbs or improved countercurrent heat ex- Fever accompanies disease so frequently and is such a re- change in the acclimatized subjects. In general, the cold liable indicator of the presence of disease that body tem- stresses that elicit a lower shell conductance after acclima- perature is probably the most commonly measured clinical tization involve either cold water immersion or exposure to index. Many of the body’s defenses against infection and air that is chilly but not so cold as to risk freezing the vaso- cancer are elicited by a group of polypeptides called cy- constricted extremities. tokines; the endogenous pyrogen is usually a member of this group, interleukin-1. However, other cytokines, par- ticularly tumor necrosis factor, interleukin-6, and the in- Cold-Induced Vasodilation and the Lewis Hunting Re- sponse. As the skin is cooled below about 15
C, its blood terferons, are also pyrogenic in certain circumstances. Ele- flow begins to increase somewhat, a response called cold- vated body temperature enhances the development of induced vasodilation (CIVD). This response is elicited these defenses. If laboratory animals are prevented from de- most easily in comfortably warm subjects and in skin rich in veloping a fever during experimentally induced infection, arteriovenous anastomoses (in the hands and feet). The survival rates may be dramatically reduced. (Although, in mechanism has not been established but may involve a di- this chapter, fever specifically means an elevation in core rect inhibitory effect of cold on the contraction of vascular temperature a resulting from pyrogens, some authors use smooth muscle or on neuromuscular transmission. The the term more generally to mean any significant elevation CIVD response varies greatly among individuals, and is of core temperature.) usually rudimentary in hands and feet unaccustomed to cold exposure. After repeated cold exposure, CIVD begins Many Factors Affect Thermoregulatory Responses earlier during cold exposure, produces higher levels of and Tolerance to Heat and Cold blood flow, and takes on a rhythmic pattern of alternating vasodilation and vasoconstriction. This is called the Lewis Regular physical exercise and heat acclimatization increase hunting response because the rhythmic pattern of blood heat tolerance and the sensitivity of the sweating response. flow suggests that it is “hunting” for its proper level. This re- Aging has the opposite effect; in healthy 65-year-old men, sponse is often well developed in workers whose hands are the sensitivity of the sweating response is half of that in 25-

CHAPTER 29 The Regulation of Body Temperature 547 year-old men. Many drugs inhibit sweating, most obvi- Heat Exhaustion. Heat exhaustion, also called heat col- ously those used for their anticholinergic effects, such as lapse, is probably the most common heat disorder, and rep- atropine and scopolamine. In addition, some drugs used for resents a failure of cardiovascular homeostasis in a hot en- other purposes, such as glutethimide (a sleep-inducing vironment. Collapse may occur either at rest or during drug), tricyclic antidepressants, phenothiazines (tranquil- exercise, and may be preceded by weakness or faintness, izers and antipsychotic drugs), and antihistamines, also confusion, anxiety, ataxia, vertigo, headache, and nausea or have some anticholinergic action. All of these and several vomiting. The patient has dilated pupils and usually sweats others have been associated with heatstroke. Congestive profusely. As in heat syncope, reduced diastolic filling of heart failure and certain skin diseases (e.g., ichthyosis and the heart appears to have a primary role in the pathogene- anhidrotic ectodermal dysplasia) impair sweating, and in sis of heat exhaustion. Although blood pressure may be low patients with these diseases, heat exposure and especially during the acute phase of heat exhaustion, the baroreflex exercise in the heat may raise body temperature to danger- responses are usually sufficient to maintain consciousness ous levels. Lesions that affect the thermoregulatory struc- and may be manifested in nausea, vomiting, pallor, cool or tures in the brainstem can also alter thermoregulation. even clammy skin, and rapid pulse. Patients with heat ex- Such lesions can produce hypothermia (abnormally low haustion usually respond well to rest in a cool environment core temperature) if they impair heat-conserving re- and oral fluid replacement. In more severe cases, however, sponses. However, hyperthermia (abnormally high core intravenous replacement of fluid and salt may be required. temperature) is a more usual result of brainstem lesions and Core temperature may be normal or only mildly elevated in is typically characterized by a loss of both sweating and the heat exhaustion. However, heat exhaustion accompanied circadian rhythm of core temperature. by hyperthermia and dehydration may lead to heatstroke. Certain drugs, such as barbiturates, alcohol, and phe- Therefore, patients should be actively cooled if rectal tem- nothiazines, and certain diseases, such as hypothyroidism, perature is 40.6
C (105
F) or higher. hypopituitarism, congestive heart failure, and septicemia, The reasons underlying the reduced diastolic filling in may impair the defense against cold. (Septicemia, espe- heat exhaustion are not fully understood. Hypovolemia cially in debilitated patients, may be accompanied by hy- contributes if the patient is dehydrated, but heat exhaustion pothermia, instead of the usual febrile response to infec- often occurs without significant dehydration. In rats heated tion.) Furthermore, newborns and many healthy older to the point of collapse, compensatory splanchnic vaso- adults are less able than older children and younger adults constriction develops during the early part of heating, but to maintain adequate body temperature in the cold. This is reversed shortly before the maintenance of blood pres- failing appears to be due to an impaired ability to conserve sure fails. A similar process may occur in heat exhaustion. body heat by reducing heat loss and to increase metabolic heat production in the cold. Heatstroke. The most severe and dangerous heat disorder is characterized by high core temperature and the develop- Heat Stress Causes or Aggravates ment of serious neurological disturbances with a loss of Several Disorders consciousness and, frequently, convulsions. Heatstroke oc- curs in two forms, classical and exertional. In the classical The harmful effects of heat stress are exerted through car- form, the primary factor is environmental heat stress that diovascular strain, fluid and electrolyte loss and, especially overwhelms an impaired thermoregulatory system, and in heatstroke, tissue injury whose mechanism is uncertain. most patients have preexisting chronic disease. In exer- In a patient suspected of having hyperthermia secondary to tional heatstroke, the primary factor is high metabolic heat heat stress, temperature should be measured in the rectum, production. Patients with exertional heatstroke tend to be since hyperventilation may render oral temperature spuri- younger and more physically fit (typically, soldiers and ath- ously low. letes) than patients with the classical form. Rhabdomyoly- sis, hepatic and renal injury, and disturbances of blood clot- Heat Syncope. Heat syncope is circulatory failure result- ting are frequent accompaniments of exertional heatstroke. ing from a pooling of blood in the peripheral veins, with a The traditional diagnostic criteria of heatstroke—coma, consequent decrease in venous return and diastolic filling hot dry skin, and rectal temperature above 41.3
C of the heart, resulting in decreased cardiac output and a fall (106
F)—are characteristic of the classical form; however, of arterial pressure. Symptoms range from light-headedness patients with exertional heatstroke may have somewhat and giddiness to loss of consciousness. Thermoregulatory lower rectal temperatures and often sweat profusely. Heat- responses are intact, so core temperature typically is not stroke is a medical emergency, and prompt appropriate substantially elevated, and the skin is wet and cool. The treatment is critically important to reducing morbidity and large thermoregulatory increase in skin blood flow in the mortality. The rapid lowering of core temperature is the heat is probably the primary cause of the peripheral pool- cornerstone of treatment, and it is most effectively accom- ing. Heat syncope affects mostly those who are not accli- plished by immersion in cold water. With prompt cooling, matized to heat, presumably because the plasma-volume vigorous hydration, maintenance of a proper airway, avoid- expansion that accompanies acclimatization compensates ance of aspiration, and appropriate treatment of complica- for the peripheral pooling of blood. Treatment consists in tions, most patients will survive, especially if they were laying the patient down out of the heat, to reduce the pe- previously healthy. ripheral pooling of blood and improve the diastolic filling The pathogenesis of heatstroke is not well understood, of the heart. but it seems clear that factors other than hyperthermia are

548 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY involved, even if the action of these other factors partly de- The preceding diagnostic categories are traditional. pends on the hyperthermia. Exercise may contribute more However, they are not entirely satisfactory for heat illness as- to the pathogenesis than simply metabolic heat production. sociated with exercise because many patients have labora- Elevated plasma levels of several inflammatory cytokines tory evidence of tissue and cellular injury, but are classified as have been reported in patients presenting with heatstroke, having heat exhaustion because they do not have the serious suggesting a systemic inflammatory component. No trigger neurological disturbances that characterize heatstroke. Some for such an inflammatory process has been established, al- more recent literature uses the term exertional heat injury though several possible candidates exist. One possible trig- for such cases. The boundaries of exertional heat injury, with ger is some product(s) of the bacterial flora in the gut, per- heat exhaustion on one hand and heatstroke on the other, are haps including lipopolysaccharide endotoxins. Several not clearly and consistently defined, and these categories lines of evidence suggest that sustained splanchnic vaso- probably represent parts of a continuum. constriction may produce a degree of intestinal ischemia Malignant hyperthermia, a rare process triggered by de- sufficient to allow these products to “leak” into the circula- polarizing neuromuscular blocking agents or certain in- tion and activate inflammatory responses. halational anesthetics, was once thought to be a form of CLINICAL FOCUS BOX 29.2 Hypothermia the cold-induced shift of the hemoglobin-O 2 dissociation Hypothermia is classified according to the patient’s core curve to the left. Acidosis aggravates the susceptibility to temperature as mild (32 to 35
C), moderate (28 to 32
C), or ventricular fibrillation. severe (below 28
C). Shivering is usually prominent in mild Treatment consists of preventing further cooling and hypothermia, but diminishes in moderate hypothermia restoring fluid, acid-base, and electrolyte balance. Patients and is absent in severe hypothermia. The pathophysiology in mild to moderate hypothermia may be warmed solely is characterized chiefly by the depressant effect of cold (via by providing abundant insulation to promote the retention the Q 10 effect) on multiple physiological processes and dif- of metabolically produced heat; those who are more se- ferences in the degree of depression of each process. verely affected require active rewarming. The most serious Other than shivering, the most prominent features of complication associated with treating hypothermia is the mild and moderate hypothermia are due to depression of development of ventricular fibrillation. Vigorous handling the central nervous system. Beginning with mood changes of the patient may trigger this process, but an increase in (commonly, apathy, withdrawal, and irritability), they the patient’s circulation (e.g., associated with warming or progress to confusion and lethargy, followed by ataxia and skeletal muscle activity) may itself increase the suscepti- speech and gait disturbances, which may mimic a cere- bility to such an occurrence, as follows. Peripheral tissues brovascular accident (stroke). In severe hypothermia, vol- of a hypothermic patient are, in general, even cooler than untary movement, reflexes, and consciousness are lost the core, including the heart, and acid products of anaero- and muscular rigidity appears. Cardiac output and respira- bic metabolism will have accumulated in underperfused tion decrease as core temperature falls. Myocardial irri- tissues while the circulation was most depressed. As the tability increases in severe hypothermia, causing a sub- circulation increases, a large increase in blood flow stantial danger of ventricular fibrillation, with the risk through cold, acidotic peripheral tissue may return enough increasing as cardiac temperature falls. The primary mech- cold, acidic blood to the heart to cause a transient drop in anism presumably is that cold depresses conduction ve- the temperature and pH of the heart, increasing its suscep- locity in Purkinje fibers more than in ventricular muscle, fa- tibility to ventricular fibrillation. voring the development of circus-movement propagation The diagnosis of hypothermia is usually straightfor- of action potentials. Myocardial hypoxia also contributes. ward in a patient rescued from the cold but may be far less In more profound hypothermia, cardiac sounds become in- clear in a patient in whom hypothermia is the result of a se- audible and pulse and blood pressure are unobtainable be- rious impairment of physiological and behavioral defenses cause of circulatory depression; the electrical activity of the against cold. A typical example is the older person, living heart and brain becomes unmeasurable; and extensive alone, who is discovered at home, cool and obtunded or muscular rigidity may mimic rigor mortis. The patient unconscious. The setting may not particularly suggest hy- may appear clinically dead, but patients have been revived pothermia, and when the patient comes to medical atten- from core temperatures as low as 17
C, so that “no one is tion, the diagnosis may easily be missed because standard dead until warm and dead.” The usual causes of death dur- clinical thermometers are not graduated low enough (usu- ing hypothermia are respiratory cessation and the failure ally only to 34.4
C) to detect hypothermia and, in any case, of cardiac pumping, because of either ventricular fibrilla- do not register temperatures below the level to which the tion or direct depression of cardiac contraction. mercury has been shaken. Because of the depressant ef- Depression of renal tubular metabolism by cold impairs fect of hypothermia on the brain, the patient’s condition the reabsorption of sodium, causing a diuresis and leading may be misdiagnosed as cerebrovascular accident or other to dehydration and hypovolemia. Acid-base disturbances primary neurological disease. Recognition of this condi- in hypothermia are complex. Respiration and cardiac out- tion depends on the physician’s considering it when ex- put typically are depressed more than metabolic rate, and amining a cool patient whose mental status is impaired a mixed respiratory and metabolic acidosis results, be- and obtaining a true core temperature with a low-reading cause of CO 2 retention and lactic acid accumulation and glass thermometer or other device.

CHAPTER 29 The Regulation of Body Temperature 549 heatstroke but is now known to be a distinct disorder that Hypothermia Occurs When the Body’s Defenses occurs in people with a genetic predisposition. In 90% of Against Cold Are Disabled or Overwhelmed susceptible individuals, biopsied skeletal muscle tissue con- tracts on exposure to caffeine or halothane in concentra- Hypothermia reduces metabolic rate via the Q 10 effect and tions having little effect on normal muscle. Susceptibility prolongs the time tissues can safely tolerate a loss of blood may be associated with any of several myopathies, but most flow. Since the brain is damaged by ischemia soon after cir- susceptible individuals have no other clinical manifesta- culatory arrest, controlled hypothermia is often used to tions. The control of free (unbound) calcium ion concen- protect the brain during surgical procedures in which its tration in skeletal muscle cytoplasm is severely impaired in circulation is occluded or the heart is stopped. Much of our susceptible individuals; and when an attack is triggered, knowledge about the physiological effects of hypothermia calcium concentration rises abnormally, activating myosin comes from observations of surgical patients. ATPase and leading to an uncontrolled hypermetabolic During the initial phases of cooling, stimulation of shiv- process that rapidly increases core temperature. Treatment ering through thermoregulatory reflexes overwhelms the with dantrolene sodium, which appears to act by reducing Q 10 effect. Metabolic rate, therefore, increases, reaching a the release of calcium ions from the sarcoplasmic reticulum, peak at a core temperature of 30 to 33
C. At lower core has dramatically reduced the mortality rate of this disorder. temperatures, however, metabolic rate is dominated by the Q 10 effect, and thermoregulation is lost. A vicious circle de- Aggravation of Disease States by Heat Exposure. Other velops, wherein a fall in core temperature depresses metab- than producing specific disorders, heat exposure aggravates olism and allows core temperature to fall further, so that at several other diseases. Epidemiological studies show that 17
C, the O 2 consumption is about 15%, and cardiac out- during unusually hot weather, mortality may be 2 to 3 times put 10%, of precooling values. that normally expected for the months in which heat waves Hypothermia that is not induced for therapeutic pur- occur. Deaths ascribed to specific heat disorders account poses is called accidental hypothermia (Clinical Focus Box for only a small fraction of the excess mortality (i.e., the in- 29.2). It occurs in individuals whose defenses are impaired crease above the expected mortality). Most of the excess by drugs (especially ethanol, in the United States), disease, mortality is accounted for by deaths from diabetes, various or other physical conditions and in healthy individuals who diseases of the cardiovascular system, and diseases of the are immersed in cold water or become exhausted working blood-forming organs. or playing in the cold. REVIEW QUESTIONS DIRECTIONS: Each of the numbered (D) Antipyretics increase skin blood Threshold for items or incomplete statements in this flow so as to dissipate more heat, Core Sweating Cutaneous Temperature Threshold Vasodilation section is followed by answers or by increasing circulatory strain during (A) Unchanged Higher Lower completions of the statement. Select the exercise (B) Unchanged Unchanged Unchanged ONE lettered answer or completion that is (E) The increased heat production (C) Higher Higher Higher BEST in each case. during exercise greatly exceeds the (D) Higher Unchanged Lower ability of antipyretics to stimulate the (E) Lower Lower Lower 1. Antipyretics such as aspirin effectively responses for heat loss 4. Compared to an unacclimatized lower core temperature during fever, 2. A surgical sympathectomy has person, one who is acclimatized to but they are not used to counteract the completely interrupted the cold has increase in core temperature that sympathetic nerve supply to a patient’s (A) Higher metabolic rate in the cold, occurs during exercise. Which of the arm. How would one expect the to produce more heat following best explains why it is thermoregulatory skin blood flow and (B) Lower metabolic rate in the cold, inappropriate to use antipyretics for sweating responses on that arm to be to conserve metabolic energy this purpose? affected? (C) Lower peripheral blood flow in the (A) The increase in core temperature Vasoconstriction Vasodilation cold, to retain heat during exercise stimulates metabolism in the Cold in the Heat Sweating (D) Higher blood flow in the hands via the Q 10 effect, helping to support (A) Abolished Intact Intact and feet in the cold, to preserve their the body’s increased metabolic energy (B) Abolished Intact Abolished function demands (C) Abolished Abolished Intact (E) Various combinations of the above, (B) A moderate increase in core (D) Abolished Abolished Abolished depending on the environment that temperature during exercise is (E) Intact Abolished Abolished produced acclimatization harmless, so there is no benefit in 3. A person resting in a constant ambient 5. Which statement best describes how preventing it temperature is tested in the early the elevated core temperature during (C) Antipyretics are ineffective during morning at 4:00 AM, and again in the fever affects the outcome of most exercise because they act on a afternoon at 4:00 PM. Compared to bacterial infections? mechanism that operates during fever, measurements made in the morning, (A) Fever benefits the patient because but not to a significant degree during one would expect to find in the most pathogens thrive best at the exercise afternoon: host’s normal body temperature (continued)

550 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY (B) Fever is beneficial because it helps osmolality equals 2 times the plasma Braunwald E, Fauci AS, Kasper DL, et stimulate the immune defenses against [Na ].) What are his plasma sodium al., eds. Harrison’s Principles of Internal infection concentration and ECF volume after he Medicine. 15th Ed. New York: Mc- (C) Fever is harmful because the has replaced all the water that he lost? Graw-Hill, 2001;107–111. accompanying protein catabolism Plasma [Na ] Dinarello CA. Cytokines as endogenous reduces the availability of amino acids (mmol/L) ECF Volume (L) pyrogens. J Infect Dis 1999;179(Suppl for the immune defenses (A) 140.5 12.1 2):S294–S304. (D) Fever is harmful because the (B) 130 13.1 Dinarello CA, Gelfand JA. Fever and hy- patient’s higher temperature favors (C) 122.3 13.9 perthermia. In: Braunwald E, Fauci AS, growth of the bacteria responsible for (D) 113.3 15. Kasper DL, et al., eds. Harrison’s Prin- infection (E) 113.3 13.9 ciples of Internal Medicine. 15th Ed. (E) Fever has little overall effect either 8. Our subject is bicycling on a long road New York: McGraw-Hill, 2001;91–94. way with a slight upward grade. His Gagge AP, Gonzalez RR. Mechanisms of 6. A manual laborer moves in March from metabolic rate (M in the heat-balance heat biophysics and physiology. In: Canada to a hot, tropical country and equation) is 800 W (48 kJ/min). He Fregly MJ, Blatteis CM, eds. Handbook becomes acclimatized by working performs mechanical work (against of Physiology. Section 4. Environmen- outdoors for a month. Compared with gravity, friction, and wind resistance) tal Physiology. New York: Oxford his responses on the first few days in at a rate of 140 W. Air temperature is University Press, 1996;45–84. the tropical country, for the same 20
C and h c , the convective heat Jessen C. Interaction of body temperatures 2 activity level after acclimatization one transfer coefficient, is 15 W/(m •
C). in control of thermoregulatory effector would expect higher Assume that his mean skin temperature mechanisms. In: Fregly MJ, Blatteis (A) Core temperature is 34
C, all the sweat he secretes is CM, eds. Handbook of Physiology. (B) Heart rate evaporated, respiratory water loss can Section 4. Environmental Physiology. (C) Sweating rate be ignored, and net heat exchange by New York: Oxford University Press, (D) Sweat salt concentration radiation is negligible. How rapidly 1996;127–138. (E) Thermoregulatory set point must he sweat to achieve heat balance? Johnson JM, Proppe DW. Cardiovascular In questions 7 to 8, assume a 70-kg (Remember that 1 W  1 J/sec  adjustments to heat stress. In: Fregly young man with the following baseline 60 J/min.) MJ, Blatteis CM, eds. Handbook of characteristics: total body water (TBW)  (A) 3.9 g/min Physiology. Section 4. Environmental 40 L, extracellular fluid (ECF) volume  (B) 7.0 g/min Physiology. New York: Oxford Uni- 15 L, plasma volume  3 L, body surface (C) 11.1 g/min versity Press, 1996;215–243. 2 area  1.8 m , plasma [Na ]  140 (D) 13.9 g/min Knochel JP, Reed G: Disorders of heat mmol/L. Heat of evaporation of water  (E) 15.0 g/min regulation. In: Narins RG, ed. Maxwell 2,425 kJ/kg  580 kcal/kg. & Kleeman’s Clinical Disorders of Fluid 7. Our subject begins an 8-hour hike in SUGGESTED READING and Electrolyte Metabolism. 5th Ed. the desert carrying 5 L of water in Boulant JA. Hypothalamic neurons regu- New York: McGraw-Hill, canteens. During the hike, he sweats at lating body temperature. In: Fregly MJ, 1994;1549–1590. a rate of 1 L/hr, his sweat [Na ] is 50 Blatteis CM, eds. Handbook of Physi- Pandolf KB, Sawka MN, Gonzalez RR, mmol/L, and he drinks all his water. ology. Section 4. Environmental Physi- eds. Human Performance Physiology After the end of his hike he rests and ology. New York: Oxford University and Environmental Medicine at Terres- consumes 3 L of water. (For simplicity Press, 1996;105–126. trial Extremes. Indianapolis: Bench- in calculations, assume that the plasma Danzl DF. Hypothermia and frostbite. In: mark, 1988.

Exercise Physiology CHAPTER 30 Alon Harris, Ph.D. 30 Bruce Martin, Ph.D. CHAPTER OUTLINE ■ THE QUANTIFICATION OF EXERCISE ■ GASTROINTESTINAL, METABOLIC, AND ENDOCRINE ■ CARDIOVASCULAR RESPONSES RESPONSES ■ RESPIRATORY RESPONSES ■ AGING, IMMUNE, AND PSYCHIATRIC RESPONSES ■ MUSCLE AND BONE RESPONSES KEY CONCEPTS 1. Exercise must be accurately defined before acute or 5. The respiratory system responds predictably to increased chronic physiological responses can be predicted. O 2 consumption and CO 2 production with exercise. 2. Maximal oxygen uptake predicts work performance and 6. In healthy individuals, muscle fatigue during exercise is the physiological responses to exercise. linked to ADP accumulation. 3. Substantial regional blood flow shifts occur during dy- 7. Chronic physical activity enhances insulin sensitivity and namic and isometric exercise. glucose entry into cells. 4. Training affects both myocardial muscle and the coronary circulation. xercise, or physical activity, is a ubiquitous physiologi- Measuring Maximal Oxygen Uptake Is the Ecal state, so common in its many forms that true physi- Most Common Method of Quantifying ological “rest” is indeed rarely achieved. Defined ultimately Dynamic Exercise in terms of skeletal muscle contraction, exercise involves every organ system in coordinated response to increased Dynamic exercise is defined as skeletal muscle contractions muscular energy demands. at changing lengths and with rhythmic episodes of relax- ation. Fundamental to any discussion of dynamic exercise is a description of its intensity. Since dynamically exercising muscle primarily generates energy from oxidative metabo- THE QUANTIFICATION OF EXERCISE lism, a traditional standard is to measure, by mouth, the Exercise is as varied as it is ubiquitous. A single episode of oxygen uptake (VO 2) of an exercising subject. This meas- exercise, or “acute” exercise, may provoke responses differ- urement is limited to dynamic exercise and usually to the ent from the adaptations seen when activity is chronic— steady state, when exercise intensity and oxygen consump- that is, during training. The forms of exercise vary as well. tion are stable and no net energy is provided from nonox- The amount of muscle mass at work (one finger? one arm? idative sources. Three implications of the original oxygen both legs?), the intensity of the effort, its duration, and the consumption measurements deserve mention. First, the type of muscle contraction (isometric, rhythmic) all influ- centrality of oxygen usage to work output gave rise to the ence the body’s responses and adaptations. now-standard term “aerobic” exercise. Second, the apparent These many aspects of exercise imply that its interaction excess in oxygen consumption during the first minutes of with disease is multifaceted. There is no simple answer as to recovery has been termed the oxygen debt (Fig. 30.1). The whether exercise promotes health. In fact, physical activity “excess” oxygen consumption of recovery results from a can be healthful, harmful, or irrelevant, depending on the multitude of physiological processes and little usable infor- patient, the disease, and the specific exercise in question. mation is obtained from its measurement. Third, and more 551

552 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY O 2 deficit Steady state chondrion reaches its capacity at about the same time. In 1.25 Repayment practical terms, this means that any lung, heart, vascular, or O 2 uptake (L/min) 0.75 will diminish a patient’s functional capacity. musculoskeletal illness that reduces oxygen flow capacity of O 2 debt 1.00 In isometric exercise, force is generated at constant mus- cle length and without rhythmic episodes of relaxation. Iso- 0.50 Resting level 0.25 the maximal voluntary contraction (MVC), the peak iso- Rest Work Recovery metric work intensity is usually described as a percentage of metric force that can be briefly generated for that specific 2 4 6 8 10 12 exercise. Analogous to work levels relative to maximal oxy- Time (min) gen uptake, the ability to endure isometric effort, and many Oxygen uptake before, during, and after physiological responses to that effort, are predictable when FIGURE 30.1 light steady-state exercise. the percentage of MVC among individuals is held constant. useful, during dynamic exercise that uses a large muscle CARDIOVASCULAR RESPONSES mass, each person has a maximal oxygen uptake, a ceiling up to 20 times basal consumption, that cannot be exceeded, Increased energy expenditure with exercise demands more although it can be increased by appropriate training. This energy production. For prolonged work, this energy is sup- maximal oxygen uptake is a useful but imperfect predictor plied by the oxidation of foodstuff, with the oxygen carried of the ability to perform prolonged dynamic external work to working muscles by the cardiovascular system. or, more specifically, of endurance athletic performance. Maximal oxygen uptake is decreased, all else being equal, Blood Flow Is Preferentially Directed to by age, bed rest, or increased body fat. Working Skeletal Muscle During Exercise Maximal oxygen uptake is also used to express relative work capacity. A world champion cross-country skier obvi- Local control of blood flow ensures that only working mus- ously has a greater capacity to consume oxygen than a cles with increased metabolic demands receive increased novice. However, when both are exercising at intensities blood and oxygen delivery. If the legs alone are active, leg requiring two thirds of their respective maximal oxygen up- muscle blood flow should increase while arm muscle blood takes (the world champion is moving much faster in doing flow remains unchanged or is reduced. At rest, skeletal mus- this, as a result of higher capacity), both become exhausted cle receives only a small fraction of the cardiac output. In at roughly the same time and for the same physiological dynamic exercise, both total cardiac output and relative reasons (Fig. 30.2). In the discussion that follows, relative as and absolute output directed to working skeletal muscle in- well as absolute (expressed as L/min of oxygen uptake) crease dramatically (Table 30.2). work levels are used to explain physiological responses. Cardiovascular control during exercise involves sys- The energy costs and relative demands of some familiar ac- temic regulation (cardiovascular centers in the brain, with tivities are listed in Table 30.1. their autonomic nervous output to the heart and systemic What causes oxygen uptake to reach a ceiling? Histori- resistance vessels) in tandem with local control. For millen- cally, many arguments claim primacy for either cardiac out- nia our ancestors successfully used exercise both to escape put (oxygen delivery) or muscle metabolic capacity (oxy- being eaten and to catch food; therefore, it is no surprise gen use) limitations. However, it may be that every link in that cardiovascular control in exercise is complex and the chain taking oxygen from the atmosphere to the mito- unique. It’s as if a brain software program entitled “Exercise” TABLE 30.1 Absolute and Relative Costs of Daily Activities % Maximal Oxygen Uptake Activity Energy Cost (kcal/min) Sedentary 22-Year-Old Sedentary 70-Year-Old Sleeping 1 6 8 Sitting 2 12 17 Standing 3 19 25 Dressing, undressing 3 19 25 Walking (3 miles/hr) 4 25 33 Making a bed 5 31 42 Dancing 7 44 58 Gardening/shoveling 8 50 67 Climbing stairs 11 69 92 Crawl swimming (50 m/min) 16 100 Running (8 miles/hr) 16 100

CHAPTER 30 Exercise Physiology 553 Blood Flow Distribution During Rest and Dynamic exercise, at its most intense level, forces the TABLE 30.2 body to choose between maximum muscle vascular dilation Dynamic Exercise in an Athlete and defense of blood pressure. Blood pressure is, in fact, Rest Heavy Exercise maintained. During strenuous exercise, sympathetic drive can begin to limit vasodilation in active muscle. When exer- Area mL/min % mL/min % cise is prolonged in the heat, increased skin blood flow and Splanchnic 1,400 24 300 1 sweating-induced reduction in plasma volume both con- Renal 1,100 19 900 4 tribute to the risk of hyperthermia and hypotension (heat ex- Brain 750 13 750 3 haustion). Although chronic exercise provides some heat ac- Coronary 250 4 1,000 4 climatization, even highly trained people are at risk for Skeletal muscle 1,200 21 22,000 86 hyperthermia and hypotension if work is prolonged and wa- Skin 500 9 600 2 ter is withheld in demanding environmental conditions. Other 600 10 100 0.5 Isometric exercise causes a somewhat different cardio- Total Cardiac Output 5,800 100 25,650 100 vascular response. Muscle blood flow increases relative to the resting condition, as does cardiac output, but the higher mean intramuscular pressure limits these flow increases much more than when exercise is rhythmic. Because the were inserted into the brain as work begins. Initially, the blood flow increase is blunted inside a statically contract- motor cortex is activated: The total neural activity is ing muscle, the fruits of hard work with too little oxygen roughly proportional to the muscle mass and its work in- appear quickly: a shift to anaerobic metabolism, the pro- tensity. This neural activity communicates with the cardio- duction of lactic acid, a rise in the ADP/ATP ratio, and fa- vascular control centers, reducing vagal tone on the heart tigue. Maintaining just 50% of the MVC is agonizing after (which raises heart rate) and resetting the arterial barore- about 1 minute and usually cannot be continued after 2 ceptors to a higher level. As work rate is increased further, minutes. A long-term sustainable level is only about 20% of lactic acid is formed in actively contracting muscles, which maximum. These percentages are much less than the equiv- stimulates muscle afferent nerves to send information to the alent for dynamic work, as defined in terms of maximal oxy- cardiovascular center that increases sympathetic outflow to gen uptake. Rhythmic exercise requiring 70% of the maxi- the heart and systemic resistance vessels. However, despite mal oxygen uptake can be maintained in healthy this muscle chemoreflex activity, within these same work- individuals for about an hour, while work at 50% of the ing muscles, low PO 2 , increased nitric oxide, vasodilator maximal oxygen uptake may be prolonged for several hours prostanoids, and associated local vasoactive factors dilate (see Fig. 30.2). arterioles despite rising sympathetic vasoconstrictor tone. The reliance on anaerobic metabolism in isometric exer- Increased sympathetic drive does elevate heart rate and car- cise triggers muscle ischemic chemoreflex responses that diac contractility, resulting in increased cardiac output; lo- raise blood pressure more and cardiac output and heart rate cal factors in the coronary vessels mediate coronary va- sodilation. Increased sympathetic vasoconstrictor tone in the renal and splanchnic vascular beds, and in inactive mus- cle, reduces blood flow to these tissues. Blood flow to these 4 inactive regions can fall 75% if exercise is strenuous. In- creased vascular resistance and decreased blood volume in these tissues helps maintain blood pressure during dynamic exercise. In contrast to blood flow reductions in the viscera and in inactive muscle, the brain autoregulates blood flow 3 Time to exhaustion (hr) at constant levels independent of exercise. The skin re- mains vasoconstricted only if thermoregulatory demands are absent. Table 30.3 shows how a profound fall in sys- temic vascular resistance matches the enormous rise in car- 2 diac output during dynamic exercise. 1 Cardiac Output, Mean Arterial Pressure, TABLE 30.3 and Systemic Vascular Resistance Changes With Exercise Strenuous Dynamic 0 Rest Exercise 25 50 75 100 Cardiac output (L/min) 6 21 Relative aerobic exercise intensity (% maximal oxygen uptake) Mean arterial pressure (mm Hg) 90 105 Systemic vascular resistance 15 5 FIGURE 30.2 Time to exhaustion during dynamic exer- (mm Hg
min/L) cise. Exhaustion is predictable on the basis of relative demand upon the maximal oxygen uptake.

554 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY 160 “respiratory pump,” which increases breath-by-breath os- cillations in intrathoracic pressure (see Chapter 18). The Isometric importance of these factors is clear in patients with heart Mean arterial pressure (mm Hg) 120 Dynamic exercise intensity as a result of increased venous return that transplants who lack extrinsic cardiac innervation. Stroke 140 volume rises in cardiac transplant patients with increasing enhances cardiac preload. In addition, circulating epineph- rine and norepinephrine from the adrenal medulla and nor- epinephrine from sympathetic nerve spillover augment heart rate and contractility. 100 Maximal dynamic exercise yields a maximal heart rate: cannot elevate heart rate further. Stroke volume, in con- trast, reaches a plateau in moderate work and is unchanged 80 further vagal blockade (e.g., via pharmacological means) as exercise reaches its maximum intensity (see Table 30.4). Rest 1 hand 1 arm 2 arms 1 leg 2 legs This plateau occurs in the face of ever-shortening filling Muscle mass time, testimony to the increasing effectiveness of the mech- anisms that enhance venous return and those that promote Effect of active muscle mass on mean arte- FIGURE 30.3 cardiac contractility. Sympathetic stimulation decreases rial pressure during exercise. The highest pressures during dynamic exercise occur when an intermediate left ventricular volume and pressure at the onset of cardiac muscle mass is involved; pressure continues to rise in isometric relaxation (as a result of increased ejection fraction), lead- exercise as more muscle is added. ing to more rapid ventricular filling early in diastole. This helps maintain stroke volume as diastole shortens. Even in untrained individuals, the ejection fraction (stroke volume as a percentage of end-diastolic volume) reaches 80% in less than in dynamic work (Fig. 30.3). Oddly, for dynamic strenuous exercise. exercise, the elevation of blood pressure is most pro- The increased blood pressure, heart rate, stroke volume, nounced when a medium muscle mass is working (see Fig. and cardiac contractility seen in exercise all increase my- 30.3). This response results from the combination of a ocardial oxygen demands. These demands are met by a lin- small, dilated active muscle mass with powerful central ear increase in coronary blood flow during exercise that can sympathetic vasoconstrictor drive. Typically, the arms ex- reach a value 5 times the basal level. This increase in flow emplify a medium muscle mass; shoveling snow is a good is driven by local, metabolically linked factors (nitric oxide, example of primarily arm and heavily isometric exercise. adenosine, and the activation of ATP-sensitive K chan- Shoveling snow can be risky for people in danger of stroke nels) acting on coronary resistance vessels in defiance of or heart attack because it substantially raises systemic arte- sympathetic vasoconstrictor tone. Coronary oxygen ex- rial pressure. The elevated pressure places compromised traction, high at rest, increases further with exercise (up to cerebral arteries at risk and presents an ischemic or failing 80% of delivered oxygen). In healthy people, there is no heart with a greatly increased afterload. evidence of myocardial ischemia under any exercise condi- tion, and there may be a coronary vasodilator reserve in even the most intense exercise (Clinical Focus Box 30.1). Acute and Chronic Responses of the Heart and Blood Vessels to Exercise Differ Over longer periods of time, the heart adapts to exercise overload much as it does to high-demand pathological In acute dynamic exercise, vagal withdrawal and increases states: by increasing left ventricular volume when exercise in sympathetic outflow elevate heart rate and contractility requires high blood flow, and by left ventricular hypertro- in proportion to exercise intensity (Table 30.4). Cardiac phy when exercise creates high systemic arterial pressure output is also aided in dynamic exercise by factors enhanc- (high afterload). Consequently, the hearts of individuals ing venous return. These include the “muscle pump,” which adapted to prolonged, rhythmic exercise that involves rel- compresses veins as muscles rhythmically contract, and the atively low arterial pressure exhibit large left ventricular TABLE 30.4 Acute Cardiac Response to Graded Exercise in a 30-Year-Old Untrained Woman Oxygen Uptake Heart Rate Stroke Volume Cardiac Output Exercise Intensity (L/min) (beats/min) (mL/beat) (L/min) Rest 0.25 72 70 5 Walking 1.0 110 90 10 Jogging 1.8 150 100 15 Running fast 2.5 190 100 19

CHAPTER 30 Exercise Physiology 555 CLINICAL FOCUS BOX 30.1 Stress Testing To detect coronary artery disease, physicians often record an electrocardiogram (ECG), but at rest, many disease suf- ferers have a normal ECG. To increase demands on the heart and coronary circulation, an ECG is performed while the patient walks on a treadmill or rides a stationary bicy- R R R R cle. It is sometimes called a stress test. T T T T Exercise increases the heart rate and the systemic arte- rial blood pressure. These changes increase cardiac work and the demand for coronary blood flow. In many patients, S S S S coronary blood flow is adequate at rest, but because of coronary arterial blockage, cannot rise sufficiently to meet 1 the increased demands of exercise. During a stress test, specific ECG changes can indicate that cardiac muscle is not receiving sufficient blood flow and oxygen delivery. As heart rate increases during exercise, the distance be- tween any portion of the ECG (for example, the R wave) on the ECG becomes shorter (Fig. 30.A and 30.B). In patients R R R R R R suffering from ischemic heart disease, however, other T T T T T T changes occur. Most common is an abnormal depression between the S and T waves, known as ST segment de- pression (see Fig. 30.B). Depression of the ST segment arises from changes in cardiac muscle electrical activity S S S S S S secondary to lack of blood flow and oxygen delivery. 2 During the stress test, the ECG is continuously analyzed for changes while blood pressure and arterial blood oxy- FIGURE 30.A Effect of exercise on the electrocardiogram gen saturation are monitored. At the start of the test, the (ECG) in a patient with ischemic heart dis- exercise load is mild. The load is increased at regular in- ease. 1, The ECG is normal at rest. 2, During exercise, the inter- tervals, and the test ends when the patient becomes ex- val between R waves is reduced, and the ECG segment between hausted, the heart rate safely reaches a maximum, signifi- the S and T waves is depressed. cant pain occurs, or abnormal ECG changes are noted. With proper supervision, the stress test is a safe method for detecting coronary artery disease. Because the exer- cise load is gradually increased, the test can be stopped at the first sign of problems. volumes with normal wall thickness, while wall thickness is training, as are cardiac muscle capillary density and peak increased at normal volume in those adapted to activities capillary exchange capacity. Training also improves en- involving isometric contraction and greatly elevated arte- dothelium-mediated regulation, responsiveness to adeno- rial pressure, such as lifting weights. sine, and control of intracellular free calcium ions within The larger left ventricular volume in people chronically coronary vessels. Preserving endothelial vasodilator func- active in dynamic exercise leads directly to larger resting tion may be the primary benefit of chronic physical activ- and exercise stroke volume. A simultaneous increase in va- ity on the coronary circulation. gal tone and decrease in -adrenergic sensitivity enhance the resting and exercise bradycardia seen after training, so The Blood Lipid Profile Is Influenced that in effect the trained heart operates further up the as- cending limb of its length-tension relationship (see Fig. by Exercise Training 10.3). Nonetheless, resting bradycardia is a poor index of Chronic, dynamic exercise is associated with increased cir- endurance fitness because genetic factors explain a much culating levels of high-density lipoproteins (HDLs) and re- larger proportion of the individual variation in resting heart duced low-density lipoproteins (LDLs), such that the ratio rate than does training. of HDL to total cholesterol is increased. These changes in The effects of endurance training on coronary blood cholesterol fractions occur at any age if exercise is regular. flow are partly mediated through changes in myocardial Weight loss and increased insulin sensitivity, which typi- oxygen uptake. Since myocardial oxygen consumption is cally accompany increased chronic physical activity in roughly proportional to the rate-pressure product (heart sedentary individuals, undoubtedly contribute to these rate
mean arterial pressure), and since heart rate falls af- changes in plasma lipoproteins. Nonetheless, in people ter training at any absolute exercise intensity, coronary with lipoprotein levels that place them at high risk for coro- flow at a fixed submaximal workload is reduced in parallel. nary heart disease, exercise appears to be an essential ad- The peak coronary blood flow is, however, increased by junct to dietary restriction and weight loss for lowering

556 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY LDL cholesterol levels. Because exercise acutely and chron- cise on insulin sensitivity and central obesity can restore ically enhances fat metabolism and cellular metabolic ca- ovulation in anovulatory obese women suffering from pacities for -oxidation of free fatty acids, it is not surpris- polycystic ovary disease. ing that regular activity increases both muscle and adipose Regular exercise may reduce the risk of spontaneous tissue lipoprotein lipase activity. Changes in lipoprotein li- abortion of a chromosomally normal fetus. Continued exer- pase activity, in concert with increased lecithin-cholesterol cise throughout pregnancy characteristically results in nor- acyltransferase activity and apo A-I synthesis, enhance the mal-term infants after relatively brief labor. These infants levels of circulating HDLs. are usually normal in length and lean body mass but reduced in fat. The risk of large infant size for gestational age, in- creased in diabetic mothers, is reduced by maternal exercise Exercise Has a Role in Preventing and Recovering through improved glucose tolerance. The incidence of um- From Several Cardiovascular Diseases bilical cord entanglement, abnormal fetal heart rate during Changes in the ratio of HDL to total cholesterol that take labor, stained amniotic fluid, and low fetal responsiveness place with regular physical activity reduce the risk of scores may all be reduced in women who are active through- atherogenesis and coronary artery disease in active people, out pregnancy. Further, when examined 5 days after birth, as compared with those who are sedentary. A lack of exer- newborns of exercising women perform better in their abil- cise is now established as a risk factor for coronary heart ity to orient to environmental stimuli and their ability to disease similar in magnitude to hypercholesterolemia, hy- quiet themselves after sound and light stimuli than weight- pertension, and smoking. A reduced risk grows out of the matched children of nonexercising mothers. changes in lipid profiles noted above, reduced insulin re- quirements and increased insulin sensitivity, and reduced cardiac -adrenergic responsiveness and increased vagal RESPIRATORY RESPONSES tone. When coronary ischemia does occur, increased vagal tone may reduce the risk of fibrillation. Increased breathing is perhaps the single most obvious Regular exercise often, but not always, reduces resting physiological response to acute dynamic exercise. Figure blood pressure. Why some people respond to chronic activ- 30.4 shows that minute ventilation (the product of breath- ity with a resting blood pressure decline and others do not re- ing frequency and tidal volume) initially rises linearly with mains unknown. Responders typically show diminished rest- work intensity and then supralinearly beyond that point. ing sympathetic tone, so that systemic vascular resistance Ventilation of the lungs in exercise is linked to the twin falls. In obesity-linked hypertension, declining insulin secre- goals of oxygen intake and carbon dioxide removal. tion and increasing insulin sensitivity with exercise may ex- plain the salutary effects of combining training with weight loss. Nonetheless, because some obese people who exercise Ventilation in Exercise Matches and lose weight show no blood pressure changes, exercise Metabolic Demands, but the Exact remains adjunctive therapy for hypertension. Control Mechanisms Is Unknown Exercise increases oxygen consumption and carbon dioxide Pregnancy Shares Many Cardiovascular production by working muscles, and the pulmonary re- Characteristics With the Trained State sponse is precisely calibrated to maintain homeostasis of these gases in arterial blood. In mild or moderate work, ar- The physiological demands and adaptations of pregnancy in some ways are similar to those of chronic exercise. Both of them increase blood volume, cardiac output, skin blood flow, and caloric expenditure. Exercise clearly has the potential to be deleterious to the fetus. Acutely, it increases body core temperature, causes splanchnic (hence, uterine and umbilical) vasoconstriction, and alters the endocrinological milieu; chronically, it increases caloric requirements. This last de- mand may be devastating if food shortages exist: the super- imposed caloric demands of successful pregnancy and lacta- tion are estimated at 80,000 kcal. Given adequate nutritional resources, however, there is little evidence of other damaging effects of maternal exercise on fetal development. The failure of exercise to harm well-nourished pregnant women may re- late in part to the increased maternal and fetal mass and blood volume, which reduces specific heat loads, moderates vaso- constriction in the uterine and umbilical circulations, and di- minishes the maternal exercise capacity. At least in previously active women, even the most in- tense concurrent exercise regimen (unless associated with The dependence of minute ventilation on excessive weight loss) does not alter fertility, implantation, FIGURE 30.4 the intensity of dynamic exercise. Ventilation or embryogenesis, although the combined effects of exer- rises linearly with intensity until exercise nears maximal levels.

CHAPTER 30 Exercise Physiology 557 terial PO 2 (and, hence, oxygen content), PCO 2 , and pH all The ventilatory control mechanisms in exercise remain remain unchanged from resting levels (Table 30.5). The undefined. Where there are stimuli—such as in mixed ve- respiratory muscles accomplish this severalfold increase in nous blood, which is hypercapnic and hypoxic in propor- ventilation primarily by increasing tidal volume, without tion to exercise intensity—there are seemingly no recep- provoking sensations of dyspnea. tors. Conversely, where there are receptors—the carotid More intense exercise presents the lungs with tougher bodies, the lung parenchyma or airways, the brainstem challenges. Near the halfway point from rest to maximal bathed by cerebrospinal fluid—no stimulus proportional to dynamic work, lactic acid formed in working muscles be- the exercise demand exists. Paradoxically, the central gins to appear in the circulation. This point, which de- chemoreceptor is immersed in increasing alkalinity as exer- pends on the type of work involved and the person’s cise intensifies, a consequence of blood-brain barrier per- training status, is called the lactate threshold. Lactate meability to CO 2 but not hydrogen ions. Perhaps exercise concentration gradually rises with work intensity, as respiratory control parallels cardiovascular control, with a more and more muscle fibers must rely on anaerobic me- central command proportional to muscle activity directly tabolism. Almost fully dissociated, lactic acid causes stimulating the respiratory center and feedback modulation metabolic acidosis. During exercise, healthy lungs re- from the lung, respiratory muscles, chest wall mechanore- spond to lactic acidosis by further increasing ventilation, ceptors, and carotid body chemoreceptors. lowering the arterial PCO 2 , and maintaining arterial blood pH at normal levels; it is the response to acidosis that spurs the supralinear ventilation rise seen in strenu- The Respiratory System Is Largely ous exercise (see Fig. 30.4). Through a range of exercise Unchanged by Training levels, the pH effects of lactic acid are fully compensated by the respiratory system; however, eventually in the The effects of training on the pulmonary system are mini- hardest work—near-exhaustion—ventilatory compensa- mal. Lung diffusing capacity, lung mechanics, and even lung volumes change little, if at all, with training. The wide- tion becomes only partial, and both pH and arterial PCO 2 spread assumption that training improves vital capacity is may fall well below resting values (see Table 30.5). Tidal volume continues to increase until pulmonary stretch re- false; even exercise designed specifically to increase inspi- ceptors limit it, typically at or near half of vital capacity. ratory muscle strength elevates vital capacity by only 3%. Frequency increases at high tidal volume produce the re- The demands placed on respiratory muscles increase their mainder of the ventilatory volume increases. endurance, an adaptation that may reduce the sensation of Hyperventilation relative to carbon dioxide produc- dyspnea in exercise. Nonetheless, the primary respiratory tion in heavy exercise helps maintain arterial oxygena- changes with training are secondary to lower lactate pro- tion. The blood returned to the lungs during exercise is duction that reduces ventilatory demands at previously more thoroughly depleted of oxygen because active mus- heavy absolute work levels. cles with high oxygen extraction receive most of the car- diac output. Because the pulmonary arterial PO 2 is re- In Lung Disease, Respiratory Limitations May Be duced in exercise, blood shunted past ventilated areas can Evidenced by Shortness of Breath or Decreased profoundly depress systemic arterial oxygen content. Oxygen Content of Arterial Blood Other than having a diminished oxygen content, pul- monary arterial blood flow (cardiac output) rises during Any compromise of lung or chest wall function is much exercise. In compensation, ventilation rises faster than more apparent during exercise than at rest. One hallmark of cardiac output: The ventilation-perfusion ratio of the lung disease is dyspnea (difficult or labored breathing) dur- lung rises from near 1 at rest to greater than 4 with stren- ing exertion, when this exertion previously was unprob- uous exercise (see Table 30.5). Healthy people maintain lematic. Restrictive lung diseases limit tidal volume, reduc- nearly constant arterial PO 2 with acute exercise, although ing the ventilatory reserve volumes and exercise capacity. the alveolar-to-arterial PO 2 gradient does rise. This in- Obstructive lung diseases increase the work of breathing, crease shows that, despite the increase in the ventilation- exaggerating dyspnea and limiting work output. Lung dis- perfusion ratio, areas of relative pulmonary underventila- eases that compromise oxygen diffusion from alveolus to tion and, possibly, some mild diffusion limitation exist blood exaggerate exercise-induced widening of the alveo- even in highly trained, healthy individuals. lar-to-arterial PO 2 gradient. This effect contributes to po- TABLE 30.5 Acute Respiratory Response to Graded Dynamic Exercise in a 30-Year-Old Untrained Woman Ventilation Ventilation- Alveolar PO 2 Arterial PO 2 Arterial PCO 2 Arterial pH Exercise Intensity (L/min) Perfusion Ratio (mm Hg) (mm Hg) (mm Hg) Rest 5 1 103 100 40 7.40 Walking 20 2 103 100 40 7.40 Jogging 45 3 106 100 36 7.40 Running fast 75 4 110 100 25 7.32

558 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY CLINICAL FOCUS BOX 30.2 Exercise in Patients with Emphysema factors unrelated to cardiovascular limitations. Second, Normally, the respiratory system does not limit exercise their primary complaint is usually shortness of breath, or tolerance. In healthy individuals, arterial blood satura- dyspnea. In fact, patients with chronic obstructive pul- tion with oxygen, which averages 98% at rest, is main- monary disease often first seek medical evaluation be- tained at or near 98% in even the most strenuous dy- cause of dyspnea experienced during such routine activi- namic or isometric exercise. The healthy response ties as climbing a flight of stairs. In healthy people, includes the ability to augment ventilation more than car- exhaustion is rarely associated solely with dyspnea. In em- diac output; the resulting rise in the ventilation-perfusion physematous patients, exercise-induced dyspnea results, ratio counterbalances the falling oxygen content of in part, from respiratory muscle fatigue exacerbated by di- mixed venous blood. aphragmatic flattening brought on by loss of lung elastic In patients with emphysema, ventilatory limitations to recoil. Third, in emphysematous patients, arterial oxygen exercise occur long before ceilings are imposed by either saturation will characteristically fall steeply and progres- skeletal muscle oxidative capacity or by the ability of the sively with increasing exercise, sometimes reaching dan- cardiovascular system to deliver oxygen to exercising gerously low levels. In emphysema, the inability to fully muscle. These limitations are manifest during a stress test oxygenate blood at rest is compounded during exercise by on the basis of three primary measurements. First, patients increased pulmonary blood flow, and by increased exer- with ventilatory limitations typically cease exercise at rela- cise oxygen extraction that more fully desaturates blood tively low heart rate, indicating that exhaustion is due to returning to the lungs. tentially dangerous systemic arterial hypoxia during exer- Muscle Fatigue Is Independent of Lactic Acid cise. The signs and symptoms of a respiratory limitation to Although strenuous exercise can reduce intramuscular pH exercise include exercise cessation with low maximal heart to values as low as 6.8 (arterial blood pH may fall to 7.2), rate, oxygen desaturation of arterial blood, and severe there is little evidence that elevations in hydrogen ion con- shortness of breath (Clinical Focus Box 30.2). The centration are the sole cause of fatigue. The best correlate prospects of training-based rehabilitation are modest, al- of fatigue in healthy individuals is ADP accumulation in the though locomotor muscle-based adaptations can reduce face of normal or slightly reduced ATP, such that the lactate production and ventilatory demands in exercise. ADP/ATP ratio is very high. Because the complete oxida- Specific training of respiratory muscles to increase their tion of glucose, glycogen, or free fatty acids to carbon diox- strength and endurance is of minimal benefit to patients ide and water is the major source of energy in prolonged with compromised lung function. work, people with defects in glycolysis or electron trans- Exercise causes bronchoconstriction in nearly every port exhibit a reduced ability to sustain exercise. asthmatic patient and is the sole provocative agent for These metabolic defects are distinct from another group asthma in many people. In healthy individuals, cate- of disorders exemplified by the various muscular dystro- cholamine release from the adrenal medulla and sympa- phies. In these illnesses, the loss of active muscle mass as a thetic nerves dilates the airways during exercise. Sympa- result of fat infiltration, cellular necrosis, or atrophy re- thetic bronchodilation in people with asthma is duces exercise tolerance despite normal capacities (in outweighed by constrictor influences, among them heat healthy fibers) for ATP production. It is unclear whether fa- loss from airways (cold, dry air is a potent bronchocon- tigue in health ever occurs centrally (pain from fatigued strictor), release of inflammatory mediators, and increases muscle may feed back to the brain to lower motivation and, in airway tissue osmolality. Leukotriene-receptor antago- possibly, to reduce motor cortical output) or at the level of nists block exercise-induced symptoms in most people. The the motor neuron or the neuromuscular junction. effects of exercise on airways are due to increased ventila- tion per se; the exercise is incidental. Individuals with exer- cise-induced bronchoconstriction are simply the most sen- Endurance Activity Enhances Muscle sitive people along a continuum; for example, breathing Oxidative Capacity high volumes of cold, dry air provokes at least mild bron- chospasm in everyone. Within skeletal muscle, adaptations to training are specific to the form of muscle contraction. Increased activity with low loads results in increased oxidative metabolic capacity without hypertrophy; increased activity with high loads MUSCLE AND BONE RESPONSES produces muscle hypertrophy. Increased activity without Events within exercising skeletal muscle are a primary fac- overload increases capillary and mitochondrial density, tor in fatigue. These same events, when repeated during myoglobin concentration, and virtually the entire enzy- training, lead to adaptations that increase exercise capacity matic machinery for energy production from oxygen and retard fatigue during similar work. Skeletal muscle con- (Table 30.6). Coordination of energy-producing and en- traction also increases stresses placed on bone, leading to ergy-utilizing systems in muscle ensures that even after at- specific bone adaptations. rophy the remaining contractile proteins are adequately

CHAPTER 30 Exercise Physiology 559 TABLE 30.6 Effects of Training and Immobilization on the Human Biceps Brachii Muscle in a 22-Year-Old Woman After After 4 Months After Strength Training Immobilization Sedentary Endurance Training Total number of cells 300,000 300,000 300,000 300,000 2 Total cross-sectional area (cm )1010136 Isometric strength (% control) 100 100 200 60 Fast-twitch fibers (% by number) 50 50 50 50 2 2 Fast-twitch fibers, average area (m  10 )67 67 87 40 Capillaries/fiber 0.8 1.3 0.8 0.6 Succinate dehydrogenase activity/unit area 100 150 77 100 (% control) Modified from Gollnick PD, Saltin B. Skeletal muscle physiology. In: Teitz CC, ed. Scientific Foundations of Sports Medicine. Toronto: BC Decker, 1989;185–242. supported metabolically. In fact, the easy fatigability of at- companied by an acute phase reaction that includes com- rophied muscle is due to the requirement that more motor plement activation, increases in circulating cytokines, neu- units be recruited for identical external force; the fatigabil- trophil mobilization, and increased monocyte cell adhesion ity per unit cross-sectional area is normal. The magnitude capacity. Training adaptation to the eccentric components of the skeletal muscle endurance training response is lim- of exercise is efficient; soreness after a second episode is ited by factors outside the muscle, since cross-innervation minimal if it occurs within two weeks of a first episode. or chronic stimulation of muscles in animals can produce Eccentric contraction-induced muscle damage and its adaptations 5 times larger than those created by the most subsequent response may be the essential stimulus for mus- intense and prolonged exercise. cle hypertrophy. While standard resistance exercise in- Local adaptations of skeletal muscle to endurance activ- volves a mixture of contraction types, careful studies show ity reduce reliance on carbohydrate as a fuel and allow that when one limb works purely concentrically and the more metabolism of fat, prolonging endurance and de- other purely eccentrically at equivalent force, only the ec- creasing lactic acid accumulation. Decreased circulating centric limb hypertrophies. The immediate changes in lactate, in turn, reduces the ventilatory demands of heavier actin and myosin production that lead to hypertrophy are work. Because metabolites accumulate less rapidly inside mediated at the posttranslational level; after a week of load- trained muscle, there is reduced chemosensory feedback to ing, mRNA for these proteins is altered. Although its pre- the central nervous system at any absolute workload. This cise role remains unclear, the activity of the 70-kDa S6 pro- reduces sympathetic outflow to the heart and blood vessels, tein kinase is tightly linked with long-term changes in reducing cardiac oxygen demands at a fixed exercise level. muscle mass. The cellular mechanisms for hypertrophy in- clude the induction of insulin-like growth factor I, and up- regulation of several members of the fibroblast growth fac- Muscle Hypertrophies in Response to tor family. Eccentric Contractions Everyone knows it is easier to walk downhill than uphill, but Exercise Plays a Role in Calcium Homeostasis the mechanisms underlying this commonplace phenome- non are complex. Muscle forces are identical in the two sit- Skeletal muscle contraction applies force to bone. Because uations. However, moving the body uphill against gravity the architecture of bone remodeling involves osteoblast involves muscle shortening, or concentric contractions. In and osteoclast activation in response to loading and un- contrast, walking downhill primarily involves muscle ten- loading, physical activity is a major site-specific influence sion development that resists muscle lengthening, or eccen- on bone mineral density and geometry. Repetitive physical tric contractions. All routine forms of physical activity, in activity can create excessive strain, leading to inefficiency fact, involve combinations of concentric, eccentric, and iso- in bone remodeling and stress fracture; however, extreme metric contractions. Because less ATP is required for force inactivity allows osteoclast dominance and bone loss. development during a contraction when external forces The forces applied to bone during exercise are related lengthen the muscle, the number of active motor units is re- both to the weight borne by the bone during activity and duced and energy demands are less for eccentric work. to the strength of the involved muscles. Consequently, However, perhaps because the force per active motor unit is bone strength and density appear to be closely related to greater in eccentric exercise, eccentric contractions can applied gravitational forces and to muscle strength. This readily cause muscle damage. These include weakness (ap- suggests that exercise programs to prevent or treat osteo- parent the first day), soreness and edema (delayed 1 to 3 porosis should emphasize weight-bearing activities and days in peak magnitude), and elevated plasma levels of in- strength as well as endurance training. Adequate dietary tramuscular enzymes (delayed 2 to 6 days). Histological ev- calcium is essential for any exercise effect: weight-bearing idence of damage may persist for 2 weeks. Damage is ac- activity enhances spinal bone mineral density in post-

560 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY Exercise Can Modify the Rate of Gastric Cyclic Emptying and Intestinal Absorption runners Dynamic exercise must be strenuous (demanding more Spine bone mineral density (mg/mL) 160 Controls monal, or intrinsic smooth muscle basis for this effect. Al- 180 than 70% of the maximal oxygen uptake) to slow gastric emptying of liquids. Little is known of the neural, hor- though gastric acid secretion is unchanged by acute exer- cise of any intensity, nothing is known about the effects of exercise on other factors relevant to the development or healing of peptic ulcers. There is some evidence that stren- uous postprandial dynamic exercise provokes gastroe- sophageal reflux by altering esophageal motility. Amenorrheic runners Chronic physical activity accelerates gastric emptying rates and small intestinal transit. These adaptive responses to chronically increased energy expenditure lead to more rapid processing of food and increased appetite. Animal 140 models of hyperphagia show specific adaptations in the small bowel (increased mucosal surface area, height of mi- Exercise and bone density. This graph shows crovilli, content of brush border enzymes and transporters) FIGURE 30.5 spine bone density in young adult women who that lead to more rapid digestion and absorption; these are nonathletes (controls), distance runners with regular men- same effects likely take place in humans rendered hyper- strual cycles (cyclic runners), and distance runners with amenor- phagic by regular physical activity. rhea (amenorrheic runners). Differences from controls indicate Blood flow to the gut decreases in proportion to exercise the roles that exercise and estrogen play in determination of bone intensity, as sympathetic vasoconstrictor tone rises. Water, mineral density. electrolyte, and glucose absorption may be slowed in paral- lel, and acute diarrhea is common in endurance athletes dur- menopausal women only when calcium intakes exceed 1 ing competition. However, these effects are transient, and g/day. Because exercise may also improve gait, balance, malabsorption as a consequence of acute or chronic exercise coordination, proprioception, and reaction time, even in does not occur in healthy people. While exercise may not older and frail persons, the risk of falls and osteoporosis improve symptoms or disease progression in inflammatory are reduced by chronic activity. In fact, the incidence of bowel disease, there is some evidence that repetitive dy- hip fracture is reduced nearly 50% when older adults are namic exercise may reduce the risk for this illness. involved in regular physical activity. However, even when Although exercise is often recommended as treatment for activity is optimal, it is apparent that genetic contribu- tions to bone mass are greater than exercise. Perhaps 75% postsurgical ileus, uncomplicated constipation, or irritable of the population variance is genetic, and 25% is due to bowel syndrome, little is known in these areas. However, different levels of activity. In addition, the predominant chronic dynamic exercise does substantially decrease the contribution of estrogen to homeostasis of bone in young risk for colon cancer, possibly via increases in food and fiber women is apparent when amenorrhea occurs secondary to intake, with consequent acceleration of colonic transit. chronic heavy exercise. These exceptionally active women are typically very thin and exhibit low levels of Chronic Exercise Increases Appetite Slightly circulating estrogens, low trabecular bone mass, and a Less Than Caloric Expenditure in Obese People high fracture risk (Fig. 30.5). Exercise also plays a role in the treatment of os- Obesity is common in sedentary societies. Obesity in- teoarthritis. Controlled clinical trials find that appropriate, creases the risk for hypertension, heart disease, and dia- regular exercise decreases joint pain and degree of disabil- betes and is characterized, at a descriptive level, as an ex- ity, although it fails to influence the requirement for anti- cess of caloric intake over energy expenditure. Because inflammatory drug treatment. In rheumatoid arthritis, ex- exercise enhances energy expenditure, increasing physical ercise also increases muscle strength and functional activity is a mainstay of treatment for obesity. capacity without increasing pain or medication require- The metabolic cost of exercise averages 100 kcal/mile ments. Whether or not exercise alters disease progression walked. For exceptionally active people, exercise expendi- in either rheumatoid arthritis or osteoarthritis is not known. ture can exceed 3,000 kcal/day added to the basal energy expenditure, which for a 55-kg woman averages about 1,400 kcal/day. At high levels of activity, appetite and food GASTROINTESTINAL, METABOLIC, intake match caloric expenditure (Fig. 30.6). The biologi- AND ENDOCRINE RESPONSES cal factors that allow this precise balance have never been defined. In obese people, modest increases in physical ac- The effects of exercise on gastrointestinal (GI) function re- tivity increase energy expenditure more than food intake, main poorly understood. However, chronic physical activ- so progressive weight loss can be instituted if exercise can ity plays a major role in the control of obesity and type 2 be regularized (see Fig. 30.6). This method of weight con- diabetes mellitus. trol is superior to dieting alone, since substantial caloric re-

CHAPTER 30 Exercise Physiology 561 3,000 Obese (during idation (thereby sparing carbohydrate stores), and oral carbo- weight gain) hydrate intake during exercise. Frank hypoglycemia rarely oc- curs in healthy people during even the most prolonged or in- Lean tense physical activity. When it does, it is usually in association with the depletion of muscle and hepatic stores and a failure to supplement carbohydrate orally. Caloric intake (kcal/day) 2,000 Obese (initially pathetic tone at the pancreatic islets. Despite acutely 2,500 Exercise suppresses insulin secretion by increasing sym- falling levels of circulating insulin, both non-insulin-de- stable weight) pendent and insulin-dependent muscle glucose uptake in- crease during exercise. Exercise recruits glucose trans- porters from their intracellular storage sites to the plasma membrane of active skeletal muscle cells. Because exercise increases insulin sensitivity, patients with type 1 diabetes (insulin-dependent) require less insulin when activity in- creases. However, this positive result can be treacherous 1,500 because exercise can accelerate hypoglycemia and increase the risk of insulin coma in these individuals. Chronic exer- 1,500 2,000 2,500 3,000 cise, through its reduction of insulin requirements, up-reg- Caloric expenditure (kcal/day) ulates insulin receptors. This effect appears to be due less to training than simply to a repeated acute stimulus; the effect Caloric intake as a function of exercise-in- FIGURE 30.6 is full-blown after 2 to 3 days of regular physical activity duced increases in daily caloric expendi- ture. For lean individuals, intake matches expenditure over a wide and can be lost as quickly. Consequently, healthy active range. For obese individuals during periods of weight gain or peri- people show strikingly greater insulin sensitivity than do ods of stable weight, increases in expenditure are not matched by their sedentary counterparts (Fig. 30.7). In addition, up- increases in caloric intake. (Modified from Pi-Sunyer FX. Exercise effects on calorie intake. Annals NY Acad Sci 1987;499:94–103.) Sedentary striction (500 kcal/day) results in both a lowered BMR 150 and a substantial loss of fat-free body mass. Exercise has other, subtler, positive effects on the energy balance equation as well. A single exercise episode may in- 100 crease basal energy expenditure for several hours and may Blood glucose (mg/dL) increase the thermal effect of feeding. The greatest practi- cal problem remains compliance with even the most precise exercise “prescription”; patient dropout rates from even 50 100 g glucose After repeated daily exercise short-term programs typically exceed 50%. ingestion Acute and Chronic Exercise Increases Insulin 0 30 60 90 120 Sensitivity, Insulin Receptor Density, and Time (min) Glucose Transport into Muscle 100 g glucose Though skeletal muscle is omnivorous, its work intensity and ingestion duration, training status, inherent metabolic capacities, and 175 Sedentary substrate availability determine its energy sources. For very short-term exercise, stored phosphagens (ATP and creatine 140 phosphate) are sufficient for crossbridge interaction between actin and myosin; even maximal efforts lasting 5 to 10 seconds 105 require little or no glycolytic or oxidative energy production. Plasma insulin (µU/mL) When work to exhaustion is paced to be somewhat longer in duration, glycolysis is driven (particularly in fast glycolytic 70 After repeated fibers) by high intramuscular ADP concentrations, and this daily exercise form of anaerobic metabolism, with its by-product lactic acid, 35 is the major energy source. The carbohydrate provided to gly- colysis comes from stored, intramuscular glycogen or blood- borne glucose. Exhaustion from work in this intensity range 0 30 60 90 120 (50 to 90% of the maximal oxygen uptake) is associated with Time (min) carbohydrate depletion. Accordingly, factors that increase Repeated daily exercise and the blood glu- carbohydrate availability improve fatigue resistance. These in- FIGURE 30.7 cose and insulin response to glucose inges- clude prior high dietary carbohydrate, cellular training adap- tion. Both responses are blunted by repeated exercise, demon- tations that increase the enzymatic potential for fatty acid ox- strating increased insulin sensitivity.

562 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY 5 4 Endurance-trained by 1 to 2 years. These facts leave open the possibility that Maximal oxygen uptake (L/min) 3 2 Sedentary creases antioxidant capacity. Food-restricted rats experi- exercise might alter biological aging. While physical activ- ity increases cellular oxidative stress, it simultaneously in- ence increased life span, and exhibit elevated spontaneous activity levels, but the role exercise may play in the appar- ent delay of aging in these animals remains unclear. Circulating Immune System Markers, but the Long-Term Effects of Training on 0 1 Acute Exercise Transiently Alters Many 10 20 30 40 50 60 70 Immune Function Are Unclear Age (yr) In protein-calorie malnutrition, the catabolism of protein Maximal oxygen uptake, endurance train- FIGURE 30.8 for energy lowers immunoglobulin levels and compromises ing, and age. Endurance-trained subjects pos- the body’s resistance to infection. Clearly, in this circum- sess greater maximal oxygen uptake than sedentary subjects, re- stance, exercise merely speeds the starvation process by in- gardless of age. creasing daily caloric expenditure and would be expected to diminish the immune response further. Nazi labor camps regulation of insulin receptors and reduced insulin release of the early 1940s became death camps, partly, by severe after chronic exercise is ideal therapy in type 2 diabetes food restrictions and incessant demands for physical (non–insulin-dependent), a disease characterized by high work—a combination guaranteed to cause starvation. insulin secretion and low receptor sensitivity. In persons If nutrition is adequate, it is less clear whether adopting with type 2 diabetes, a single episode of exercise results in an active versus a sedentary lifestyle alters immune respon- substantial glucose transporter translocation to the plasma sivity. In healthy people, an acute episode of exercise membrane in skeletal muscle. briefly increases blood leukocyte concentration and tran- siently enhances neutrophil production of microbicidal re- active oxygen species and natural killer cell activity. How- AGING, IMMUNE, AND ever, it remains unproven that regular exercise over time PSYCHIATRIC RESPONSES can lower the frequency or reduce the intensity of, for ex- ample, upper respiratory tract infections. In HIV-positive Maximal dynamic and isometric exercise capacities are men and in men with AIDS and advanced muscle wasting, lower at age 70 than at age 20. There is overwhelming evi- strength and endurance training yield normal gains. There dence, however, that declines in strength and endurance is also incomplete evidence that training may slow progres- with advancing age can be substantially mitigated by train- sion to AIDS in HIV-positive men, with a corresponding ing. Changes in functional capacity, as well as protection increase in CD4 lymphocytes. against heart disease and diabetes, do increase longevity in active persons. However, it remains controversial if chronic exercise enhances lifespan, or if exercise boosts the immune Exercise May Help Relieve Depression, but Its system, prevents insomnia, or enhances mood. Efficacy and Neurochemical Effects Are Uncertain In healthy people, prolonged exercise increases subse- As People Age, the Effects of Exercise quent deep sleep, defined as stages 3 and 4 of slow-wave on Functional Capacity Are More Profound sleep (see Chapter 7). This effect is apparently mediated Than Their Effect on Longevity entirely through the thermal effects of exercise, since equivalent passive heating produces the same result. The influence of exercise on strength and endurance at any Whether or not exercise can improve sleep in patients age is dramatic. Although the ceiling for oxygen uptake with insomnia is not known. during work gradually falls with age, the ability to train to- Clinical depression is characterized by sleep and ap- ward an age-appropriate ceiling is as intact at age 70 as it is petite dysfunction and profound changes in mood. at age 20 (Fig. 30.8). In fact, a highly active 70-year-old, Whether acute or chronic exercise can help relieve depres- otherwise healthy, will typically display an absolute exer- sion remains unproven. The two most prominent biological cise capacity greater than a sedentary 20-year-old. Aging theories of depression—the dysregulation of central affects all the links in the chain of oxygen transport and use, monoamine activity and dysfunction of the hypothalamic- so aging-induced declines in lung elasticity, lung diffusing pituitary-adrenal axis—have received almost no study with capacity, cardiac output, and muscle metabolic potential regard to the impact of exercise. take place in concert. Consequently, the physiological Panic disorder patients, often characterized by agora- mechanisms underlying fatigue are similar at all ages. phobia, have reduced exercise capacity. Although sodium Regular dynamic exercise, compared with inactivity, in- lactate infusion does provoke panic in these patients, the creases longevity in rats and humans. In descriptive terms, anxiety mediator appears to be hypernatremia, not lactate; the effects of exercise are modest; all-cause mortality is re- even strenuous exercise with substantial lactic acidosis will duced, but only in amounts sufficient to increase longevity not trigger panic attacks in these individuals.

CHAPTER 30 Exercise Physiology 563 REVIEW QUESTIONS DIRECTIONS: Each of the numbered (E) Will be balanced by local dilation (D) Reduce risk of myocardial items or incomplete statements in this in these vascular beds infarction despite elevated total section is followed by answers or by 5. A young, healthy, highly trained cholesterol levels completions of the statement. Select the individual enters a marathon (40 km) (E) Elevate HDL and lower LDL ONE lettered answer or completion that is run on a warm, humid day (32C, 70% 9. A healthy individual, aged 60, BEST in each case. humidity). The best medical advice for completes a 500 m freestyle swim this individual is to be concerned about at an age-group competition. 1. In an effort to strengthen selected the possibility for Breathing hard after the race, she muscles after surgery and (A) Heat exhaustion explains that her increased immobilization has led to muscle (B) Coronary ischemia ventilation is a normal response to atrophy, isometric exercise is (C) Renal ischemia and anoxia heavy, dynamic exercise. Her recommended. The intensity of (D) Hypertension increased ventilation results in isometric exercise is best quantified (E) Gastric mucosal ischemia and (A) Clinically significant systemic (A) Relative to the maximal oxygen increased risk for gastric ulceration arterial hypoxemia uptake 6. An individual with hypertension has (B) Normal or reduced arterial PCO 2 (B) As mild, moderate, or strenuous been advised to increase physical (C) Respiratory alkalosis (C) As percentage of the maximum activity. At the same time, this person (D) Respiratory acidosis voluntary contraction has been counseled to avoid activities (E) Dizziness and decreased cerebral (D) In terms of anaerobic metabolism that substantially increase the systemic blood flow (E) On the basis of the total muscle arterial blood pressure. In terms of 10.A 33-year-old woman embarks on an mass involved dynamic exercise, this individual extensive program of daily exercise, 2. Two people, one highly trained and should avoid exercise that with both strenuous dynamic and one not, each exercising at 75% of the (A) Causes fatigue isometric exercise included. After two maximal oxygen uptake, become (B) Is prolonged years, her maximal voluntary fatigued (C) Uses untrained muscle groups contraction of many major muscle (A) For similar physiological reasons (D) Is substituted for isometric exercise groups and her maximal oxygen (B) Very slowly (E) Involves an intermediate muscle mass uptake, are both increased 30%. (C) At different times 7. In a patient with heart disease, a Predictably, pulmonary function tests (D) While performing equally well for treadmill test involving graded show at least a short period of time dynamic exercise results in falling (A) A 30% rise in vital capacity (E) Despite much higher circulating blood pressure at each exercise level. (B) No effect on lung elasticity, lactic acid levels in the trained person Eventually, faintness and dizziness inspiratory or expiratory flow rates, or 3. A patient completes a graded, dynamic cause termination of the test. These vital capacity exercise test on a treadmill while results arise from inadequate cardiac (C) An increase in resting pulmonary showing a modest rise (25%) in mean output during exercise because the diffusing capacity of 30 to 50% arterial blood pressure. In contrast, baroreceptors, during exercise, (D) A 25% increase in maximal forced during the highest level of exercise at (A) Reset blood pressure to a lower expiratory flow rate the end of the test, an indirect method level (E) Decreases in residual volume and shows that cardiac output has risen (B) Are “turned off” airways resistance at rest 300% from rest. These results indicate (C) Are increased in sensitivity by 11.In older adults at risk for falls, that during graded, dynamic exercise training osteoporosis, and fractures, a program to exhaustion, systemic vascular (D) Are decreased in sensitivity by of weight-bearing exercise resistance training (A) Increases the risk of hip fracture (A) Is constant (E) Reset blood pressure to a higher (B) Decreases bone mineral density (B) Rises slightly level (C) Leaves gait, coordination, (C) Falls only if work is prolonged 8. A man with a family history of heart proprioception, and reaction time (D) Falls dramatically disease has both diabetes and unaltered (E) Cannot be measured hypertension. His total serum (D) Reduces the risk of osteoporosis, 4. A patient with inflammatory bowel cholesterol is 270 mg/dL. In addition, falls, and fractures disease and compromised kidney his LDL cholesterol is elevated and his (E) Is less valuable than dynamic function asks if exercise will alter blood HDL cholesterol is reduced, compared exercise during water immersion flow to either the gastrointestinal tract with individuals with low 12.A 57-year-old woman, told that she is or to the kidneys. The answer is that cardiovascular disease risk. When at risk for osteoporosis, starts an vasoconstriction in both the renal and exercise and diet are recommended, exercise class that emphasizes weight- splanchnic vascular beds during this individual asks what effect a long- bearing activities and development of exercise term exercise program will have on the muscle strength. She develops (A) Rarely occurs blood lipid profile. The answer is that extensive muscle soreness after the first (B) Occurs only after prolonged exercise, over time, will two sessions, indicating that the training (A) Have no independent effect on exercise that she performed (C) Helps maintain arterial blood blood cholesterol levels (A) Involved isometric contractions pressure (B) Elevate both HDL and LDL (B) Produced muscle ischemia (D) Allows renal and splanchnic flows (C) Lower HDL and LDL, thereby (C) Was actually most effective for to parallel cerebral blood flow lowering total cholesterol increasing muscle endurance (continued)

564 PART VIII TEMPERATURE REGULATION AND EXERCISE PHYSIOLOGY (D) Involved eccentric contractions His specific concern is the impact that ity, and disease. Physiol Rev (E) Required at least 50% of the an acute episode of exercise will have 2000;80:1215–1265. maximum voluntary contractile force on his blood glucose levels and insulin Booth FW, Gordon SE, Carlson CJ, et al. 13.A high-school football player injures a requirements. He is correctly informed Waging war on modern chronic dis- knee early in the season. The knee that during exercise, an important eases: Primary prevention through ex- requires immobilization for six weeks, factor to consider is that ercise biology. J Appl Physiol after which time the athlete undergoes (A) Muscle glucose uptake decreases in 2000;88:774–787. rehabilitation before joining the team. patients with either type 1 or type 2 Bray MS. Genomics, genes, and environ- Immediately after rehabilitation begins, diabetes mental interaction: the role of exercise. the individual notices that the flexors (B) The pancreas will release increased J Appl Physiol 2000;88:788–792. and extensors of the knee are much amounts of both insulin and glucagon Clapp JF 3rd. Exercise during pregnancy. weaker than before the injury because (C) Muscle glucose uptake will A clinical update. Clin Sports Med during contraction at a fixed force increase only if endogenous or 2000;19:273–286. (A) Fewer motor units are involved exogenous insulin levels rise Fairfield WP, Treat M, Rosenthal DI, et al. (B) There is a relative excess of (D) Muscle glucose transporters will be Effects of testosterone and exercise on contractile protein translocated to the plasma membrane, muscle leanness in eugonadal men with (C) Muscle cells are small, so more increasing insulin-dependent and AIDS wasting. J Appl Physiol cells are required to perform the same insulin-independent glucose uptake 2001;90:2166–2171. work (E) Insulin-independent glucose uptake Gielen S, Schuler G, Hambrecht R. Exer- (D) Oxidative energy-producing is reduced in active muscles cise training in coronary artery disease systems are up-regulated 16.A highly active woman is pregnant for and coronary vasomotion. Circulation (E) Eccentric work is less, while the first time. She asks what benefits 2001;103:E1–E6. concentric work is increased might ensue from continued physical Jones NL, Killian KJ. Exercise limitation in 14.A tenth-grade distance runner finishes activity during pregnancy. Which of health and disease. N Engl J Med in the top five of her statewide high the following is a predictable effect of 2000;343:632–641. school cross-country championships. chronic, dynamic exercise during Marcus R. Role of exercise in preventing Encouraged, she redoubles her training pregnancy? and treating osteoporosis. Rheum Dis intensity, only to find that her (A) Increased average gestational Clin North Am 2001;27:131–141. menstrual periods cease for nearly a length Pedersen BK, Hoffman-Goetz L. Exercise year. After finally visiting her doctor, (B) Increased fetal weight at term and the immune system: regulation, in- her serum estrogen levels are found to (C) Decreased risk of maternal tegration, and adaptation. Physiol Rev be well below normal. In addition, it is gestational diabetes 2000;80:1055–1081. predictable that this young woman will (D) Increased risk of spontaneous Peters HP, De Vries WR, Vanberge-Hene- be found to have abortion during the first trimester gouwen GP, et al. Potential benefits (A) Dynamic exercise endurance less (E) Decreased neonatal responsiveness and hazards of physical activity and ex- than an untrained person scores ercise on the gastrointestinal tract. Gut (B) Weak leg muscles 2001;48:435–439. (C) Normal body weight SUGGESTED READING Ryder JW, Chibalin AV, Zierath JR. In- (D) No risk for fractures as a result of Beck LH. Update in preventive medicine. tracellular mechanisms underlying in- her young age Ann Intern Med 2001;134:128–135. creases in glucose uptake in response (E) Low trabecular bone mass Berchtold MW, Brinkmeier H, Muntener to insulin or exercise in skeletal mus- 15.A man with recently diagnosed type 2 M. Calcium ion in skeletal muscle: Its cle. Acta Physiol Scand diabetes asks for advice about exercise. crucial role for muscle function, plastic- 2001;171:249–257. CASE STUDIES FOR PART VIII • • • CASE STUDY FOR CHAPTER 29 appears dazed, and his answers to questions are coherent but slow. He cannot produce a urine sample. Blood sam- Heat Exhaustion with Dehydration ples are drawn, and an intravenous drip is started. The lab- oratory report shows serum [Na ] of 156 mmol/L (normal A Michigan National Guard infantry unit was sent at the end of May to Louisiana for a field training exercise. Spring range,135 to 145 mmol/L). Two liters of normal saline in Michigan was cool, but during the exercise in Louisiana, (0.9% NaCl) are infused over 45 minutes. Well before the the temperature reached at least 30C (86F) every after- end of the infusion, the patient is alert, his nausea disap- noon. At 3:30 PM on the second day of the exercise, a 70-kg pears, and he asks for, and is given, water to drink. After infantryman became unsteady and, after a few more steps, the end of the infusion he is sent back to his unit with in- sat on the ground. He told his comrades that he was dizzy structions to consume salt with dinner, drink at least three and had a headache. When they urged him to drink from quarts of fluid before going to bed, and to return for fol- his canteen, he took a few swallows and said that he was low-up in the morning. sick in his stomach. Questions At the field aid station, he is observed to be sweating, 1. What is the likely basis of the patient’s nausea, which also his rectal temperature is 38.5C, and his pulse is rapid. He contributes to his inability to produce a urine specimen?

CHAPTER 30 Exercise Physiology 565 2. If we assume that the patient’s total body water was 36 L CASE STUDY FOR CHAPTER 30 when he came for treatment, it can be shown that giving the patient 3 L of water without salt (by mouth and/or as an in- A Patient With Dyspnea During Exercise travenous infusion of glucose in water) would reduce serum A 56-year-old man complained of shortness of breath and [Na ] to 144 mmol/L. Such treatment would improve the pa- chest pain when climbing stairs or mowing the lawn. He is tient’s condition considerably. How might the medical offi- subjected to a stress test, with noninvasive monitoring of cer argue the case for giving 2 L of normal saline? heart rate, blood pressure, arterial blood oxygen saturation, 3. What other (and relatively unusual) condition could produce and cardiac electrical activity. His resting heart rate is 73 the patient’s symptoms? Did the medical officer rule this beats/min; blood pressure, 118/75 mm Hg; arterial blood possibility out by appropriate means? oxygen saturation, 96%; and the ECG, normal (Fig. 30.A, 1). Answers to Case Study Questions for Chapter 29 After 3.5 minutes of increasingly intense exercise, the test is 1. The patient’s nausea is probably a result of constriction of terminated because of the subject’s severe dyspnea. His the splanchnic vascular beds, which is part of the homeo- heart rate is 119 beats/min (his age and sex-adjusted pre- static cardiovascular response that helps maintain cardiac dicted maximal heart rate is 168 beats/min), blood pressure output and blood pressure when central blood volume is re- is 146/76 mm Hg, arterial blood oxygen saturation is 88%, duced. Central blood volume, in turn, was reduced by the and the ECG is normal (Fig. 30.A, 2). loss of body water and pooling of blood in the peripheral Questions vascular beds. This homeostatic response also includes 1. What are three lines of evidence for ventilatory limitation to constriction of the renal vascular beds, which, in turn, con- this subject’s exercise? tributes (along with the release of vasopressin and activa- 2. Why did arterial blood oxygen saturation fall during exer- tion of the renin-angiotensin system) to scanty urine pro- cise? duction. 3. Why did exhaustion occur before maximal heart rate was 2. Because the weather was cool back home, the patient prob- reached? ably was probably not acclimatized to heat and was not 4. Why did the pulse pressure rise in exercise? conserving salt in his sweat. He was probably secreting 5. Why would endurance exercise training likely increase this large amounts of sweat, and losing correspondingly large individual’s exercise capacity? amounts of salt because of the weather and the activity in- Answers to Case Study Questions for Chapter 30 volved in the exercise. If the patient returns to training the 1. Ventilatory limitation is evidenced by severe dyspnea as a next morning without correcting the salt deficit, he is likely primary symptom in exercise, falling arterial blood oxy- to have further difficulties in the heat. Even if the medical genation, and exercise termination at relatively low heart officer has guessed incorrectly about the patient’s salt bal- rate. ance, a patient with normal renal function and adequate 2. Arterial blood oxygen saturation fell during exercise be- fluid intake should be able to excrete any excess salt result- cause increased cardiac output (increased pulmonary blood ing from the treatment. flow) and decreased pulmonary arterial blood oxygen con- 3. Hyponatremia can produce symptoms similar to the pa- tent (a result of increased skeletal muscle oxygen extrac- tient’s symptoms. However, the medical officer was able to tion) increase demands for oxygenation in lungs with inade- exclude hyponatremia (although not necessarily some de- quate diffusing capacity. gree of salt deficit) on the basis of elevated serum [Na ]. 3. Exhaustion occurred before a maximal heart rate was Giving a hyponatremic patient large volumes of fluid with- reached because lung disease creates severe dyspnea even in mild exercise. out an equivalent of salt (which would have been a reason- 4. The pulse pressure rose during exercise because sympa- able alternative treatment for the patient in this example) would worsen the hyponatremia, perhaps to a dangerous thetic stimulation and enhanced venous return increase the stroke volume at constant arterial compliance. degree. 5. Endurance exercise training would have little effect on any Reference aspect of lung function. However, training would cause Knochel JP. Clinical complications of body fluid and elec- adaptations within exercising muscle that would increase trolyte balance. In: Buskirk ER, Puhl SM, eds. Body Fluid Bal- muscle oxidative capacity and reduce lactic acid production. ance: Exercise and Sport. Boca Raton, FL: CRC Press, By reducing the ventilatory demands of exercise, these 1996;297–317. changes would increase exercise capacity in this individual.

PART IX Endocrine Physiology CHAPTER Endocrine Control 31 31 Mechanisms Daniel E. Peavy, Ph.D. CHAPTER OUTLINE ■ GENERAL CONCEPTS OF ENDOCRINE CONTROL ■ MECHANISMS OF HORMONE ACTION ■ THE NATURE OF HORMONES KEY CONCEPTS 1. Hormones are chemical substances, involved in cell-to-cell transported in the bloodstream bound to carrier proteins, communication, that promote the maintenance of home- whereas most peptide and protein hormones are soluble in ostasis. the plasma and are carried free in solution. 2. There are six classes of steroid hormones, based on their 5. RIA and ELISA have provided major advancements in the primary actions. field of endocrinology, but each type of assay has limita- 3. Most polypeptide hormones are initially synthesized as tions. preprohormones. 6. Altered hormone-receptor interactions may lead to en- 4. Steroid hormones and thyroid hormones are generally docrine abnormalities. ndocrinology is the branch of physiology concerned GENERAL CONCEPTS OF ENDOCRINE CONTROL Ewith the description and characterization of processes involved in the regulation and integration of cells and or- Hormones are bloodborne substances involved in regulat- gan systems by a group of specialized chemical substances ing a variety of processes. The word “hormone” is derived called hormones. The diagnosis and treatment of a large from the Greek hormaein, which means to “excite” or to “stir number of endocrine disorders is an important aspect of up.” The endocrine system forms an important communica- any general medical practice. Certain endocrine disease tion system that serves to regulate, integrate, and coordi- states, such as diabetes mellitus, thyroid disorders, and re- nate a variety of different physiological processes. The productive disorders, are fairly common in the general pop- processes that hormones regulate fall into four areas: (1) the ulation; therefore, it is likely that they will be encountered digestion, utilization, and storage of nutrients; (2) growth repeatedly in the practice of medicine. and development; (3) ion and water balance; and (4) repro- In addition, because hormones either directly or indi- ductive function. rectly affect virtually every cell or tissue in the body, a num- ber of other prominent diseases not primarily classified as Hormones Regulate and endocrine diseases may have an important endocrine com- Coordinate Many Functions ponent. Atherosclerosis, certain forms of cancer, and even certain psychiatric disorders are examples of conditions in It is difficult to describe hormones in absolute terms. As a which an endocrine disturbance may contribute to the pro- working definition, however, it can be said that hormones gression or severity of disease. serve as regulators and coordinators of various biological 567

568 PART IX ENDOCRINE PHYSIOLOGY functions in the animals in which they are produced. They Feedback Regulation Is an Important are highly potent, specialized, organic molecules produced Part of Endocrine Function by endocrine cells in response to specific stimuli and exert their actions on specific target cells. These target cells are The endocrine system, like many other physiological sys- equipped with receptors that bind hormones with high tems, is regulated by feedback mechanisms. The mecha- affinity and specificity; when bound, they initiate charac- nism is usually negative feedback, although a few positive teristic biological responses by the target cells. feedback mechanisms are known. Both types of feedback In the past, definitions or descriptions of hormones usu- control occur because the endocrine cell, in addition to ally included a phrase indicating that these substances were synthesizing and secreting its own hormone product, has secreted into the bloodstream and carried by the blood to the ability to sense the biological consequences of secre- a distant target tissue. Although many hormones travel by tion of that hormone. This enables the endocrine cell to ad- this mechanism, we now realize that there are many hor- just its rate of hormone secretion to produce the desired mones or hormone-like substances that play important level of effect, ensuring the maintenance of homeostasis. roles in cell-to-cell communication that are not secreted di- Hormone secretion may be regulated via simple first-or- rectly into the bloodstream. Instead, these substances reach der feedback loops or more complex multilevel second- or their target cells by diffusion through the interstitial fluid. third-order feedback loops. Since negative feedback is Recall the discussion of autocrine and paracrine mecha- most prevalent in the endocrine system, only examples of nisms in Chapter 1. this type are illustrated here. Simple Feedback Loops. First-order feedback regulation Hormone Receptors Determine Whether a is the simplest type and forms the basis for more complex Cell Will Respond to a Hormone modes of regulation. Figure 31.1A illustrates a simple first- order feedback loop. In this example, an endocrine cell se- In the endocrine system, a hormone molecule secreted into the blood is free to circulate and contact almost any cretes a hormone that produces a specific biological effect cell in the body. However, only target cells, those cells in its target tissue. It also senses the magnitude of the effect that possess specific receptors for the hormone, will re- produced by the hormone. As the biological response in- spond to that hormone. A hormone receptor is the mo- creases, the amount of hormone secreted by the endocrine lecular entity (usually a protein or glycoprotein) either cell is appropriately decreased. outside or within a cell that recognizes and binds a par- ticular hormone. When a hormone binds to its receptor, Complex Feedback Loops. More commonly, feedback biological effects characteristic of that hormone are initi- regulation in the endocrine system is complex, involving ated. Therefore, in the endocrine system, the basis for second- or third-order feedback loops. For example, multi- specificity in cell-to-cell communication rests at the level ple levels of feedback regulation may be involved in regu- of the receptor. Similar concepts apply to autocrine and lating hormone production by various endocrine glands un- paracrine mechanisms of communication. der the control of the anterior pituitary (Fig. 31.1B). The A certain degree of specificity is ensured by the re- regulation of target gland hormone secretion, such as adre- stricted distribution of some hormones. For example, sev- nal steroids or thyroid hormones, begins with production eral hormones produced by the hypothalamus regulate of a releasing hormone by the hypothalamus. The releasing hormone secretion by the anterior pituitary. These hor- hormone stimulates production of a trophic hormone by mones are carried via small blood vessels directly from the the anterior pituitary, which, in turn, stimulates the pro- hypothalamus to the anterior pituitary, prior to entering duction of the target gland hormone by the target gland. As the general systemic circulation. The anterior pituitary is, indicated by the dashed lines in Figure 31.1B, the target therefore, exposed to considerably higher concentrations gland hormone may have negative-feedback effects to in- of these hypothalamic hormones than the rest of the body; hibit secretion of both the trophic hormone from the ante- as a result, the actions of these hormones focus on cells of rior pituitary and the releasing hormone from the hypo- the anterior pituitary. Another mechanism that restricts thalamus. In addition, the trophic hormone may inhibit the distribution of active hormone is the local transforma- releasing hormone secretion from the hypothalamus, and tion of a hormone within its target tissue from a less active in some cases, the releasing hormone may inhibit its own to a more active form. An example is the formation of di- secretion by the hypothalamus. hydrotestosterone from testosterone, occurring in such an- The more complex multilevel form of regulation appears drogen target tissues as the prostate gland. Dihydrotestos- to provide certain advantages compared with the simpler sys- terone is a much more potent androgen than testosterone. tem. Theoretically, it permits a greater degree of fine-tuning Because the enzyme that catalyzes this conversion is found of hormone secretion, and the multiplicity of regulatory steps only in certain locations, its cell or tissue distribution minimizes changes in hormone secretion in the event that partly localizes the actions of the androgens to these sites. one component of the system is not functioning normally. Therefore, while receptor distribution is the primary fac- It is important to bear in mind the normal feedback rela- tor in determining the target tissues for a specific hor- tionships that control the secretion of each individual hor- mone, other factors may also focus the actions of a hor- mone are discussed in the chapters that follow. Clinical di- mone on a particular tissue. agnoses are often made based on the evaluation of

CHAPTER 31 Endocrine Control Mechanisms 569 A Hormone involve a prescribed perturbation of the feedback relation- ship(s); the range of response in a normal individual is well established, while a response outside the normal range is in- dicative of abnormal function at some level and greatly en- hances information gained from static measurements of hormone concentrations (see Clinical Focus Box 31.1). Endocrine Target cell cell Signal Amplification Is an Important Characteristic of the Endocrine System Another important feature of the endocrine system is signal amplification. Blood concentrations of hormones are ex- ceedingly low, generally, 10
9 to 10
12 mol/L. Even at the Biological effect higher concentration of 10
9 mol/L, only one hormone molecule would be present for roughly every 50 billion wa- ter molecules. Therefore, for hormones to be effective reg- B ulators of biological processes, amplification must be part of the overall mechanism of hormone action. Hypothalamus Amplification generally results from the activation of a se- ries of enzymatic steps involved in hormone action. At each Releasing hormone step, many times more signal molecules are generated than were present at the prior step, leading to a cascade of ever- increasing numbers of signal molecules. The self-multiplying nature of the hormone action pathways provides the molec- Anterior ular basis for amplification in the endocrine system. pituitary Trophic hormone Pleiotropic Hormone Effects and Multiplicity of Regulation Also Characterize the Endocrine System Target Most hormones have multiple actions in their target tissues gland and are, therefore, said to have pleiotropic effects. For ex- ample, insulin exhibits pleiotropic effects in skeletal mus- cle, where it stimulates glucose uptake, stimulates glycoly- sis, stimulates glycogenesis, inhibits glycogenolysis, Target gland stimulates amino acid uptake, stimulates protein synthesis, hormone and inhibits protein degradation. In addition, some hormones are known to have different effects in several different target tissues. For example, testos- terone, the male sex steroid, promotes normal sperm forma- Biological effect tion in the testes, stimulates growth of the accessory sex glands, such as the prostate and seminal vesicles, and pro- Simple and complex feedback loops in the FIGURE 31.1 motes the development of several secondary sex character- endocrine system. A, A simple first-order feedback loop. B, A complex, multilevel feedback loop: the hy- istics, such as beard growth and deepening of the voice. pothalamic-pituitary-target gland axis. Solid lines indicate stim- Multiplicity of regulation is also common in the en- ulatory effects; dashed lines indicate inhibitory, negative-feed- docrine system. The input of information from several back effects. sources allows a highly integrated response to a variety of stimuli, which is of ultimate benefit to the whole animal. For example, liver glycogen metabolism may be regulated hormone-effector pairs relative to normal feedback rela- or influenced by several different hormones, including in- tionships. For example, in the case of anterior pituitary hor- sulin, glucagon, epinephrine, thyroid hormones, and adre- mones, measuring both the trophic hormone and the target nal glucocorticoids. gland hormone concentration provides important informa- tion to help determine whether a defect in hormone pro- Hormones Are Often Secreted duction exists at the level of the pituitary or at the level of the target gland. Furthermore, most dynamic tests of en- in Definable Patterns docrine function performed clinically are based on our The secretion of any particular hormone is either stimu- knowledge of these feedback relationships. Dynamic tests lated or inhibited by a defined set of chemical substances in

570 PART IX ENDOCRINE PHYSIOLOGY CLINICAL FOCUS BOX 31.1 Growth Hormone and Pulsatile Hormone Secretion tain reliable information about growth hormone secretion, Growth hormone is a 191-amino acid protein hormone endocrinologists employ a dynamic test of growth hor- that is synthesized and secreted by somatotrophs of the mone secretory capacity. There are several variations of anterior lobe of the pituitary gland. As described in Chap- this test that are used at different hospitals. In one test, a ter 32, the hormone plays a role in regulating bone growth bolus of arginine, which is known to stimulate growth hor- and energy metabolism in skeletal muscle and adipose tis- mone secretion, is given and a blood sample is taken a sue. A deficiency in growth hormone production during short time later for the measurement of growth hormone adolescence results in dwarfism and overproduction re- concentrations. Another test makes use of the fact that hy- sults in gigantism. Measurements of circulating growth poglycemia is a known stimulus for growth hormone se- hormone levels are, therefore, desirable in children whose cretion. Mild hypoglycemia is induced by an injection of in- growth rate is not appropriate for their age. sulin, and a blood sample is drawn a short time later. Like many other peptide hormones, growth hormone Regardless of which test is used, by perturbing the system secretion occurs in a pulsatile fashion. The most consistent in a well-prescribed fashion, the endocrinologist is able to pulse occurs just after the onset of deep sleep and lasts for gain important information about growth hormone secre- about 1 hour. There are usually 4 to 6 irregularly timed tion that would not be possible if a random blood sample pulses throughout the remainder of the day. In order to ob- were used. the blood or environmental factors. In addition to these in the synthesis of these hormones are discussed in detail in specific secretagogues, many hormones are secreted in a later chapters. defined, rhythmic pattern. These rhythms can take several forms. For example, they may be pulsatile, episodic spikes in secretion lasting just a few minutes, or they may follow a Many Hormones Are Polypeptides daily, monthly, or seasonal change in overall pattern. Pul- Hormones in the polypeptide group are quite diverse in satile secretion may occur in addition to other longer se- size and complexity. They may be as small as the tripeptide cretory patterns. thyrotropin-releasing hormone (TRH) or as large as human For these reasons, a single randomly drawn blood sam- chorionic gonadotropin (hCG), which is composed of sep- ple for determining a certain hormone concentration may arate alpha and beta subunits, has a molecular weight of ap- be of little or no diagnostic value. A dynamic test of en- proximately 34 kDa, and is a glycoprotein comprised of docrine function in which hormone secretion is specifically 16% carbohydrate by weight. stimulated by a known agent often provides much more Within the polypeptide class of hormones are a number meaningful information. of families of hormones, some of which are listed in Table 31.1. Hormones can be grouped into these families as a result of considerable homology with regard to amino acid THE NATURE OF HORMONES sequence and structure. Presumably, the similarity of struc- Hormones can be categorized by a number of criteria. Grouping them by chemical structure is convenient, since in many cases, hormones with similar structures also use TABLE 31.1 Examples of Peptide Hormone Families similar mechanisms to produce their biological effects. In addition, hormones with similar chemical structures are Insulin Family usually produced by tissues with similar embryonic ori- Insulin gins. Hormones can generally be classed as one of three Insulin-like growth factor I chemical types. Insulin-like growth factor II Relaxin Glycoprotein Family The Simplest Hormones, in Terms of Structure, Luteinizing hormone (LH) Consist of One or Two Modified Amino Acids Follicle-stimulating hormone (FSH) Thyroid-stimulating hormone (TSH) Hormones derived from one or two amino acids are small Human chorionic gonadotropin (hCG) in size and often hydrophilic. These hormones are formed Growth Hormone Family by conversion from a commonly occurring amino acid; ep- Growth hormone (GH) inephrine and thyroxine, for example, are derived from ty- Prolactin (PRL) rosine. Each of these hormones is synthesized by a particu- Human placental lactogen (hPL) lar sequence of enzymes that are primarily localized in the Secretin Family endocrine gland involved in its production. The synthesis Secretin of amino acid-derived hormones can, therefore, be influ- Vasoactive intestinal peptide (VIP) enced in a relatively specific fashion by a variety of envi- Glucagon Gastric inhibitory peptide (GIP) ronmental or pharmacological agents. The steps involved

CHAPTER 31 Endocrine Control Mechanisms 571 ture in these families resulted from the evolution of a single Androgens, such as testosterone, are primarily produced ancestral hormone into each of the separate and distinct in the testes, but physiologically significant amounts can be hormones. In many cases, there is also considerable homol- synthesized by the adrenal cortex as well. The primary fe- ogy among receptors for the hormones within a family. male sex hormone is estradiol, a member of the estrogen family, produced by the ovaries and placenta. Progestins, such as progesterone, are involved in maintenance of preg- Steroid Hormones Are Derived From Cholesterol nancy and are produced by the ovaries and placenta. Steroids are lipid-soluble, hydrophobic molecules synthe- The calciferols, such as 1,25-dihydroxycholecalciferol, sized from cholesterol. They can be classified into six cate- are involved in the regulation of calcium homeostasis. 1,25- gories, based on their primary biological activity. An ex- dihydroxycholecalciferol is the hormonally active form of ample of each category is shown in Figure 31.2. vitamin D and is formed by a sequence of reactions occur- Glucocorticoids, such as cortisol, are primarily pro- ring in skin, liver, and kidneys. duced in cells of the adrenal cortex and regulate processes involved in glucose, protein, and lipid homeostasis. Gluco- Polypeptide and Protein Hormones Are corticoids generally produce effects that are catabolic in Synthesized in Advance of Need and nature. Aldosterone, a primary example of a mineralocorti- Stored in Secretory Vesicles coid, is produced in cells of the outermost portion of the adrenal cortex. Aldosterone is primarily involved in regu- Steroid hormones are synthesized and secreted on demand, lating sodium and potassium balance by the kidneys and is but polypeptide hormones are typically stored prior to se- the principal mineralocorticoid in the body. cretion. Steroid hormone synthesis and secretion are dis- Cortisol (Aldehyde) (Hemiacetal) (a glucocorticoid) Aldosterone (a mineralocorticoid) Testosterone Estradiol (an androgen) (an estrogen) Progesterone (a progestin) 1,25 (OH) 2 Cholecalciferol (a calciferol) Examples of the six types of naturally occurring steroids. FIGURE 31.2

572 PART IX ENDOCRINE PHYSIOLOGY cussed in Chapter 34; the discussion here is confined to the cleaved precursor molecules having limited biological ac- synthesis and secretion of polypeptide hormones. tivity may be found circulating in the blood in some of these cases. Preprohormones and Prohormones. Like other proteins In some disease states, large amounts of intact precursor destined for secretion, polypeptide hormones are synthe- molecules are found in the circulation. This situation may sized with a pre- or signal peptide at their amino terminal end be the result of endocrine cell hyperactivity or even un- that directs the growing peptide chain into the cisternae of controlled production of hormone precursor by nonen- the rough ER. Most, if not all, polypeptide hormones are docrine tumor cells. Although precursors usually have rela- synthesized as part of an even larger precursor or prepro- tively low biological activity, if they are secreted in hormone. The prepeptide is cleaved off upon entry of the sufficiently high amounts, they may still produce biological preprohormone into the rough ER, to form the prohor- effects. In some cases, these effects may be the first recog- mone. As the prohormone is processed through the Golgi nized sign of neoplasia. apparatus and packaged into secretory vesicles, it is prote- Tissue-specific differences in the processing of prohor- olytically cleaved at one or more sites to yield active hor- mones are well known. Although the same prohormone mone. In many cases, preprohormones may contain the se- gene may be expressed in different tissues, tissue-specific quences for several different biologically active molecules. differences in the way the molecule is cleaved give rise to These active elements may, in some cases, be separated by different final secretory products. For example, within alpha inactive spacer segments of peptide. cells of the pancreas, proglucagon is cleaved at two posi- Examples of prohormones that are the precursors for tions to yield three peptides, illustrated in Figure 31.4 (left). polypeptide hormones, which illustrate the multipotent na- Glucagon, an important hormone in the regulation of car- ture of these precursors, are shown schematically in Figure bohydrate metabolism, is the best characterized of the three 31.3. Note, for example, that proopiomelanocortin peptides. In contrast, in other cells of the gastrointestinal (POMC) actually contains the sequences for several bio- (GI) tract in which proglucagon is also produced, the mole- logically active signal molecules. Propressophysin serves as cule is cleaved at three different positions such that gli- the precursor for the nonapeptide hormone arginine vaso- centin, glucagon-like peptide-1 (GLP-1), and glucagon-like pressin (AVP). The precursor for TRH contains five repeats peptide-2 (GLP-2) are produced (Fig. 31.4, right). of the TRH tripeptide in one single precursor molecule. In general, two basic amino acid residues, either lys-arg Intracellular Movement of Secretory Vesicles and Exocy- or arg-arg, demarcate the point(s) at which the prohor- tosis. Upon insertion of the preprohormone into the cis- mone will be cleaved into its biologically active compo- ternae of the ER, the prepeptide or signal peptide is rapidly nents. Presumably, these two basic amino acids serve as cleaved from the amino terminal end of the molecule. The specific recognition sites for the trypsin-like endopepti- resulting prohormone is translocated to the Golgi appara- dases thought to be responsible for cleavage of the prohor- mones. Although somewhat rare, there are documented cases of inherited diseases in which a point mutation in- Proglucagon volving an amino acid residue at the cleavage site results in an inability to convert the prohormone into active hor- N-peptide Glucagon IP-1 GLP-1 IP-2 GLP-2 mone, resulting in a state of hormone deficiency. Partially Pancreatic Gastrointestinal alpha cells tract ACTH Glicentin γ-MSH α-MSH CLIP γ-LPH β-Endorphin N-peptide N-peptide Glucagon IP-1 Proopiomelanocortin (POMC) GLP-1 Glucagon AVP Neurophysin IP-2 Propressophysin IP-1 GLP-1 IP-2 GLP-2 TRH TRH TRH TRH TRH GLP-2 The differential processing of prohor- FIGURE 31.4 Prothyrotropin-releasing hormone mones. In alpha cells of the pancreas (left), the major bioactive product formed from proglucagon is glucagon it- The structure of three prohormones. Rela- self. It is not currently known whether the other peptides are FIGURE 31.3 tive sizes of individual peptides are only ap- processed to produce biologically active molecules. In intestinal proximations. MSH  melanocyte-stimulating hormone; CLIP cells (right), proglucagon is cleaved to produce the four peptides  corticotropin-like intermediate lobe peptide; LPH  shown. Glicentin is the major glucagon-containing peptide in the lipotropin; AVP  arginine vasopressin; TRH  thyrotropin- intestine. IP-1, intervening peptide 1; IP-2, intervening peptide 2; releasing hormone. GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide 2.

CHAPTER 31 Endocrine Control Mechanisms 573 CLINICAL FOCUS BOX 31.2 Pancreatic Beta Cell Function and C-Peptide For these reasons, measurements of circulating C-pep- Beta cells of the human pancreas produce and secrete in- tide levels can provide a valuable indirect assessment of sulin. The product of the insulin gene is a peptide known beta cell insulin secretory capacity. In diabetic patients as preproinsulin. As with other secretory peptides, the who are receiving exogenous insulin injections, the meas- prepeptide or signal peptide is cleaved off early in the urement of circulating insulin levels would not provide any biosynthetic process, yielding proinsulin. Proinsulin is an useful information about their own pancreatic function be- 86-amino acid protein that is subsequently cleaved at two cause it would primarily be the injected insulin that would sites to yield insulin and a 31-amino acid peptide known as be measured. However, an evaluation of C-peptide levels C-peptide. Insulin and C-peptide are, therefore, localized in such patients would provide an indirect measure of how within the same secretory vesicle and are co-secreted into well the beta cells were functioning with regard to insulin the bloodstream. production and secretion. tus, where it is processed and packaged for export. After Transport of Steroid and Thyroid Hormones. In most processing in the Golgi apparatus, peptide hormones are cases, 90% or more of steroid and thyroid hormones in the stored in membrane-enclosed secretory vesicles. Secretion blood are bound to plasma proteins. Some of the plasma pro- of the peptide hormone occurs by exocytosis; the secretory teins that bind hormones are specialized, in that they have a vesicle is translocated to the cell surface, its membrane considerably higher affinity for one hormone over another, fuses with the plasma membrane, and its contents are re- whereas others, such as serum albumin, bind a variety of hy- leased into the extracellular fluid. Movement of the secre- drophobic hormones. The extent to which a hormone is pro- tory vesicle and membrane fusion are triggered by an in- tein-bound and the extent to which it binds to specific ver- crease in cytosolic calcium stemming from an influx of sus nonspecific transport proteins vary from one hormone to calcium into the cytoplasm from internal organelles or the another. The principal binding proteins involved in specific extracellular fluid. In some cells, an increase in cAMP and and nonspecific transport of steroid and thyroid hormones the subsequent activation of protein kinases is also involved are listed in Table 31.2. These proteins are synthesized and in the stimulus-secretion coupling process. Elements of the secreted by the liver, and their production is influenced by microtubule-microfilament system play a role in the move- changes in various nutritional and endocrine factors. ment of secretory vesicles from their intracellular storage Typically, for hormones that bind to carrier proteins, sites toward the cell membrane. only 1 to 10% of the total hormone present in the plasma The cleavage of prohormone into active hormone mole- exists free in solution. However, only this free hormone is cules typically takes place during transit through the Golgi biologically active. Bound hormone cannot directly inter- apparatus or, perhaps, soon after entry into secretory vesi- act with its receptor and, thus, is part of a temporarily inac- cles. Secretory vesicles, therefore, contain not only active tive pool. However, free hormone and carrier-bound hor- hormone but also the excised biologically inactive frag- mone are in a dynamic equilibrium with each other ments. When active hormone is released into the blood, a (Fig. 31.5). The size of the free hormone pool and, there- quantitatively similar amount of inactive fragment is also re- fore, the amount available to receptors are influenced not leased. In some instances, this forms the basis for an indirect only by changes in the rate of secretion of the hormone but assessment of hormone secretory activity (see Clinical Focus also by the amount of carrier protein available for hormone Box 31.2). Other types of processing of peptide hormones binding and the rate of degradation or removal of the hor- that may occur during transit through the Golgi apparatus mone from the plasma. include glycosylation and coupling of subunits. TABLE 31.2 Circulating Transport Proteins Many Hormones Reach Their Target Cells by Transport in the Bloodstream Principal Hormone(s) According to the classical definition, hormones are carried Transport Protein Transported by the bloodstream from their site of synthesis to their tar- get tissues. However, the manner in which different hor- Specific Cortisol, aldosterone Corticosteroid-binding globulin mones are carried in the blood varies. (CBG, transcortin) Thyroxine-binding globulin Thyroxine, triiodothyronine Transport of Amino Acid-Derived and Polypeptide Hor- (TBG) mones. Most amino acid-derived and polypeptide hor- Sex hormone-binding globulin Testosterone, estrogen mones dissolve readily in the plasma, and thus no special (SHBG) mechanisms are required for their transport. Steroid and Nonspecific thyroid hormones are relatively insoluble in plasma. Mech- Serum albumin Most steroids, thyroxine, anisms are present to promote their solubility in the aque- triiodothyronine ous phase of the blood and ultimate delivery to a target cell. Transthyretin (prealbumin) Thyroxine, some steroids

574 PART IX ENDOCRINE PHYSIOLOGY 1,000 times greater than its affinity for albumin, but albu- min is present in much higher concentrations than CBG. Therefore, about 70% of plasma cortisol is bound to CBG, 20% is bound to albumin, and the remaining 10% is free in solution. Aldosterone also binds to CBG, but with a much lower affinity, such that only 17% is bound to CBG, 47% associates with albumin, and 36% is free in solution. As this example indicates, more than one hormone may be capable of binding to a specific transport protein. When several such hormones are present simultaneously, they com- pete for a limited number of binding sites on these transport proteins. For example, cortisol and aldosterone compete for CBG binding sites. Increases in plasma cortisol result in dis- placement of aldosterone from CBG, raising the unbound (active) concentration of aldosterone in the plasma. Simi- larly, prednisone, a widely used synthetic corticosteroid, can displace about 35% of the cortisol normally bound to CBG. As a result, with prednisone treatment, the free cortisol con- The relationship between hormone secre- FIGURE 31.5 centration is higher than might be predicted from measured tion, carrier protein binding, and hormone degradation. This relationship determines the amount of free concentrations of total cortisol and CBG. hormone available for receptor binding and the production of bi- ological effects. Peripheral Transformation, Degradation, and Excretion of Hormones, in Part, Determine Their Activity In addition to increasing the total amount of hormone that can be carried in plasma, transport proteins also pro- As a general rule, hormones are produced by their gland or vide a relatively large reservoir of hormone that buffers tissue of origin in an active form. However, for a few no- rapid changes in free hormone concentrations. As unbound table exceptions, the peripheral transformation of a hor- hormone leaves the circulation and enters cells, additional mone plays a very important role in its action. hormone dissociates from transport proteins and replaces free hormone that is lost from the free pool. Similarly, fol- Peripheral Transformation of Hormones. Specific hor- lowing a rapid increase in hormone secretion or the thera- mone transformations may be impaired because of a con- peutic administration of a large dose of hormone, the ma- genital enzyme deficiency or drug-induced inhibition of jority of newly appearing hormone is bound to transport enzyme activity, resulting in endocrine abnormalities. proteins, since under most conditions these are present in Well-known transformations are the conversion of testos- considerable excess. terone to dihydrotestosterone (see Chapter 37) and the Protein binding greatly slows the rate of clearance of conversion of thyroxine to triiodothyronine (see Chapter hormones from plasma. It not only slows the entry of hor- 33). Other examples are the formation of the octapeptide mones into cells, slowing the rate of hormone degradation, angiotensin II from its precursor, angiotensinogen (see but also prevents loss by filtration in the kidneys. Chapter 34), and the formation of 1,25-dihydroxychole- From a diagnostic standpoint, it is important to recog- calciferol from cholecalciferol (see Chapter 36). nize that most hormone assays are reported in terms of to- tal concentration (i.e., the sum of free and bound hor- Mechanisms of Hormone Degradation and Excretion. mone), not just free hormone concentration. The amount As in any regulatory control system, it is necessary for the of transport protein and the total plasma hormone content hormonal signal to dissipate or disappear once appropriate are known to change under certain physiological or patho- information has been transferred and the need for further logical conditions, while the free hormone concentration stimulus has ceased. As described earlier, steady-state may remain relatively normal. For example, increased con- plasma concentrations of hormone are determined not only centrations of binding proteins are seen during pregnancy by the rate of secretion but also by the rate of degradation. and decreased concentrations are seen with certain forms of Thus, any factor that significantly alters the degradation of liver or kidney disease. Assays of total hormone content a hormone can potentially alter its circulating concentra- might be misleading, since free hormone concentrations tion. Commonly, however, secretory mechanisms can may be in the normal range. In such cases, it is helpful to compensate for altered degradation such that plasma hor- determine the extent of protein binding, so free hormone mone concentrations remain within the normal range. concentrations can be estimated. Processes of hormone degradation show little, if any, regu- The proportion of a hormone that is free, bound to a lation; alterations in the rates of hormone synthesis or se- specific transport protein, and bound to albumin varies de- cretion in most cases provide the primary mechanism for al- pending on its solubility, its relative affinity for the two tering circulating hormone concentrations. classes of transport proteins, and the relative abundance of For most hormones, the liver is quantitatively the most the transport proteins. For example, the affinity of cortisol important site of degradation; for a few others, the kidneys for corticosteroid-binding globulin (CBG) is more than play a significant role as well. Diseases of the liver and kid-

CHAPTER 31 Endocrine Control Mechanisms 575 neys may, therefore, indirectly influence endocrine status One approach to measuring MCR involves injecting a as a result of altering the rates at which hormones are re- small amount of radioactive hormone into the subject and moved from the circulation. Various drugs also alter normal then collecting a series of timed blood samples to deter- rates of hormone degradation; thus, the possibility of indi- mine the amount of radioactive hormone remaining. Based rect drug-induced endocrine abnormalities also exists. In on the rate of disappearance of hormone from the blood, its addition to the liver and kidneys, target tissues may take up half-life and MCR can be calculated. The MCR and half- and degrade quantitatively smaller amounts of hormone. In life are inversely related—the shorter the half-life, the the case of peptide and protein hormones, this occurs via greater the MCR. The half-lives of different hormones vary receptor-mediated endocytosis. considerably, from 5 minutes or less for some to several The nature of specific structural modification(s) in- hours for others. The circulating concentration of hor- volved in hormone inactivation and degradation differs mones with short half-lives can vary dramatically over a for each hormone class. As a general rule, however, spe- short period of time. This is typical of hormones that regu- cific enzyme-catalyzed reactions are involved. Inactiva- late processes on an acute minute-to-minute basis, such as a tion and degradation may involve complete metabolism number of those involved in regulating blood glucose. Hor- of the hormone to entirely different products, or it may be mones for which rapid changes in concentration are not re- limited to a simpler process involving one or two steps, quired, such as those with seasonal variations and those such as a covalent modification to inactivate the hor- that regulate the menstrual cycle, typically have longer mone. Urine is the primary route of excretion of hormone half-lives. degradation products, but small amounts of intact hor- mone may also appear in the urine. In some cases, meas- uring the urinary content of a hormone or hormone The Measurement of Hormone Concentrations metabolite provides a useful, indirect, noninvasive means Is an Important Tool in Endocrinology of assessing endocrine function. The concentration of hormone present in a biological fluid The degradation of peptide and protein hormones has is often measured to make a clinical diagnosis of a suspected been studied only in a limited number of cases. However, endocrine disease or to study basic endocrine physiology. it appears that peptide and protein hormones are inacti- Substantial advancements have been made in measuring vated in a variety of tissues by proteolytic attack. The first hormone concentrations. step appears to involve attack by specific peptidases, re- sulting in the formation of several distinct hormone frag- Bioassay. Even before hormones were chemically char- ments. These fragments are then metabolized by a variety acterized, they were quantitated in terms of biological re- of nonspecific peptidases to yield the constituent amino sponses they produced. Thus, early assays for measuring acids, which can be reused. hormones were bioassays that depended on a hormone’s The metabolism and degradation of steroid hormones ability to produce a characteristic biological response. As a has been studied in much more detail. The primary organ result, hormones came to be quantitated in terms of units, involved is the liver, although some metabolism also takes defined as an amount sufficient to produce a response of place in the kidneys. Complete steroid metabolism gener- specified magnitude under a defined set of conditions. A ally involves a combination of one or more of five general unit of hormone is, thus, arbitrarily determined. Although classes of reactions: reduction, hydroxylation, side chain bioassays are rarely used today for diagnostic purposes, cleavage, oxidation, and esterification. Reduction reactions many hormones are still standardized in terms of biological are the principal reactions involved in the conversion of bi- activity units. For example, commercial insulin is still sold ologically active steroids to forms that possess little or no and dispensed based on the number of units in a particular activity. Esterification (or conjugation) reactions are also preparation, rather than by the weight or the number of particularly important. Groups added in esterification reac- moles of insulin. tions are primarily glucuronate and sulfate. The addition of Bioassays in general suffer from a number of shortcom- such charged moieties enhances the water solubility of the ings, including a relative lack of specificity and a lack of metabolites, facilitating their excretion. Steroid metabo- sensitivity. In many cases, they are slow and cumbersome lites are eliminated from the body primarily via the urine, to perform, and often they are expensive, since biological although smaller amounts also enter the bile and leave the variability often requires the inclusion of many animals in body in the feces. the assay. At times, quantitative information concerning the rate of hormone metabolism is clinically useful. One index of the Radioimmunoassay. Development of the radioim- rate at which a hormone is removed from the blood is the munoassay (RIA) in the late 1950s and early 1960s was a metabolic clearance rate (MCR). The metabolic clearance major step forward in clinical and research endocrinology. of a hormone is analogous to that of renal clearance (see Much of our current knowledge of endocrinology is based Chapter 23). The MCR is the volume of plasma cleared of on this method. A RIA or closely related assay is now avail- the hormone in question per unit time. It is calculated from able for virtually every known hormone. In addition, RIAs the equation: have been developed to measure circulating concentrations MCR  Hormone removed per unit time (mg/min) (1) of a variety of other biologically relevant proteins, drugs, Plasma concentration (mg/mL) and vitamins. The RIA is a prototype for a larger group of assays and is expressed in mL plasma/min. termed competitive binding assays. These are modifica-

576 PART IX ENDOCRINE PHYSIOLOGY tions and adaptations of the original RIA, relying to a large degree on the principle of competitive binding on which 100 the RIA is based. It is beyond the scope of this text to de- scribe in detail the competitive binding assays currently used to measure hormone concentrations, but the princi- 80 ples are the same as those for the RIA. The two key components of a RIA are a specific anti- body (Ab) that has been raised against the hormone in 60 question and a radioactively labeled hormone (H*). If the hormone being measured is a peptide or protein, the mole- Radioactive hormone-antibody complex (percentage of maximum) cule is commonly labeled with a radioactive iodine atom 40 ( 125 I or 131 I) that can be readily attached to tyrosine residues of the peptide chain. For substances lacking tyro- sine residues, such as steroids, labeling may be accom- 20 14 plished by incorporating radioactive carbon ( C) or hy- 3 drogen ( H). In either case, the use of the radioactive hormone permits detection and quantification of very small 0 amounts of the substance. 0123456 The RIA is performed in vitro using a series of test tubes. Unlabeled hormone Fixed amounts of Ab and of H* are added to all tubes (arbitrary units) (Fig. 31.6A). Samples (plasma, urine, cerebrospinal fluid, FIGURE 31.7 A typical RIA standard curve. As indicated etc.) to be measured are added to individual tubes. Varying by the dashed lines, the hormone content in known concentrations of unlabeled hormone (the stan- unknown samples can be deduced from the standard curve. (Mod- dards) are added to a series of identical tubes. The principle ified from Hedge GA, Colby HD, Goodman RL. Clinical En- of the RIA, as indicated in Figure 31.6B, is that labeled and docrine Physiology. Philadelphia: WB Saunders, 1987.) unlabeled hormone compete for a limited number of anti- body binding sites. The amount of each hormone that is bound to antibody is a proportion of that present in solu- One major limitation of RIAs is that they measure im- tion. In a sample containing a high concentration of hor- munoreactivity, rather than biological activity. The pres- mone, less radioactive hormone will be able to bind to the ence of an immunologically related but different hormone antibody, and less antibody will be able to bind to the ra- or of heterogeneous forms of the same hormone can com- dioactive hormone. In each case, the amount of radioactiv- plicate the interpretation of the results. For example, ity present as antibody-bound H* is determined. The re- POMC, the precursor of ACTH, is often present in high sponse produced by the standards is used to generate a concentrations in the plasma of patients with bronchogenic standard curve (Fig. 31.7). Responses produced by the un- carcinoma. Antibodies for ACTH may cross-react with known samples are then compared to the standard curve to POMC. The results of a RIA for ACTH in which such an determine the amount of hormone present in the unknowns antibody is used may suggest high concentrations of (see dashed lines in Fig. 31.7). ACTH, when actually POMC is being detected. Because POMC has less than 5% of the biological potency of ACTH, there may be little clinical evidence of significantly A elevated ACTH. If appropriate measures are taken, how- ever, such possible pitfalls can be overcome in most cases, and reliable results from the RIA can be obtained. One important modification of the RIA is the radiore- Antibody Radioactive Hormone-antibody ceptor assay, which uses specific hormone receptors rather (Ab) hormone complex than antibodies as the hormone-binding reagent. In theory, (H*) (Ab-H*) this method measures biologically active hormone, since receptor binding rather than antibody recognition is as- B sessed. However, the need to purify hormone receptors and the somewhat more complex nature of this assay limit its usefulness for routine clinical measurements. It is more likely to be used in a research setting. ELISA. The enzyme-linked immunosorbent assay (ELISA) is a solid-phase, enzyme-based assay whose use The principles of radioimmunoassay (RIA). FIGURE 31.6 and application have increased considerably over the past A, Specific antibodies (Ab) bind with radioactive hormone (H*) to form hormone-antibody complexes (Ab-H*). B, two decades. A typical ELISA is a colorimetric or fluoro- When unlabeled hormone (open circles) is also introduced into the metric assay, and therefore, the ELISA, unlike the RIA, does system, less radioactive hormone binds to the antibody. (Modified not produce radioactive waste, which is an advantage, con- from Hedge GA, Colby HD, Goodman RL. Clinical Endocrine sidering environmental concerns and the rapidly increasing Physiology. Philadelphia: WB Saunders, 1987.) cost of radioactive waste disposal. In addition, because it is

CHAPTER 31 Endocrine Control Mechanisms 577 The binding of a hormone to its receptor with subsequent activation of the receptor is the first step in hormone action and also the point at which specificity is determined within the endocrine system. Abnormal interactions of hormones with their receptors are involved in the pathogenesis of a number of endocrine disease states, and therefore, consider- able attention has been paid to this aspect of hormone action. Enz The Kinetics of Hormone-Receptor Binding Determines, in Part, the Biological Response Ab 3 The probability that a hormone-receptor interaction will occur is related to both the abundance of cellular receptors Ab 2 and the receptor’s affinity for the hormone relative to the ambient hormone concentration. The more receptors avail- able to interact with a given amount of hormone, the greater the likelihood of a response. Similarly, the higher Ab the affinity of a receptor for the hormone, the greater the 1 likelihood that an interaction will occur. The circulating hormone concentration is, of course, a function of the rate The basic components of an ELISA. A typi- of hormone secretion relative to hormone degradation. FIGURE 31.8 cal ELISA is performed in a 3
5-inch plastic The association of a hormone with its receptor generally plate containing 96 small wells. Each well is precoated with an behaves as if it were a simple, reversible chemical reaction antibody (Ab 1 ) that is specific for the hormone (H) being meas- that can be described by the following kinetic equation: ured. Unknown samples or standards are introduced into the wells, followed by a second hormone-specific antibody (Ab 2 ). A [H]  [R] [HR] (2) third antibody (Ab 3 ), which recognizes Ab 2 , is then added. Ab 3 is coupled to an enzyme that will convert an appropriate substrate where [H] is the free hormone concentration, [R] is the un- (S) into a colored or fluorescent product (P). The amount of occupied receptor concentration, and [HR] is the hor- product formed can be determined using optical methods. After mone-receptor complex (also referred to as bound hor- the addition of each antibody or sample to the wells, the plates mone or occupied receptor). are incubated for an appropriate period of time to allow antibod- Assuming a simple chemical equilibrium, it follows that ies and hormones to bind. Any unbound material is washed out of the well before the addition of the next reagent. The amount of K a  [HR]/[H]
[R] (3) colored product formed is directly proportional to the amount of hormone present in the standard or unknown sample. Concentra- where K a is the association constant. If R 0 is defined as tions are determined using a standard curve. For simplicity, only the total receptor number (i.e., [R]  [HR]), then after one Ab 1 molecule is shown in the bottom of the well, when, in substituting and rearranging, we obtain the following re- fact, there is an excess of Ab 1 relative to the amount of hormone lationship: to be measured. [HR]/[H] 
K a [HR]  K a R 0 (4) Literally translated, this equation states: a solid-phase assay, the ELISA can be automated to a large Bound hormone 
K a
Bound hormone (5) degree, which reduces costs. Figure 31.8 shows a relatively  K a
Total receptor number simple version of an ELISA. More complex assays using Free hormone similar principles have been developed to overcome a vari- Notice that equations 4 and 5 have the general form of ety of technical problems, but the basic principle remains an equation for a straight line: y  mx  b. the same. In recent years the RIA has been the primary as- To obtain information regarding a particular hormone- say used clinically; its use has expanded considerably, and receptor system, a fixed number of cells (and, therefore, a it will likely be the predominant assay in the future because fixed number of receptors) is incubated in vitro in a series of of the advantages listed above. test tubes with increasing amounts of hormone. At each higher hormone concentration, the amount of receptor- bound hormone is increased until all receptors are occupied by hormone. Receptor number and affinity can be obtained MECHANISMS OF HORMONE ACTION by using the relationships given in equation 5 above and As indicated earlier, hormones are one mechanism by which plotting the results as the ratio of receptor-bound hormone cells communicate with one another. Fidelity of communi- to free hormone ([HR]/[H]) as a function of the amount of cation in the endocrine system depends on each hormone’s bound hormone ([HR]). This type of analysis is known as a ability to interact with a specific receptor in its target tissues. Scatchard plot (Fig. 31.9). In theory, a Scatchard plot of This interaction results in the activation (or inhibition) of a simple, reversible equilibrium binding is a straight line (Fig. series of specific events in cells that results in precise bio- 31.9A), with the slope of the line being equal to the nega- logical responses characteristic of that hormone. tive of the association constant (
K a) and the x-intercept