REGULATION OF SKIN CIRCULATION DURING PROLONGED EXERCISE * John M. Johnson University of Texas Health Science Center San Antonio, Texas 78284
INTRODUCTION Major demands on the circulation attending prolonged exercise are maintenance of blood flow to .working skeletal muscle, dissipation of heat arising from the increased metabolic activity of skeletal muscle and maintenance of arterial blood pressure. The cardiovascular system is often unable to meet these competing demands in such events as the marathon. Cardiac output is constant or little changed during prolonged steady-state exercise.', * Even when exercise is performed in hot environments, cardiac output is not increased over levels achieved at the same level of work in a cool envir~nment.~. Also, there are only small further reductions in visceral blood flow after the first few minutes of exercise.s*6 If blood flow to active skeletal muscle is maintained during prolonged exercise, skin blood flow and the regulation of internal temperature must suffer. Manifestations of this limitation have been observed '-lo where rectal temperatures as high as 41" C were measured after distance races. Skin thus represents the principle site of competition between thermal and nonthermal demands on blood flow distribution during exercise. Were the skin circulation regulated solely by body temperature, blood flow to skin would rise to high levels with the elevation in internal temperature accompanying exercise. In the face of a constant cardiac output, active muscle blood flow and/or arterial blood pressure would fall markedly in such a setting. However, if skin blood flow did not rise during exercise, internal temperature would quickly reach levels of extreme hyperthermia. Few studies have dealt directly with the competitive nature of regulation of the cutaneous circulation during prolonged exercise. Thus, studies have dealt with the responses of the cutaneous circulation to heating at rest l1, l2 or with the responses during exercise 13-15 but have not considered the similarities or differences between the two settings. The focus here, therefore, is on the control of skin blood flow during exercise. The objective is to show how competing demands for cardiac output limit skin blood flow. Emphasis is placed on how such control differs from that observed at rest. Specific problems attacked here include ( a ) whether skin blood low is lower during exercise than at the same level of internal temperature at rest, (b) the response of skin blood flow to prolonged work, (c) whether the reflex response of skin blood flow to rising skin temperature is influenced by exercise, and ( d ) the response of skin blood flow to the combination of heat stress and exercise when work in the heat is prolonged.
* This work was supported by National Heart and Lung Institute Grants HL-09773
and HL-16910.
195
196
Annals New York Academy of Sciences
Methods employed in this study have been reported in detail elsewhere. Since there is currently no method for the measurement of total skin blood flow, alterations in the vasomotor state of skin were assessed from changes in skin blood flow of the forearm. The neurogenic control of forearm skin blood flow reflects that over most of the body surface.16 Further, the increase in forearm blood flow reflects the pattern and extent of increments in total skin blood flow during whole body direct heating at rest.';, lS Briefly, changes in skin blood flow were assessed by measuring changes in forearm blood flow. Since forearm muscle blood flow does not rise during whole-body direct heating,19 indirect 21 local heating of the forearm,22 or leg exercise,13*2 3 elevations in forearm blood flow are confined to skin. Forearm blood flow was measured by venous occlusion plethysmography with a mercury-in-silastic circumference Internal temperature was measured as esophageal temperature with a thermocouple at the level of the left atrium. Skin temperature was measured as the electrical average of ten thermocouples placed at representative sites over the body surface. Whole-body skin temperature was controlled in some studies by dressing the subject in a water-perfused suit and passing hot or cold water through the suit 26 Exercise was performed at a constant level on a bicycle ergometer. Workloads were chosen to represent moderate levels of exercise. Response of Skin Blood Flow to Rising Internal Temperature
A first step in the study of the cutaneous circulation during exercise was to find whether its regulation was indeed modified by upright exercise. A number of studies have noted an initial forearm or hand vasoconstriction with the onset of leg exercise, which was succeeded by a steady vasodilation as exercise continued.13-15*2i Zelis et found the initial forearm vasoconstriction to include both skin and muscle and to vary with the level of work. It was not clear from these studies whether the cutaneous vasoconstriction was of only a transient nature or, alternatively, whether the skin remained vasoconstricted relative to the level of internal temperature. Thus the critical question was, is this response different than what would have been observed at rest at the same level of internal temperature? To force internal temperature to rise at rest, it was necessary to conduct studies at an elevated skin temperature (controlled by water-perfused suits). Therefore, all of these studies were performed at the same elevated skin temperature. A temperature of 38" C was chosen as a level that would yield an elevation of approximately 1"-1.5" C in internal temperature at rest, and had been observed in exercise in hot, natural environments.2S Thus the relationship of forearm blood flow to internal temperature was observed in four settings: supine rest, supine exercise, upright rest, and upright exercise.29 FIGURES 1 and 2 show representative results from this study. Note that in FIGURE 1 the elevations in forearm blood flow and in internal temperature are considerably less in the upright than in the supine posture. These findings are consistent with earlier findings that the skin is vasoconstricted by o r t h o s t a ~ i s 31 ,~~~ and that this vasoconstriction is sustained in the face of a competing thermoregulatory drive for v a ~ o d i l a t i o n 33 . ~ ~FIGURE ~ 2 compares the responses to upright and supine exercise. Note that the postural effects mentioned above persist. FIGURE 3 relates forearm blood flow to esophageal temperature in each of the
UPRIGHT R E S T
I
FBF, mV100ml~min
r
minuter
15
37
38
c3
HR* bpm
120 r
in one subject. Whole-body skin temperature ( T , ) was held a t 38" C in each case. Note that during upright rest, esophageal temperature ( T c , ) rose more slowly, indicating a relatively vasoconstricted skin. This point is borne out by the low levels of FBF achieved in the upright posture. Responses in heart rate (HR) are also shown. (From Johnson et a/." By permission of the American Physiological Society.)
FIGURE1. Response of forearm blood flow (FBF) to whole-body direct heating during supine (left) and upright seated rest (right)
37
r
SUPINE R E S T
4
\o
c
..
198
Annals New York Academy of Sciences UPRIGHT
I
I
mlnutrs
FIGURE2. Responses of FBF, Ts,,and H R to upright (right) and supine (left) exercise at a T, of 38" C in one subject. Symbols and abbreviations are as in FIGURE 1. The periods of exercise are denoted by the vertical lines. Work load was 750 kpm/min (125 W) in each case. Note the more marked rise in FBF during supine (as compared to upright) exercise. (From Johnson ef al." By permission of the American Physiological Society. ) four conditions. There are several points to be made from these data. First, at a given level of internal temperature, forearm blood flow is lower in the upright position than in the supine posture either at rest or during exercise. Second, in either the upright or the supine posture, at a given level of internal temperature forearm blood flow was lower during exercise than at rest. Third, the forearm vasoconstriction relative to internal temperature is greatest when upright posture and exercise are combined. These results offer direct confirmation that skin remains relatively vasoconstricted during exercise. Although there is some elevation in skin blood flow as exercise continues and internal temperature rises, this elevation is much less than that observed at rest. Thus skin is on the efferent arm of vasoconstrictor reflexes associated with exercise per se, as are the splanchnic,e. 34 rena1,Ss 3 5 and resting skeletal muscle 13-15, 23 circulations. This augmented vasoconstrictor drive to skin yields an attenuated response to thermoregulatory reflexes arising from elevations in internal temperature. Such an attenuated response must exist at high levels of work, as maximum oxygen intake can be reached in a
Johnson: Skin Circulation
I99
hot However, sufficient heat stress can reduce maximal oxygen consumption,:" indicating that a large fraction of the cardiac output can be directed to skin in that setting. Response of Skin Blood Flow to Prolonged Exercise in Normal Environments Given the responses noted in the preceding section, one would predict similar restrictions on skin blood flow during upright exercise in a cool or neutral environment. An additional vasoconstricting drive would arise from the lower levels of skin temperature in that setting, as opposed to the elevated skin temperatures used in the study mentioned above. Several studies o * :ix noted progressive cardiovascular adjustments and responses to prolonged exercise. These include steadily falling central venous pressure, stroke volume, and mean arterial pressure, with a steadily rising heart rate and little or no change in cardiac output. Possible mechanisms for these changes have been recently reviewed." Briefly, one explanation for these findings (the so-called cardiovascular drift) 30, FBF. m1/100ml min DBG 27. 24-
21
"
-
365
37
325 TOS,
38
r:
FIGURE 3. Composite of responses in FBF to rising T.. during supine rest (SR), supine exercise (SX),upright rest (UR),and upright exericse (UX) in one subject. Skin temperature was 38" C in all cases. Data from each experiment were fitted with a regression line, as shown. Note that at a given level of T#,,FBF is reduced by upright posture both at rest and during exercise and that FBF is reduced by exercise in 1. (From Johnson et al.- By permission either posture. Abbreviations as in FIGURE of the American Physiological Society.)
Annals New York Academy of Sciences
200
is that prolonged heavy work results in myocardial fatigue.*, 38 Such a notion is supported to some extent by the finding of increased duration of systole attending prolonged exercise.l An alternative explanation offered by Rowell l7 points out that some or all of these changes might be accounted for by a steady peripheral displacement of blood volume. Such a displacement would reduce filling pressures and stroke volume. Heart rate increases would compensate for the reduction in stroke volume, maintaining cardiac output. A logical site for such a peripheral displacement of blood volume is the cutaneous vascular bed. Raising local compliance or pressure in cutaneous veins would raise this volume. Cutaneous venous pressure would passively rise in response to a similar increase in skin blood flow. Consistent with this explanation, we observed a progressive increase in forearm skin blood flow during one hour of continuous exerci~e.~3 The workload was 600 kpm/min (100 W) for one subject and 750 kpm/min (125 W) for the other four subjects. FIGURE4 shows results from one of these experiments.
HR, bpm
,
60 l e a , .C
365
12 -
1
I
1
1
I
1
I
FBF, mi/i00mi~min
16
8-
minuter
FIGURE4. Responses of FBF, Te,, and HR to one hour of exercise (750 kpm/ min; 125 W) in a neutral environment (ambient temperature 24" C ) . LFBF is left forearm blood flow and RFBF is right forearm blood flow. Other abbreviations as in FIGURE1. (From Johnson & Rowell." By permission of the American Physiological Society.)
Johnson: Skin Circulation
20 1
MBF. ml/ 100 mbmin
FBF, m1/100ml~min I2rI
-
FIGURE 5. Composite responses of HR, Tc,, forearm muscle blood flow (MBF), and FBF during rest and one hour of exercise from all subjects studied. Each bar shows the mean and standard error of the response for each parameter for each 10min period. MBF was measured from the clearance of a depot of yI]-antipyrine 1. injected 1 cm into the brachioradiolis muscle. Other abbreviations as in FIGURE (From Johnson & Rowell." By permission of the American Physiological Society.)
Thus we see a progressive rise in forearm blood flow, beginning at about 10 minutes of exercise and continuing throughout the remainder of the work period. FIGURE 5 shows the responses of the entire group, averaged over each 10-minute interval of exercise. Although skin blood flow progressively rose, and may indeed account for other circulatory changes attending prolonged exercise, the
202
Annals New York Academy of Sciences
final levels achieved were still less than what would be expected at a comparable level of internal temperature in a resting individual. The problems associated with the combination of an elevated internal temperature and a relatively low skin blood flow become increasingly severe with the level of work or environmental temperature. Rectal temperature is maintained at essentially the same level for a given workload over a wide variation in environmental temperature~,3~ indicating skin blood flow must be increased with environmental temperature. This increment in skin blood flow is apparently met by further redistribution of flow from the viscera,.lo~~*l as cardiac output is not increased.:{* However, as environmental conditions become more extreme, internal temperature is no longer stable and visceral blood flow reaches potentially ischemic 1evek4* Similarly, high levels of heat production can stress the ability of the cardiovascular system both to meet thermoregulatory needs and to deliver oxygen to skeletal muscle. Clearly, the combination of high levels of exercise and heat stress tax the cardiovascular system to severe limits. Influence of Skin Temperature during Exercise
The foregoing studies show that competition between body temperature regulation and exercise per se for the control of skin blood flow yields a vasoconstriction relative to the level of body temperature and a vasodilation relative to drives from upright posture and exercise. One notable difference between studies at high and neutral levels of skin temperature was that skin blood flow increased from the beginning when exercise was performed at a high level of skin temperature (FIGURE2) but failed to increase for the first 10 minutes of exercise in the study performed at a low skin temperature (FIGURE 4). This observation indicates that skin temperature plays an important role in the responses to rising internal temperature during exercise. However, observations on resting man assign only a minor role to skin temperature.ll?l 2 On the other hand, Rowell et aLZ5noted a marked rise in cardiac output in response to a rise in whole-body skin temperature during exercise. Is the reflex response to an elevation in skin temperature altered during exercise? Also, to what extent can the above elevation in cardiac output be ascribed to direct (nonreflex) effects of heating the skin? To answer these questions, whole-body skin temperature was rapidly raised during exercise, as well as at rest. Forearm blood flow was measured in both arms. One arm was left exposed to ambient conditions, or controlled at 32" C, thus reflecting reflex vasomotor adjustments. The other arm was warmed according to the wholebody skin temperature protocol, thus reflecting responses to combined direct and reflex effects of raising skin temperature. FIGURE 6 shows an example of one such study. At 10 minutes, exercise was initiated at 525 kpm/min (88 W) and at a skin temperature of 32" C. At 30 minutes, skin temperature was rapidly elevated toward 38" C. Esophageal temperature ( T e a )fell transiently, and during this period of rising skin temperature and reduced or unchanged esophageal temperature forearm blood flow rose markedly in both arms. Forearm blood flow (FBF) showed only a small further rise while skin temperature was held at 38" C and internal temperature rose above preheating levels. This was usually the case. FIGURE 7 shows the relation between FBF and T,, during the same protocol in another subject. In this case the workload was 750 kpm/min (125 W ) . Again, there was a prompt elevation
Johnson: Skin Circulation
203
in forearm blood flow in both arms with the elevation in skin temperature with no change in esophageal temperature. This corresponds to the vertical portion of the data in FIGURE7. Here, as in most subjects the level of forearm blood flow leveled off, despite a marked further rise in esophageal temperature. Of the six subjects studied with this protocol, four showed this "leveling off" pheI
35
I
525 kom/min
-
32;
1
0
10. O
@
0
20:
..
5-
0 aDO .
0.".
pP
U * dog
0
$&
0
0.
?-\ &%P
.
0 00 0 0 0%
0
,"
0
.
0
0
0 0
B
0 @o0O
0
,&*
"*# .S*%
: .* J
nomenon. Application of the same protocol to resting men revealed little or no elevation in forearm blood flow with rising skin temperature in the arm held at a neutral temperature, and only a modest elevation in the blood flow to the arm heated with the rest of the body. As in previous studies most of the increase in FBF was due to rising internal temperature during whole-body direct heating
Annals New York Academy of Sciences
204 20
-
FBF, m1/100ml~min
g o o 0
15.
0
0
0
0
0
0
0
8
0 0
0
10 '
0 0
e
m
' * e
e
*e
5.
I
O:S.s
37
I
37.5
Tor, .C
1
I
38
38.5
1
39
FIGURE 7. FBF vs T., from a protocol like that shown in FIGURE 6. The open symbols represent FBF from the arm heated according to the whole-body T , protocol and the closed symbols represent FBF from the arm kept,cool. The horizontal portion of the data (in the lower left hand portion of the plot) are from the period of rising T., and essentially constant FBF during the first few minutes of exercise at low T.. The vertical portion of the data show the response during the period of rapidly rising T, (imposed by water perfused suits) with unchanging Tea. The horizontal portion of the data in the upper right of the figure represent the final 10 min of exercise at a T. of 38" C. Data from the left (warmed arm, open symbols) indicate the response to combined effects of rising T,,T e n ,and local temperature while data from the arm kept cool indicate reflex responses only. Abbreviations as in FIGURE 1.
at rest; l1* l2. 2o thus the roles of skin and internal temperatures appear to be somewhat reversed between rest and exercise. That is, during whole-body direct heating at rest, there is only a minor contribution by skin temperature and a major contribution by internal temperature to cutaneous vasodilation. During 1 shows exercise, there appears to be a major effect of skin temperature. TABLE the results of multiple linear regression analysis of data from these protocols. These coefficients show the rise in forearm blood flow per O C rise in internal temperature and skin temperature, respectively. Data are given for both the cool arm and the arm warmed with the rest of the body, both at rest and during exercise. Note the increase in the response to skin temperature and the decrease in the response to internal temperature during exercise as opposed t o rest. These coefficients probably d o not apply to all levels of exercise. It is also likely that the level of internal temperature is a major determinant of the response to rising
Johnson : Skin Circulation
205
skin temperature. For example, one might hypothesize that the combined vasoconstrictor drives from low skin temperature, upright posture, and exercise would be sufficient to mask effects of vasodilator drive from increased internal temperature. When skin temperature is suddenly raised, however, much of this previously suppressed vasodilator drive is allowed to act, and skin blood flow rises markedly. Although this explanation is consistent with these observations, other models of control could also explain the data. The point here is that it is currently unclear how the various drives for skin blood flow interact, and that linear additive models for control of the cutaneous circulation by skin and internal temperatures are presumptive. Nevertheless, two points are evident from this analysis. First, the reflex vasomotor responses in skin to elevations in skin and/or internal temperature are markedly altered during exercise (as compared to rest). Second, the elevation in cardiac output with whole-body
33
I ,
,
I
I
I
1
0
20
W
40
50
60
MINUTES
FIGURE 8. FBF, T,.,, and HR responses to prolonged (30 min) exercise at high T , (38" C ) . At 5 min T, was elevated and when it had reached 38" C the subject began to exercise (125 W or 750 kpm/min). Note the rapid rise in FBF until 25 min (when T,.. had reached approximately 38" C ) after which there was little or no further rise in FBF, despite a marked further elevation in T,... Abbreviations as in FIGURE 1.
Annals New York Academy of Sciences
206
direct heating at rest 28 or during exercise 2 6 includes a significant component due to the direct local effects of elevating skin temperature. Taken together, the results from the three experiments discussed so far indicate the effect of skin temperature is essentially to inhibit or permit reflex vasomotor responses in skin to internal temperature. Thus, with exercise at a cool skin temperature, internal temperature rises appreciably, but is not accom4 & 5 ) . Removal of panied by a similar response in skin blood flow (FIGURES
RESULTSOF
REGRESSION
TABLE1 ANALYSIS FOR FBF RESPONSETO AT REST AND DURING EXERCISE *
CHANGE IN
T.
AND
T.,
Regression Coefficients Subject DG (rest) D G (825 kpmlmin; 135 W)
RK (rest) RK (600 kpm/min; 100 W)
G N (rest) G N (750 kpmlmin; 125 W) DW (rest) DW (750 kpmlmin; 125 W ) SF (750 kpmlmin; 125 W) JJ (525 kpm/min; 88 W )
C W C W C W C W C W C W C W C W C W C W
9.78 10.15 3.77 3.89 10.19 7.93 3.69 5.16 17.45 24.35 1.13 2.08 14.78 10.09
NS NS 1.62 3.15
NS NS
NS 0.80 1.28 2.53 0.12 1.03 1.44 2.54 0.17 0.48 1.05 1.76
NS 1.49 2.14 2.53 0.72 1.36 0.42 1.02
* See FIGURE 6 for specific protocol. Subjects are listed according to whether the study was done at rest or during exercise. Work loads are given in parenthesis. Regression coefficients for the arm kept cool (C)and for the arm warmed according to the whole-body T, protocol (W) show the rise in FBF per degree rise in T., (a) and the rise in FBF per degree rise in T. ( p ) . NS indicates the value was not significantly different from 0. Units for a and p are m1/100 ml.min."C. this inhibition due to low skin temperature (by elevating skin temperature) before (FIGURES 2 & 3 ) or during exercise (FIGURES 6 & 7 ) allows much of the effect of the elevation in internal temperature to become manifest. Parenthetically, skin blood flow is reflexly controlled by two distinct arms of the sympathetic nervous 43 It is consistent with these results and the findings of others 11, 4 3 - 44 that the vasoconstrictor arm is responsive to changes in skin temperature, while the vasodilator arm is responsive to changes in in-
Johnson: Skin Circulation
207
ternal temperature. As vasoconstrictor outflow to skin is also increased by upright posture and exercise, it seems likely that such augmented vasoconstrictor outflow would restrict responses to rising vasodilator outflow. Thus, during the first few minutes of upright exercise at a cool skin temperature, internal temperature could rise by a significant amount without a corresponding rise in skin blood flow. This is what we observed. Withdrawal of a significant portion of the vasoconstrictor outflow due to rising skin temperature would allow the effects of previously overridden vasodilator outflow to become manifest. The findings in the foregoing experiment are consistent with such a scheme of control for skin blood flow. Responses to Prolonged Exercise at High Skin Temperature
Whatever the involvement of the two arms of the sympathetic nervous system in the control of skin blood flow, the "leveling off' phenomenon was unexpected. Heat stress at even higher levels of skin and internal temperatures reveal no comparable phenomenon at 11' To insure that such an observation was not in some way dependent on the specific protocol, we elevated skin temperature to 38" C just prior to the initiation of 30 minutes of exercise."? FIGURE 8 shows the results of one such study. This protocol is identical to that in the first series of experiments reported here, except that the duration of exercise was extended to 30 minutes. As seen in the experiment shown in FIGURE 8, forearm blood flow rose with internal temperature in a linear fashion. However, at an esophageal temperature of approximately 38" C, forearm blood flow leveled off. Thus skin blood flow responds to rising internal temperature during exercise only over a limited range of internal temperature. Although not all subjects revealed the "leveling off' phenomenon as dramatically as in this case, most did. Further, no subject showed more than a modest rise in forearm blood flow above an esophageal temperature of 38" C, despite further large increments in internal temperature. Such a phenomenon shows that the ability of the cardiovascular system to meet extreme challenges to temperature regulation during exercise is severely limited. Only when skin temperature is raised, as in this experiment, is cardiac output known to rise when heat stress is added to exercise.25 Even in that case the elevation in cardiac output is limited. Redistribution of blood flow from nonactive regions is also limited, leaving only active muscle as a possible source of blood flow to skin. Therefore, given that the supply of blood is limited, skin blood flow must have a limitation of its response during exercise. This is borne out by the observation, here, of the apparent upper limit to forearm skin blood flow. Such an upper limit would contribute to the hyperthermia of exercise in natural environments such as the marathon. DISCUSSION The experiments reported here show skin blood flow to be responsive to more than thermoregulatory drives. During exercise skin is vasoconstricted at any given level of internal temperature (relative to supine rest). Both posture and exercise per se contribute to the vasoconstrictor drive, while high internal temperature and skin temperature contribute to competing drives for vasodila-
208
Annals New
York Academy of Sciences
tion. Thus, at a given level of internal temperature, skin blood flow is less during exercise than at rest. These observations offer direct corroboration of a low skin blood flow in exercise predicted l 7 on the basis of ( a ) no increase in cardiac output, (b) limited redistribution capacity from the viscera, and (c) the ability to sometimes (but not always) achieve maximal oxygen consumption during exercise in the heat. The only situation wherein cardiac output is increased by heat stress during exercise occurs when the skin over the entire body surface is heated to high levels, as by water perfused suits. Even in this extreme situation, the elevation in skin blood flow (i.e., cardiac output) is limited. Thus, the elevation in cardiac output of only 2-2.5 liters/min observed previously,25 and the constancy of forearm blood flow above an internal temperature of approximately 3 8 ° C were both observed to accompany a rapid elevation in skin temperature during exercise. What are the consequences of such a competitive scheme of control for skin blood flow? First, the ability of the body to lose heat is compromised during exercise. Although sweat rate may be extremely high, convective transfer of heat to the surface is determined by skin blood flow. Second, compensatory vasoconstriction of splachnic and renal vascular beds becomes extreme during the combination of heat stress and exercise. Rowell et ~ 1 . 'observed ~ hepatic venous oxygen contents as low as 0.5 ml O , / 100 ml blood during heavy exercise in a hot environment. They also observed an outpouring of hepatic glucose that is often the sign of hepatic ischemia. Renal function is also subject to compromise, as indicated by findings of protein, red blood cells and myoglobin in urine following exercise in the heat.'".'' Clearly, as duration or humidity or level of exercise or ambient conditions become more extreme, the probability of heat stroke increases markedly. Comprehensive treatments of heat stroke .'M" show the incidence of heat deaths and disorders to be greatest when exercise, cardiovascular disease, and hot, humid environments are combined. A third consequence of vasomotor adjustments in skin is the redistribution of blood volume to cutaneous veins. As cutaneous blood flow rises, blood volume in cutaneous veins must also passively increase. Cutaneous venomotor activity has only been studied for short durations of exercise.l". 51, na There is a marked cutaneous venoconstriction at the initiation of exercise. As internal temperature rises, cutaneous venous compliance returns toward resting levels. If local skin temperature or whole body skin temperature is elevated, cutaneous venoconstrictor responses to exercise are abolished. At any level of cutaneous venous compliance, cutaneous blood volume will passively rise as veins are distended by rising skin blood flow. A high cutaneous blood volume is efficacious for heat elimination, i.e., linear velocity of blood is low, allowing time for heat transfer. However, a high cutaneous blood volume poses a problem for the central cardiovascular adjustments to exercise. As cutaneous blood volume rises, blood volume in other areas falls accordingly. Central blood volume and probably splanchnic blood volume fall, as does right atrial pressure.2z The consequent fall in cardiac filling pressures leads to a reduction in stroke volume.', 23 Compensatory increments in heart rate maintain cardiac output in a neutral environment,', but may fail to do so in hot ambient conditions.' Ironically, the mechanism that tends to slow the accumulation of blood in cutaneous veins is vasoconstriction (i.e., lowering the rate of filling) rather than venoconstriction (lowering the ultimate volume). With respect to the marathon, the relevance of these observations of CU-
Johnson: Skin Circulation
209
taneous vasomotor and venomotor adjustments to prolonged work or to work in the heat is as follows. First, work rates are generally quite highj3 and internal temperature often rises to high levels. Marathons are often conducted when ambient conditions (i.e., temperature and humidity) are elevated. Pugh et aL8 and Wyndahm et al.9 found the rectal temperature of marathon winners to be about 41 O C in mild environmental conditions. Heat stroke, injury, or death have occurred following marathon running, or cycling, with rectal temperatures as high as 43" C.lz Pathology of renal and splanchnic regions associated with excessive body temperatures following competitive events are common.4x-"fl, 3 1 As sweat rates are usually high, these high levels of internal temperature are due to relatively low levels of skin blood flow. Finally, measurements of air temperature do not consider the radiant heat loads to which the competitor is subjected. On a clear day, solar radiation can be a major source of heat. Simulation of solar radiant heating can yield skin temperatures of 3 7 ' 4 1 " C in exposed areas at rest.;>-;: However, equivalent data from exercise are unavailable. Thus skin blood flow participates in reflexes other than those involved in temperature regulation. The temperature we maintain in conditions other than supine rest is largely the resultant of competing vasodilator and vasoconstrictor drives to skin. When drives for vasoconstriction are great, as the result of upright posture, exercise, or disease, temperature regulation can fall victim to blood pressure regulation and/or to adjustments to exercise. When heat stress becomes severe then even blood pressure regulation can fail, with pathologic consequences for renal and splanchnic tissues. The common findings of anuria and nausea are therefore not surprising. As the marathon represents possibly the greatest stress to which man voluntarily taxes his cardiovascular system, problems arising from competition for control of skin blood flow are a natural consequence, ACKNOWLEDGMENTS The author is grateful for helpful suggestions from Dr. Loring B. Rowel1 and Dr. Ethan R. Nadel. REFERENCES 1. EKLUND, L. G. 1972. Circulatory and respiratory adaptation during prolonged exercise. Acta Physiol. Scand. 70 (Suppl. 292). 2. SALTIN, B. & J. STENBERG. 1964. Circulatory response to prolonged severe exercise. J Appl. Physiol. 19: 833-838. C. G., G. A. G. BREDELL,C. H. WYNDHAM, N. B STRYDOM, J. F. 3. WILLIAMS, MORRISON, J. PETER,P. W. FLEMING & J S . WARD. 1962. Circulatory and metabolic reactions to work in the heat. J. Appl. Physiol. 17: 625-638. 4. ROWELL, L. B., H. J. MARX,R. A. BRUCE,R. D. CONN& F. KUSUMI.1966. Reductions i n cardiac output, central blood volume, and stroke volume with thermal stress in normal men during exercise. J. Clin. Invest. 45: 1801-1816. 5. GRIMBY, G. 1965. Renal clearances during prolonged supine exercise at different loads. J. Appl. Physiol. 20: 1294-1298. L. B., K. K. KRANING 11, T. 0. EVANS, J. W.KENNEDY, I. R. BLACKMON, 6. ROWELL, & F. KUSUMI. 1966. Splanchnic removal of lactate and pyruvate during prolonged exercise in man. J. Appl. Physiol. 21: 1773-1783.
Annals New York Academy of Sciences
210
7. ROBINSON,S. 1949. Physiological Adjustments to Heat. L. H. Newburgh, Ed. : 193-231. W. B. Saunders Company. Philadelphia, Pa. 8. PUGH,L. G. C. E., J. L. CORBETT& R. H. JOHNSON.1967. Rectal temperatures, weight losses, and sweat rates in marathon running. J. Appl. Physiol. 23: 347352. 9. WYNDHAM, C. H. & N. B. STRYDOM.1969. The danger of inadequate water intake during marathon running. S. Afr. Mrd. J . 43: 893-896. 10. C O S T U , D. L., W. F. KAMMER& A. FISHER. 1970. Fluid ingestion during distance running. Arch. Environ. Health 21: 520-525. 11. WYSS, C. R., G. L. BRENGELMANN, J. M. JOHNSON,L. B. ROWELL& M. NIEDERBERGER. 1974. Control of skin blood flow, sweating, and heart rate: role of skin vs. core temperature. J. Appl. Physiol. 36: 726-733. J. M. JOHNSON, L. B. ROWELL& D. SILVER12. WYSS, C. R., G. L. BRENGELMANN, STEIN. 1975. Altered control of skin blood flow at high skin and core temperatures. J. Appl. Physiol. 38: 839-845. 13. BLAIR,D. A., W. E. GLOVER & I. C. RODDIE.1961. Vasomotor responses in the human arm during leg exercise. Circ. Res. 9: 264-274. 14. BEVEGARD, B. S. & J. T. SHEPHERD.1966. Reaction in man of resistance and capacity vessels in forearm and hand to leg exercise. J. Appl. Physiol. 21: 123-132. 15. ZELIS,R., D .T. MASON& E. BRAUNWALD. 1967. Partition of blood flow to the 16. 17. 18. 19. 20.
cutaneous and muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. Circ. Res. 24: 799-806. Fox, R. H. & 0. G. EDHOLM. 1963. Nervous control of the cutaneous circulation. Brit. Med. Bull. 19: 110-1 14. ROWELL,L. B. 1974. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54: 75-159. KOROXENIDIS, G. T. & J. T. SHEPHERD.1961. Cardiovascular response to acute heat stress. J. Appl. Physiol. 16: 869-872. DETRY, J.-M. R., G . L. BRENGELMANN, L. B. ROWELL& C. WYSS. 1972. Skin and muscle components of forearm blood flow in directly heated resting man. J. Appl. Physiol. 32: 506-5 1 1. EDHOLM,0. G., R. H. Fox & R. K. MACPHERSON. 1956. The effect of body heating on the circulation in skin and muscle. J. Physiol. (London) 134: 612-
619. & R. F. WHELAN.1956. Evidence from venous 21. RODDIE,I. C., J. T. SHEPHERD 22. 23. 24. 25. 26.
oxygen saturation measurements that the increase in forearm blood flow during body heating is confined to the skin. J. Physiol. (London) 134: 444-450. JOHNSON, J. M., G. L. BRENGELMANN & L. B. ROWELL.1976. Interaction between local and reflex influences on human forearm skin blood flow. J. Appl. Physiol. 41: 826-83 1. JOHNSON, J. M. & L. B. ROWELL.1975. Forearm skin and muscle vascular responses to prolonged leg exercise in man. J. Appl. Physiol. 39: 920-924. WHITNEY,R. J. 1953. The measurement of volume changes in human limbs. J. Physiol. (London) 121: 1-27. ROWELL, L. B., J. A. MURRAY, G. L. BRENGELMANN & K. K. KRANING 11. 1969. Human cardiovascular adjustments to rapid changes in skin temperature during exercise. Circ. Res. 24: 71 1-724. ROWELL,L. B., G . L. BRENGELMANN & J. A. MURRAY.1969. Cardiovascular responses to sustained high skin temperature in resting man. J. Appl. Physiol.
27: 673-680. E. H., M. NIELSEN& B. HANNISDAHL. 1942. Investigations of the 27. CHRISTENSEN,
circulation in the skin at the beginning of muscular work. Acta Physiol. Scand. 4: 162-170.
IJ, J. W. KENNEDY & T. 0. EVANS. 1967. Cen28. ROWELL,L. B., K. K. KRANJNG tral circulatory responses to work in dry heat before and after acclimatization. J. Appl. Physiol. 22: 509-518.
Johnson: Skin Circulation
21 1
J. M., L. B. ROWELL& G . L. BRENGELMANN. 1974. Modification of 29. JOHNSON, the skin blood flow-body temperature relationship by upright exercise. J. Appl. Physiol. 37: 880-886. 1970. 30. BEISER,G. D., R. ZELIS,S. E. EPSTEIN,D. T. MASON& E. BRAUNWALD. The role of skin and muscle redistance vessels in reflexes mediated by the baroreceptor system. J. Clin. Invest. 49: 225-23 1. 1973. Sustained human 31. ROWELL,L. B., C. R. WYSS& G. L. BRENGELMANN. skin and muscle vasoconstriction with reduced baroreceptor activity. J. Appl. Physiol. 34: 639-643. R. J., A. D. M. GREENFIELD, G.C. PLASSARAS & D. STEPHENS.1966. 32. CROSSLEY, The interrelation of thermoregulatory and baroreceptor reflexes in the control of blood vessels in the human forearm. J. Physiol. (London) 183: 628-636. 33. JOHNSON,J. M., M. NIEDERBERGER, L. B. ROWELL,M. M. EISMAN& G. L. 1973. Competition between cutaneous vasodilator and vasoBRENGELMANN. constrictor reflexes in man. J. Appl. Physiol. 35: 798-803. 34. ROWELL,L. B., J. R. BLACKMON & R. A. BRUCE. 1966. Indocynanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man. J. Clin. Invest. 43: 1677-1690. C. B., A. HENSCHEL, 1. MINCKLER, A. FORSGREN & A. KEYS. 1948. 35. CHAPMAN, The effect of exercise on renal plasma flow in normal male subjects. J. Clin. Invest. 27: 639-644. J. A. MURRAY, K. K. KRANINGI1 & F. 36. ROWELL,L. B., G. L. BRENGELMANN, KUSUMI.1969. Human metabolic responses to hyperthermia during mild to maximal exercise. J. Appl. Physiol. 2 6 395-402. F., R. DEROANNE & J. M. PETIT. 1970. Maximal oxygen consumption 37. PIRNAY, in a hot environment. J. Appl. Physiol. 28: 642-645. L. H. & B. SALTIN.1968. Reduction of stroke volume and increase in 38. HARTLEY, heart rate after a previous heavier submaximal workload. Scand. J. Clin. Lab. Invest. 22: 211-223. 39. NIELSEN,M. 1938. Die Regulation der Korpertemperatur bei Muskelarbeit. Skand. Arch. Physiol. 79: 193-230. 40. ROWELL,L. B., J. R. BLACKMON, R. H. MARTIN,J. A. MAZZARELLA & R. A. BRUCE.1965. Hepatic clearance of indocynanine green in man under thermal and exercise stress. J. Appl. Physiol. 2 0 384-394. 41. RADIGAN, L. R. & S. ROBINSON.1949. Effects of environmental heat stress and exercise on renal blood flow and filtration rate. J. Appl. Physiol. 2: 185-191. J. R. BLACKMON, R. D. Twrss & F. KUSUMI. 42. ROWELL,L. B., G.L. BRENGELMANN, 1968. Splanchnic blood flow and metabolism in heat-stressed man. J. Appl. Physiol. 24: 475-484. 43. EDHOLM, 0. G., R. H. Fox & R. K. MACPHERSON. 1957. Vasomotor control of the cutaneous blood vessels in the human forearm. J. Physiol. (London) 139: 455-465. 44. RODDIE,I. C., J. T. SHEPHERD & R. F. WHELAN.1957. The vasomotor nerve supply to the skin and muscle of the human forearm. Clin. Sci. 1 6 67-74. 45. BRENGELMANN, G. L., J. M. JOHNSON, L. B. ROWELL,L. HERMANSEN & H. D. PATTON. 1976. Upper limit to skin blood flow in exercising man. Fed. Proc. 35: 482. & C. C. TISHER.1967. Nephropathy asso46. SCHRIER,R. W., H. S. HENDERSON ciated with heat stress and exercise. Ann. Int. Med. 67: 356-376. 47. SMITH,R. F. 1968. Exertional rhabdomyolysis in naval officer candidates. Arch. Int. Med. 121: 3 13-3 19. C. S. & A. R. LIND. 1964. Heat Stress and Heat Disorders. Davis. 48. LEITHEAD, Philadelphia, Pa. 49. ELLIS, F. P. 1972. Mortality from heat illness and heat-aggravated illness in the United States. Environ. Res. 5: 1-58. S., M. C. LANCASTER & Y. DANON.1976. Heat stroke: A review. 50. SHIBOLET, Aviat. Space Environ. Med. 47: 280-301.
212
Annals New York Academy of Sciences
J. M. R. DETRY& C. WYSS. 1971. Veno51. ROWELL,L. B., G. L. BRENGELMANN, 52. 53. 54.
55. 56. 57.
motor responses to rapid changes in skin temperature in exercising man. J. Appl. Physiol. 3 0 64-71. ZITNIK,R. S., E. AMBROSIONI & J. T. SHEPHERD.1971. Effect of temperature on cutaneous venomotor reflexes in man. J. Appl. Physiol. 31: 507-512. COSTILL,D. L. & E. L. Fox. 1969. Energetics of marathon running. Med. Sci. Sports. 1: 81-96. WYNDHAM, C. H. 1973. The physiology of exercise under heat stress. Ann. Rev. Physiol. 3 5 193-220. STOLWIJK, J. A. J. & J. D . HARDY. 1965. Skin and subcutaneous temperature changes during exposure to intense thermal radiation. J. Appl. Physiol. 20: 1006-1 0 13. NADEL, E. R., R. W. BULLARD & J. A. J. STOLWIIK.1971. Importance of skin temperature in the regulation of sweating. J. Appl. Physiol. 31: 80-87. HARDY,J. D . 1963. Thermal effects of solar radiation in man. Solar Effects on Building Design, No. 1007: 19-30.
INTRODUCTION Major demands on the circulation attending prolonged exercise are maintenance of blood flow to .working skeletal muscle, dissipation of heat arising from the increased metabolic activity of skeletal muscle and maintenance of arterial blood pressure. The cardiovascular system is often unable to meet these competing demands in such events as the marathon. Cardiac output is constant or little changed during prolonged steady-state exercise.', * Even when exercise is performed in hot environments, cardiac output is not increased over levels achieved at the same level of work in a cool envir~nment.~. Also, there are only small further reductions in visceral blood flow after the first few minutes of exercise.s*6 If blood flow to active skeletal muscle is maintained during prolonged exercise, skin blood flow and the regulation of internal temperature must suffer. Manifestations of this limitation have been observed '-lo where rectal temperatures as high as 41" C were measured after distance races. Skin thus represents the principle site of competition between thermal and nonthermal demands on blood flow distribution during exercise. Were the skin circulation regulated solely by body temperature, blood flow to skin would rise to high levels with the elevation in internal temperature accompanying exercise. In the face of a constant cardiac output, active muscle blood flow and/or arterial blood pressure would fall markedly in such a setting. However, if skin blood flow did not rise during exercise, internal temperature would quickly reach levels of extreme hyperthermia. Few studies have dealt directly with the competitive nature of regulation of the cutaneous circulation during prolonged exercise. Thus, studies have dealt with the responses of the cutaneous circulation to heating at rest l1, l2 or with the responses during exercise 13-15 but have not considered the similarities or differences between the two settings. The focus here, therefore, is on the control of skin blood flow during exercise. The objective is to show how competing demands for cardiac output limit skin blood flow. Emphasis is placed on how such control differs from that observed at rest. Specific problems attacked here include ( a ) whether skin blood low is lower during exercise than at the same level of internal temperature at rest, (b) the response of skin blood flow to prolonged work, (c) whether the reflex response of skin blood flow to rising skin temperature is influenced by exercise, and ( d ) the response of skin blood flow to the combination of heat stress and exercise when work in the heat is prolonged.
* This work was supported by National Heart and Lung Institute Grants HL-09773
and HL-16910.
195
196
Annals New York Academy of Sciences
Methods employed in this study have been reported in detail elsewhere. Since there is currently no method for the measurement of total skin blood flow, alterations in the vasomotor state of skin were assessed from changes in skin blood flow of the forearm. The neurogenic control of forearm skin blood flow reflects that over most of the body surface.16 Further, the increase in forearm blood flow reflects the pattern and extent of increments in total skin blood flow during whole body direct heating at rest.';, lS Briefly, changes in skin blood flow were assessed by measuring changes in forearm blood flow. Since forearm muscle blood flow does not rise during whole-body direct heating,19 indirect 21 local heating of the forearm,22 or leg exercise,13*2 3 elevations in forearm blood flow are confined to skin. Forearm blood flow was measured by venous occlusion plethysmography with a mercury-in-silastic circumference Internal temperature was measured as esophageal temperature with a thermocouple at the level of the left atrium. Skin temperature was measured as the electrical average of ten thermocouples placed at representative sites over the body surface. Whole-body skin temperature was controlled in some studies by dressing the subject in a water-perfused suit and passing hot or cold water through the suit 26 Exercise was performed at a constant level on a bicycle ergometer. Workloads were chosen to represent moderate levels of exercise. Response of Skin Blood Flow to Rising Internal Temperature
A first step in the study of the cutaneous circulation during exercise was to find whether its regulation was indeed modified by upright exercise. A number of studies have noted an initial forearm or hand vasoconstriction with the onset of leg exercise, which was succeeded by a steady vasodilation as exercise continued.13-15*2i Zelis et found the initial forearm vasoconstriction to include both skin and muscle and to vary with the level of work. It was not clear from these studies whether the cutaneous vasoconstriction was of only a transient nature or, alternatively, whether the skin remained vasoconstricted relative to the level of internal temperature. Thus the critical question was, is this response different than what would have been observed at rest at the same level of internal temperature? To force internal temperature to rise at rest, it was necessary to conduct studies at an elevated skin temperature (controlled by water-perfused suits). Therefore, all of these studies were performed at the same elevated skin temperature. A temperature of 38" C was chosen as a level that would yield an elevation of approximately 1"-1.5" C in internal temperature at rest, and had been observed in exercise in hot, natural environments.2S Thus the relationship of forearm blood flow to internal temperature was observed in four settings: supine rest, supine exercise, upright rest, and upright exercise.29 FIGURES 1 and 2 show representative results from this study. Note that in FIGURE 1 the elevations in forearm blood flow and in internal temperature are considerably less in the upright than in the supine posture. These findings are consistent with earlier findings that the skin is vasoconstricted by o r t h o s t a ~ i s 31 ,~~~ and that this vasoconstriction is sustained in the face of a competing thermoregulatory drive for v a ~ o d i l a t i o n 33 . ~ ~FIGURE ~ 2 compares the responses to upright and supine exercise. Note that the postural effects mentioned above persist. FIGURE 3 relates forearm blood flow to esophageal temperature in each of the
UPRIGHT R E S T
I
FBF, mV100ml~min
r
minuter
15
37
38
c3
HR* bpm
120 r
in one subject. Whole-body skin temperature ( T , ) was held a t 38" C in each case. Note that during upright rest, esophageal temperature ( T c , ) rose more slowly, indicating a relatively vasoconstricted skin. This point is borne out by the low levels of FBF achieved in the upright posture. Responses in heart rate (HR) are also shown. (From Johnson et a/." By permission of the American Physiological Society.)
FIGURE1. Response of forearm blood flow (FBF) to whole-body direct heating during supine (left) and upright seated rest (right)
37
r
SUPINE R E S T
4
\o
c
..
198
Annals New York Academy of Sciences UPRIGHT
I
I
mlnutrs
FIGURE2. Responses of FBF, Ts,,and H R to upright (right) and supine (left) exercise at a T, of 38" C in one subject. Symbols and abbreviations are as in FIGURE 1. The periods of exercise are denoted by the vertical lines. Work load was 750 kpm/min (125 W) in each case. Note the more marked rise in FBF during supine (as compared to upright) exercise. (From Johnson ef al." By permission of the American Physiological Society. ) four conditions. There are several points to be made from these data. First, at a given level of internal temperature, forearm blood flow is lower in the upright position than in the supine posture either at rest or during exercise. Second, in either the upright or the supine posture, at a given level of internal temperature forearm blood flow was lower during exercise than at rest. Third, the forearm vasoconstriction relative to internal temperature is greatest when upright posture and exercise are combined. These results offer direct confirmation that skin remains relatively vasoconstricted during exercise. Although there is some elevation in skin blood flow as exercise continues and internal temperature rises, this elevation is much less than that observed at rest. Thus skin is on the efferent arm of vasoconstrictor reflexes associated with exercise per se, as are the splanchnic,e. 34 rena1,Ss 3 5 and resting skeletal muscle 13-15, 23 circulations. This augmented vasoconstrictor drive to skin yields an attenuated response to thermoregulatory reflexes arising from elevations in internal temperature. Such an attenuated response must exist at high levels of work, as maximum oxygen intake can be reached in a
Johnson: Skin Circulation
I99
hot However, sufficient heat stress can reduce maximal oxygen consumption,:" indicating that a large fraction of the cardiac output can be directed to skin in that setting. Response of Skin Blood Flow to Prolonged Exercise in Normal Environments Given the responses noted in the preceding section, one would predict similar restrictions on skin blood flow during upright exercise in a cool or neutral environment. An additional vasoconstricting drive would arise from the lower levels of skin temperature in that setting, as opposed to the elevated skin temperatures used in the study mentioned above. Several studies o * :ix noted progressive cardiovascular adjustments and responses to prolonged exercise. These include steadily falling central venous pressure, stroke volume, and mean arterial pressure, with a steadily rising heart rate and little or no change in cardiac output. Possible mechanisms for these changes have been recently reviewed." Briefly, one explanation for these findings (the so-called cardiovascular drift) 30, FBF. m1/100ml min DBG 27. 24-
21
"
-
365
37
325 TOS,
38
r:
FIGURE 3. Composite of responses in FBF to rising T.. during supine rest (SR), supine exercise (SX),upright rest (UR),and upright exericse (UX) in one subject. Skin temperature was 38" C in all cases. Data from each experiment were fitted with a regression line, as shown. Note that at a given level of T#,,FBF is reduced by upright posture both at rest and during exercise and that FBF is reduced by exercise in 1. (From Johnson et al.- By permission either posture. Abbreviations as in FIGURE of the American Physiological Society.)
Annals New York Academy of Sciences
200
is that prolonged heavy work results in myocardial fatigue.*, 38 Such a notion is supported to some extent by the finding of increased duration of systole attending prolonged exercise.l An alternative explanation offered by Rowell l7 points out that some or all of these changes might be accounted for by a steady peripheral displacement of blood volume. Such a displacement would reduce filling pressures and stroke volume. Heart rate increases would compensate for the reduction in stroke volume, maintaining cardiac output. A logical site for such a peripheral displacement of blood volume is the cutaneous vascular bed. Raising local compliance or pressure in cutaneous veins would raise this volume. Cutaneous venous pressure would passively rise in response to a similar increase in skin blood flow. Consistent with this explanation, we observed a progressive increase in forearm skin blood flow during one hour of continuous exerci~e.~3 The workload was 600 kpm/min (100 W) for one subject and 750 kpm/min (125 W) for the other four subjects. FIGURE4 shows results from one of these experiments.
HR, bpm
,
60 l e a , .C
365
12 -
1
I
1
1
I
1
I
FBF, mi/i00mi~min
16
8-
minuter
FIGURE4. Responses of FBF, Te,, and HR to one hour of exercise (750 kpm/ min; 125 W) in a neutral environment (ambient temperature 24" C ) . LFBF is left forearm blood flow and RFBF is right forearm blood flow. Other abbreviations as in FIGURE1. (From Johnson & Rowell." By permission of the American Physiological Society.)
Johnson: Skin Circulation
20 1
MBF. ml/ 100 mbmin
FBF, m1/100ml~min I2rI
-
FIGURE 5. Composite responses of HR, Tc,, forearm muscle blood flow (MBF), and FBF during rest and one hour of exercise from all subjects studied. Each bar shows the mean and standard error of the response for each parameter for each 10min period. MBF was measured from the clearance of a depot of yI]-antipyrine 1. injected 1 cm into the brachioradiolis muscle. Other abbreviations as in FIGURE (From Johnson & Rowell." By permission of the American Physiological Society.)
Thus we see a progressive rise in forearm blood flow, beginning at about 10 minutes of exercise and continuing throughout the remainder of the work period. FIGURE 5 shows the responses of the entire group, averaged over each 10-minute interval of exercise. Although skin blood flow progressively rose, and may indeed account for other circulatory changes attending prolonged exercise, the
202
Annals New York Academy of Sciences
final levels achieved were still less than what would be expected at a comparable level of internal temperature in a resting individual. The problems associated with the combination of an elevated internal temperature and a relatively low skin blood flow become increasingly severe with the level of work or environmental temperature. Rectal temperature is maintained at essentially the same level for a given workload over a wide variation in environmental temperature~,3~ indicating skin blood flow must be increased with environmental temperature. This increment in skin blood flow is apparently met by further redistribution of flow from the viscera,.lo~~*l as cardiac output is not increased.:{* However, as environmental conditions become more extreme, internal temperature is no longer stable and visceral blood flow reaches potentially ischemic 1evek4* Similarly, high levels of heat production can stress the ability of the cardiovascular system both to meet thermoregulatory needs and to deliver oxygen to skeletal muscle. Clearly, the combination of high levels of exercise and heat stress tax the cardiovascular system to severe limits. Influence of Skin Temperature during Exercise
The foregoing studies show that competition between body temperature regulation and exercise per se for the control of skin blood flow yields a vasoconstriction relative to the level of body temperature and a vasodilation relative to drives from upright posture and exercise. One notable difference between studies at high and neutral levels of skin temperature was that skin blood flow increased from the beginning when exercise was performed at a high level of skin temperature (FIGURE2) but failed to increase for the first 10 minutes of exercise in the study performed at a low skin temperature (FIGURE 4). This observation indicates that skin temperature plays an important role in the responses to rising internal temperature during exercise. However, observations on resting man assign only a minor role to skin temperature.ll?l 2 On the other hand, Rowell et aLZ5noted a marked rise in cardiac output in response to a rise in whole-body skin temperature during exercise. Is the reflex response to an elevation in skin temperature altered during exercise? Also, to what extent can the above elevation in cardiac output be ascribed to direct (nonreflex) effects of heating the skin? To answer these questions, whole-body skin temperature was rapidly raised during exercise, as well as at rest. Forearm blood flow was measured in both arms. One arm was left exposed to ambient conditions, or controlled at 32" C, thus reflecting reflex vasomotor adjustments. The other arm was warmed according to the wholebody skin temperature protocol, thus reflecting responses to combined direct and reflex effects of raising skin temperature. FIGURE 6 shows an example of one such study. At 10 minutes, exercise was initiated at 525 kpm/min (88 W) and at a skin temperature of 32" C. At 30 minutes, skin temperature was rapidly elevated toward 38" C. Esophageal temperature ( T e a )fell transiently, and during this period of rising skin temperature and reduced or unchanged esophageal temperature forearm blood flow rose markedly in both arms. Forearm blood flow (FBF) showed only a small further rise while skin temperature was held at 38" C and internal temperature rose above preheating levels. This was usually the case. FIGURE 7 shows the relation between FBF and T,, during the same protocol in another subject. In this case the workload was 750 kpm/min (125 W ) . Again, there was a prompt elevation
Johnson: Skin Circulation
203
in forearm blood flow in both arms with the elevation in skin temperature with no change in esophageal temperature. This corresponds to the vertical portion of the data in FIGURE7. Here, as in most subjects the level of forearm blood flow leveled off, despite a marked further rise in esophageal temperature. Of the six subjects studied with this protocol, four showed this "leveling off" pheI
35
I
525 kom/min
-
32;
1
0
10. O
@
0
20:
..
5-
0 aDO .
0.".
pP
U * dog
0
$&
0
0.
?-\ &%P
.
0 00 0 0 0%
0
,"
0
.
0
0
0 0
B
0 @o0O
0
,&*
"*# .S*%
: .* J
nomenon. Application of the same protocol to resting men revealed little or no elevation in forearm blood flow with rising skin temperature in the arm held at a neutral temperature, and only a modest elevation in the blood flow to the arm heated with the rest of the body. As in previous studies most of the increase in FBF was due to rising internal temperature during whole-body direct heating
Annals New York Academy of Sciences
204 20
-
FBF, m1/100ml~min
g o o 0
15.
0
0
0
0
0
0
0
8
0 0
0
10 '
0 0
e
m
' * e
e
*e
5.
I
O:S.s
37
I
37.5
Tor, .C
1
I
38
38.5
1
39
FIGURE 7. FBF vs T., from a protocol like that shown in FIGURE 6. The open symbols represent FBF from the arm heated according to the whole-body T , protocol and the closed symbols represent FBF from the arm kept,cool. The horizontal portion of the data (in the lower left hand portion of the plot) are from the period of rising T., and essentially constant FBF during the first few minutes of exercise at low T.. The vertical portion of the data show the response during the period of rapidly rising T, (imposed by water perfused suits) with unchanging Tea. The horizontal portion of the data in the upper right of the figure represent the final 10 min of exercise at a T. of 38" C. Data from the left (warmed arm, open symbols) indicate the response to combined effects of rising T,,T e n ,and local temperature while data from the arm kept cool indicate reflex responses only. Abbreviations as in FIGURE 1.
at rest; l1* l2. 2o thus the roles of skin and internal temperatures appear to be somewhat reversed between rest and exercise. That is, during whole-body direct heating at rest, there is only a minor contribution by skin temperature and a major contribution by internal temperature to cutaneous vasodilation. During 1 shows exercise, there appears to be a major effect of skin temperature. TABLE the results of multiple linear regression analysis of data from these protocols. These coefficients show the rise in forearm blood flow per O C rise in internal temperature and skin temperature, respectively. Data are given for both the cool arm and the arm warmed with the rest of the body, both at rest and during exercise. Note the increase in the response to skin temperature and the decrease in the response to internal temperature during exercise as opposed t o rest. These coefficients probably d o not apply to all levels of exercise. It is also likely that the level of internal temperature is a major determinant of the response to rising
Johnson : Skin Circulation
205
skin temperature. For example, one might hypothesize that the combined vasoconstrictor drives from low skin temperature, upright posture, and exercise would be sufficient to mask effects of vasodilator drive from increased internal temperature. When skin temperature is suddenly raised, however, much of this previously suppressed vasodilator drive is allowed to act, and skin blood flow rises markedly. Although this explanation is consistent with these observations, other models of control could also explain the data. The point here is that it is currently unclear how the various drives for skin blood flow interact, and that linear additive models for control of the cutaneous circulation by skin and internal temperatures are presumptive. Nevertheless, two points are evident from this analysis. First, the reflex vasomotor responses in skin to elevations in skin and/or internal temperature are markedly altered during exercise (as compared to rest). Second, the elevation in cardiac output with whole-body
33
I ,
,
I
I
I
1
0
20
W
40
50
60
MINUTES
FIGURE 8. FBF, T,.,, and HR responses to prolonged (30 min) exercise at high T , (38" C ) . At 5 min T, was elevated and when it had reached 38" C the subject began to exercise (125 W or 750 kpm/min). Note the rapid rise in FBF until 25 min (when T,.. had reached approximately 38" C ) after which there was little or no further rise in FBF, despite a marked further elevation in T,... Abbreviations as in FIGURE 1.
Annals New York Academy of Sciences
206
direct heating at rest 28 or during exercise 2 6 includes a significant component due to the direct local effects of elevating skin temperature. Taken together, the results from the three experiments discussed so far indicate the effect of skin temperature is essentially to inhibit or permit reflex vasomotor responses in skin to internal temperature. Thus, with exercise at a cool skin temperature, internal temperature rises appreciably, but is not accom4 & 5 ) . Removal of panied by a similar response in skin blood flow (FIGURES
RESULTSOF
REGRESSION
TABLE1 ANALYSIS FOR FBF RESPONSETO AT REST AND DURING EXERCISE *
CHANGE IN
T.
AND
T.,
Regression Coefficients Subject DG (rest) D G (825 kpmlmin; 135 W)
RK (rest) RK (600 kpm/min; 100 W)
G N (rest) G N (750 kpmlmin; 125 W) DW (rest) DW (750 kpmlmin; 125 W ) SF (750 kpmlmin; 125 W) JJ (525 kpm/min; 88 W )
C W C W C W C W C W C W C W C W C W C W
9.78 10.15 3.77 3.89 10.19 7.93 3.69 5.16 17.45 24.35 1.13 2.08 14.78 10.09
NS NS 1.62 3.15
NS NS
NS 0.80 1.28 2.53 0.12 1.03 1.44 2.54 0.17 0.48 1.05 1.76
NS 1.49 2.14 2.53 0.72 1.36 0.42 1.02
* See FIGURE 6 for specific protocol. Subjects are listed according to whether the study was done at rest or during exercise. Work loads are given in parenthesis. Regression coefficients for the arm kept cool (C)and for the arm warmed according to the whole-body T, protocol (W) show the rise in FBF per degree rise in T., (a) and the rise in FBF per degree rise in T. ( p ) . NS indicates the value was not significantly different from 0. Units for a and p are m1/100 ml.min."C. this inhibition due to low skin temperature (by elevating skin temperature) before (FIGURES 2 & 3 ) or during exercise (FIGURES 6 & 7 ) allows much of the effect of the elevation in internal temperature to become manifest. Parenthetically, skin blood flow is reflexly controlled by two distinct arms of the sympathetic nervous 43 It is consistent with these results and the findings of others 11, 4 3 - 44 that the vasoconstrictor arm is responsive to changes in skin temperature, while the vasodilator arm is responsive to changes in in-
Johnson: Skin Circulation
207
ternal temperature. As vasoconstrictor outflow to skin is also increased by upright posture and exercise, it seems likely that such augmented vasoconstrictor outflow would restrict responses to rising vasodilator outflow. Thus, during the first few minutes of upright exercise at a cool skin temperature, internal temperature could rise by a significant amount without a corresponding rise in skin blood flow. This is what we observed. Withdrawal of a significant portion of the vasoconstrictor outflow due to rising skin temperature would allow the effects of previously overridden vasodilator outflow to become manifest. The findings in the foregoing experiment are consistent with such a scheme of control for skin blood flow. Responses to Prolonged Exercise at High Skin Temperature
Whatever the involvement of the two arms of the sympathetic nervous system in the control of skin blood flow, the "leveling off' phenomenon was unexpected. Heat stress at even higher levels of skin and internal temperatures reveal no comparable phenomenon at 11' To insure that such an observation was not in some way dependent on the specific protocol, we elevated skin temperature to 38" C just prior to the initiation of 30 minutes of exercise."? FIGURE 8 shows the results of one such study. This protocol is identical to that in the first series of experiments reported here, except that the duration of exercise was extended to 30 minutes. As seen in the experiment shown in FIGURE 8, forearm blood flow rose with internal temperature in a linear fashion. However, at an esophageal temperature of approximately 38" C, forearm blood flow leveled off. Thus skin blood flow responds to rising internal temperature during exercise only over a limited range of internal temperature. Although not all subjects revealed the "leveling off' phenomenon as dramatically as in this case, most did. Further, no subject showed more than a modest rise in forearm blood flow above an esophageal temperature of 38" C, despite further large increments in internal temperature. Such a phenomenon shows that the ability of the cardiovascular system to meet extreme challenges to temperature regulation during exercise is severely limited. Only when skin temperature is raised, as in this experiment, is cardiac output known to rise when heat stress is added to exercise.25 Even in that case the elevation in cardiac output is limited. Redistribution of blood flow from nonactive regions is also limited, leaving only active muscle as a possible source of blood flow to skin. Therefore, given that the supply of blood is limited, skin blood flow must have a limitation of its response during exercise. This is borne out by the observation, here, of the apparent upper limit to forearm skin blood flow. Such an upper limit would contribute to the hyperthermia of exercise in natural environments such as the marathon. DISCUSSION The experiments reported here show skin blood flow to be responsive to more than thermoregulatory drives. During exercise skin is vasoconstricted at any given level of internal temperature (relative to supine rest). Both posture and exercise per se contribute to the vasoconstrictor drive, while high internal temperature and skin temperature contribute to competing drives for vasodila-
208
Annals New
York Academy of Sciences
tion. Thus, at a given level of internal temperature, skin blood flow is less during exercise than at rest. These observations offer direct corroboration of a low skin blood flow in exercise predicted l 7 on the basis of ( a ) no increase in cardiac output, (b) limited redistribution capacity from the viscera, and (c) the ability to sometimes (but not always) achieve maximal oxygen consumption during exercise in the heat. The only situation wherein cardiac output is increased by heat stress during exercise occurs when the skin over the entire body surface is heated to high levels, as by water perfused suits. Even in this extreme situation, the elevation in skin blood flow (i.e., cardiac output) is limited. Thus, the elevation in cardiac output of only 2-2.5 liters/min observed previously,25 and the constancy of forearm blood flow above an internal temperature of approximately 3 8 ° C were both observed to accompany a rapid elevation in skin temperature during exercise. What are the consequences of such a competitive scheme of control for skin blood flow? First, the ability of the body to lose heat is compromised during exercise. Although sweat rate may be extremely high, convective transfer of heat to the surface is determined by skin blood flow. Second, compensatory vasoconstriction of splachnic and renal vascular beds becomes extreme during the combination of heat stress and exercise. Rowell et ~ 1 . 'observed ~ hepatic venous oxygen contents as low as 0.5 ml O , / 100 ml blood during heavy exercise in a hot environment. They also observed an outpouring of hepatic glucose that is often the sign of hepatic ischemia. Renal function is also subject to compromise, as indicated by findings of protein, red blood cells and myoglobin in urine following exercise in the heat.'".'' Clearly, as duration or humidity or level of exercise or ambient conditions become more extreme, the probability of heat stroke increases markedly. Comprehensive treatments of heat stroke .'M" show the incidence of heat deaths and disorders to be greatest when exercise, cardiovascular disease, and hot, humid environments are combined. A third consequence of vasomotor adjustments in skin is the redistribution of blood volume to cutaneous veins. As cutaneous blood flow rises, blood volume in cutaneous veins must also passively increase. Cutaneous venomotor activity has only been studied for short durations of exercise.l". 51, na There is a marked cutaneous venoconstriction at the initiation of exercise. As internal temperature rises, cutaneous venous compliance returns toward resting levels. If local skin temperature or whole body skin temperature is elevated, cutaneous venoconstrictor responses to exercise are abolished. At any level of cutaneous venous compliance, cutaneous blood volume will passively rise as veins are distended by rising skin blood flow. A high cutaneous blood volume is efficacious for heat elimination, i.e., linear velocity of blood is low, allowing time for heat transfer. However, a high cutaneous blood volume poses a problem for the central cardiovascular adjustments to exercise. As cutaneous blood volume rises, blood volume in other areas falls accordingly. Central blood volume and probably splanchnic blood volume fall, as does right atrial pressure.2z The consequent fall in cardiac filling pressures leads to a reduction in stroke volume.', 23 Compensatory increments in heart rate maintain cardiac output in a neutral environment,', but may fail to do so in hot ambient conditions.' Ironically, the mechanism that tends to slow the accumulation of blood in cutaneous veins is vasoconstriction (i.e., lowering the rate of filling) rather than venoconstriction (lowering the ultimate volume). With respect to the marathon, the relevance of these observations of CU-
Johnson: Skin Circulation
209
taneous vasomotor and venomotor adjustments to prolonged work or to work in the heat is as follows. First, work rates are generally quite highj3 and internal temperature often rises to high levels. Marathons are often conducted when ambient conditions (i.e., temperature and humidity) are elevated. Pugh et aL8 and Wyndahm et al.9 found the rectal temperature of marathon winners to be about 41 O C in mild environmental conditions. Heat stroke, injury, or death have occurred following marathon running, or cycling, with rectal temperatures as high as 43" C.lz Pathology of renal and splanchnic regions associated with excessive body temperatures following competitive events are common.4x-"fl, 3 1 As sweat rates are usually high, these high levels of internal temperature are due to relatively low levels of skin blood flow. Finally, measurements of air temperature do not consider the radiant heat loads to which the competitor is subjected. On a clear day, solar radiation can be a major source of heat. Simulation of solar radiant heating can yield skin temperatures of 3 7 ' 4 1 " C in exposed areas at rest.;>-;: However, equivalent data from exercise are unavailable. Thus skin blood flow participates in reflexes other than those involved in temperature regulation. The temperature we maintain in conditions other than supine rest is largely the resultant of competing vasodilator and vasoconstrictor drives to skin. When drives for vasoconstriction are great, as the result of upright posture, exercise, or disease, temperature regulation can fall victim to blood pressure regulation and/or to adjustments to exercise. When heat stress becomes severe then even blood pressure regulation can fail, with pathologic consequences for renal and splanchnic tissues. The common findings of anuria and nausea are therefore not surprising. As the marathon represents possibly the greatest stress to which man voluntarily taxes his cardiovascular system, problems arising from competition for control of skin blood flow are a natural consequence, ACKNOWLEDGMENTS The author is grateful for helpful suggestions from Dr. Loring B. Rowel1 and Dr. Ethan R. Nadel. REFERENCES 1. EKLUND, L. G. 1972. Circulatory and respiratory adaptation during prolonged exercise. Acta Physiol. Scand. 70 (Suppl. 292). 2. SALTIN, B. & J. STENBERG. 1964. Circulatory response to prolonged severe exercise. J Appl. Physiol. 19: 833-838. C. G., G. A. G. BREDELL,C. H. WYNDHAM, N. B STRYDOM, J. F. 3. WILLIAMS, MORRISON, J. PETER,P. W. FLEMING & J S . WARD. 1962. Circulatory and metabolic reactions to work in the heat. J. Appl. Physiol. 17: 625-638. 4. ROWELL, L. B., H. J. MARX,R. A. BRUCE,R. D. CONN& F. KUSUMI.1966. Reductions i n cardiac output, central blood volume, and stroke volume with thermal stress in normal men during exercise. J. Clin. Invest. 45: 1801-1816. 5. GRIMBY, G. 1965. Renal clearances during prolonged supine exercise at different loads. J. Appl. Physiol. 20: 1294-1298. L. B., K. K. KRANING 11, T. 0. EVANS, J. W.KENNEDY, I. R. BLACKMON, 6. ROWELL, & F. KUSUMI. 1966. Splanchnic removal of lactate and pyruvate during prolonged exercise in man. J. Appl. Physiol. 21: 1773-1783.
Annals New York Academy of Sciences
210
7. ROBINSON,S. 1949. Physiological Adjustments to Heat. L. H. Newburgh, Ed. : 193-231. W. B. Saunders Company. Philadelphia, Pa. 8. PUGH,L. G. C. E., J. L. CORBETT& R. H. JOHNSON.1967. Rectal temperatures, weight losses, and sweat rates in marathon running. J. Appl. Physiol. 23: 347352. 9. WYNDHAM, C. H. & N. B. STRYDOM.1969. The danger of inadequate water intake during marathon running. S. Afr. Mrd. J . 43: 893-896. 10. C O S T U , D. L., W. F. KAMMER& A. FISHER. 1970. Fluid ingestion during distance running. Arch. Environ. Health 21: 520-525. 11. WYSS, C. R., G. L. BRENGELMANN, J. M. JOHNSON,L. B. ROWELL& M. NIEDERBERGER. 1974. Control of skin blood flow, sweating, and heart rate: role of skin vs. core temperature. J. Appl. Physiol. 36: 726-733. J. M. JOHNSON, L. B. ROWELL& D. SILVER12. WYSS, C. R., G. L. BRENGELMANN, STEIN. 1975. Altered control of skin blood flow at high skin and core temperatures. J. Appl. Physiol. 38: 839-845. 13. BLAIR,D. A., W. E. GLOVER & I. C. RODDIE.1961. Vasomotor responses in the human arm during leg exercise. Circ. Res. 9: 264-274. 14. BEVEGARD, B. S. & J. T. SHEPHERD.1966. Reaction in man of resistance and capacity vessels in forearm and hand to leg exercise. J. Appl. Physiol. 21: 123-132. 15. ZELIS,R., D .T. MASON& E. BRAUNWALD. 1967. Partition of blood flow to the 16. 17. 18. 19. 20.
cutaneous and muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. Circ. Res. 24: 799-806. Fox, R. H. & 0. G. EDHOLM. 1963. Nervous control of the cutaneous circulation. Brit. Med. Bull. 19: 110-1 14. ROWELL,L. B. 1974. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54: 75-159. KOROXENIDIS, G. T. & J. T. SHEPHERD.1961. Cardiovascular response to acute heat stress. J. Appl. Physiol. 16: 869-872. DETRY, J.-M. R., G . L. BRENGELMANN, L. B. ROWELL& C. WYSS. 1972. Skin and muscle components of forearm blood flow in directly heated resting man. J. Appl. Physiol. 32: 506-5 1 1. EDHOLM,0. G., R. H. Fox & R. K. MACPHERSON. 1956. The effect of body heating on the circulation in skin and muscle. J. Physiol. (London) 134: 612-
619. & R. F. WHELAN.1956. Evidence from venous 21. RODDIE,I. C., J. T. SHEPHERD 22. 23. 24. 25. 26.
oxygen saturation measurements that the increase in forearm blood flow during body heating is confined to the skin. J. Physiol. (London) 134: 444-450. JOHNSON, J. M., G. L. BRENGELMANN & L. B. ROWELL.1976. Interaction between local and reflex influences on human forearm skin blood flow. J. Appl. Physiol. 41: 826-83 1. JOHNSON, J. M. & L. B. ROWELL.1975. Forearm skin and muscle vascular responses to prolonged leg exercise in man. J. Appl. Physiol. 39: 920-924. WHITNEY,R. J. 1953. The measurement of volume changes in human limbs. J. Physiol. (London) 121: 1-27. ROWELL, L. B., J. A. MURRAY, G. L. BRENGELMANN & K. K. KRANING 11. 1969. Human cardiovascular adjustments to rapid changes in skin temperature during exercise. Circ. Res. 24: 71 1-724. ROWELL,L. B., G . L. BRENGELMANN & J. A. MURRAY.1969. Cardiovascular responses to sustained high skin temperature in resting man. J. Appl. Physiol.
27: 673-680. E. H., M. NIELSEN& B. HANNISDAHL. 1942. Investigations of the 27. CHRISTENSEN,
circulation in the skin at the beginning of muscular work. Acta Physiol. Scand. 4: 162-170.
IJ, J. W. KENNEDY & T. 0. EVANS. 1967. Cen28. ROWELL,L. B., K. K. KRANJNG tral circulatory responses to work in dry heat before and after acclimatization. J. Appl. Physiol. 22: 509-518.
Johnson: Skin Circulation
21 1
J. M., L. B. ROWELL& G . L. BRENGELMANN. 1974. Modification of 29. JOHNSON, the skin blood flow-body temperature relationship by upright exercise. J. Appl. Physiol. 37: 880-886. 1970. 30. BEISER,G. D., R. ZELIS,S. E. EPSTEIN,D. T. MASON& E. BRAUNWALD. The role of skin and muscle redistance vessels in reflexes mediated by the baroreceptor system. J. Clin. Invest. 49: 225-23 1. 1973. Sustained human 31. ROWELL,L. B., C. R. WYSS& G. L. BRENGELMANN. skin and muscle vasoconstriction with reduced baroreceptor activity. J. Appl. Physiol. 34: 639-643. R. J., A. D. M. GREENFIELD, G.C. PLASSARAS & D. STEPHENS.1966. 32. CROSSLEY, The interrelation of thermoregulatory and baroreceptor reflexes in the control of blood vessels in the human forearm. J. Physiol. (London) 183: 628-636. 33. JOHNSON,J. M., M. NIEDERBERGER, L. B. ROWELL,M. M. EISMAN& G. L. 1973. Competition between cutaneous vasodilator and vasoBRENGELMANN. constrictor reflexes in man. J. Appl. Physiol. 35: 798-803. 34. ROWELL,L. B., J. R. BLACKMON & R. A. BRUCE. 1966. Indocynanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man. J. Clin. Invest. 43: 1677-1690. C. B., A. HENSCHEL, 1. MINCKLER, A. FORSGREN & A. KEYS. 1948. 35. CHAPMAN, The effect of exercise on renal plasma flow in normal male subjects. J. Clin. Invest. 27: 639-644. J. A. MURRAY, K. K. KRANINGI1 & F. 36. ROWELL,L. B., G. L. BRENGELMANN, KUSUMI.1969. Human metabolic responses to hyperthermia during mild to maximal exercise. J. Appl. Physiol. 2 6 395-402. F., R. DEROANNE & J. M. PETIT. 1970. Maximal oxygen consumption 37. PIRNAY, in a hot environment. J. Appl. Physiol. 28: 642-645. L. H. & B. SALTIN.1968. Reduction of stroke volume and increase in 38. HARTLEY, heart rate after a previous heavier submaximal workload. Scand. J. Clin. Lab. Invest. 22: 211-223. 39. NIELSEN,M. 1938. Die Regulation der Korpertemperatur bei Muskelarbeit. Skand. Arch. Physiol. 79: 193-230. 40. ROWELL,L. B., J. R. BLACKMON, R. H. MARTIN,J. A. MAZZARELLA & R. A. BRUCE.1965. Hepatic clearance of indocynanine green in man under thermal and exercise stress. J. Appl. Physiol. 2 0 384-394. 41. RADIGAN, L. R. & S. ROBINSON.1949. Effects of environmental heat stress and exercise on renal blood flow and filtration rate. J. Appl. Physiol. 2: 185-191. J. R. BLACKMON, R. D. Twrss & F. KUSUMI. 42. ROWELL,L. B., G.L. BRENGELMANN, 1968. Splanchnic blood flow and metabolism in heat-stressed man. J. Appl. Physiol. 24: 475-484. 43. EDHOLM, 0. G., R. H. Fox & R. K. MACPHERSON. 1957. Vasomotor control of the cutaneous blood vessels in the human forearm. J. Physiol. (London) 139: 455-465. 44. RODDIE,I. C., J. T. SHEPHERD & R. F. WHELAN.1957. The vasomotor nerve supply to the skin and muscle of the human forearm. Clin. Sci. 1 6 67-74. 45. BRENGELMANN, G. L., J. M. JOHNSON, L. B. ROWELL,L. HERMANSEN & H. D. PATTON. 1976. Upper limit to skin blood flow in exercising man. Fed. Proc. 35: 482. & C. C. TISHER.1967. Nephropathy asso46. SCHRIER,R. W., H. S. HENDERSON ciated with heat stress and exercise. Ann. Int. Med. 67: 356-376. 47. SMITH,R. F. 1968. Exertional rhabdomyolysis in naval officer candidates. Arch. Int. Med. 121: 3 13-3 19. C. S. & A. R. LIND. 1964. Heat Stress and Heat Disorders. Davis. 48. LEITHEAD, Philadelphia, Pa. 49. ELLIS, F. P. 1972. Mortality from heat illness and heat-aggravated illness in the United States. Environ. Res. 5: 1-58. S., M. C. LANCASTER & Y. DANON.1976. Heat stroke: A review. 50. SHIBOLET, Aviat. Space Environ. Med. 47: 280-301.
212
Annals New York Academy of Sciences
J. M. R. DETRY& C. WYSS. 1971. Veno51. ROWELL,L. B., G. L. BRENGELMANN, 52. 53. 54.
55. 56. 57.
motor responses to rapid changes in skin temperature in exercising man. J. Appl. Physiol. 3 0 64-71. ZITNIK,R. S., E. AMBROSIONI & J. T. SHEPHERD.1971. Effect of temperature on cutaneous venomotor reflexes in man. J. Appl. Physiol. 31: 507-512. COSTILL,D. L. & E. L. Fox. 1969. Energetics of marathon running. Med. Sci. Sports. 1: 81-96. WYNDHAM, C. H. 1973. The physiology of exercise under heat stress. Ann. Rev. Physiol. 3 5 193-220. STOLWIJK, J. A. J. & J. D . HARDY. 1965. Skin and subcutaneous temperature changes during exposure to intense thermal radiation. J. Appl. Physiol. 20: 1006-1 0 13. NADEL, E. R., R. W. BULLARD & J. A. J. STOLWIIK.1971. Importance of skin temperature in the regulation of sweating. J. Appl. Physiol. 31: 80-87. HARDY,J. D . 1963. Thermal effects of solar radiation in man. Solar Effects on Building Design, No. 1007: 19-30.
