JOURNALOF APPLIED PHYSIOLOGY Vol. 39, No. 6, December 1975. Printed
Forearm
in U.S.A.
skin and muscle
prolonged
vascular
responses to
leg exercise in man
JOHN M. JOHNSON AND LORING B. ROWELL Department of Physiology and Biophysics, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington 9819.5
JOHNSON, JOHN M., AND LORING B. ROWELL. Forearm skin and muscle zlascular responses to prolonged leg exercise in man. J. Appl. Physiol. 39(6) : 920-924. 1975.-To determine the cutaneous and resting skeletal muscle vascular responses to prolonged exercise, total forearm blood flow (FBF-plethysmography) (5 men) and forearm muscle blood flow (MBF-[1251]antipyrine clearance) (4 men) were measured throughout 55-60 min of bicycle exercise (600-750 kpm/min). Heart rate (HR) and esophageal temperature (T,,) were also measured throughout exercise. FBF showed only small changes during the first 10 min followed by progressive increments during the lo-40 min interval and smaller rises thereafter. For the full 60 min of exercise, there was an average increase in FBF of 8.26 ml/ 100 ml min. MBF showed an initial fall with the onset of exercise (on the average from 3.84 to 2.13 ml/l00 ml mmin) which was sustained or fell further as exercise continued, indicating that increments in FBF were confined to skin. Much of the increase in FBF occurred despite essentially constant T, + Results suggest that the progressive decrements in central venous pressure, stroke volume, and arterial pressure previously seen during prolonged exercise are due in part to progressive increments in cutaneous blood flow and volume.
Wenger et al. (23) measured forearm blood flow (FBF) increments during 30 min of leg exercise. It is unknown whether this increase was confined to skin or whether increments in contributed
THE
blood flow; temperature clearance; blood flow
FIRST
FEW
MINUTES
of
regulation; distribution
dynamic
plethysmography;
exercise
are
muscle response.
blood
flow
(MBF)
might
have
A further indication that cutaneous blood flow might progressively rise during prolonged exercise is the finding that central venous pressure, stroke volume, arterial pressure, and total peripheral resistance all show progressive reductions (8, 12). Th ese alterations indicate a peripheral shift of blood volume which might be displaced primarily to skin. Although skin venous tone usually returns to nearcontrol values during the first few minutes of exercise (18, 27), further increments in skin venous volume would be achieved by increasing skin blood flow (SkBF). One indication that SkBF might not be progressively increased during prolonged exercise is the finding that esophageal temperature (T,,) which closely parallels cutaneous vasodilatation at rest (25), often reaches a plateau after approximately 15-20 min of moderate exercise (14, 21) The major question asked in this study was whether SkBF shows a progressive rise during prolonged exercise. To answer this question, we plethysmographically measured FBF throughout 60 min of upright exercise. A second major question was whether resting MBF shows a sustained reduction during prolonged work. We therefore measured the response of forearrn MBF from the clearance of [1251]antipyrine from resting forearm muscle. These measurements would indicate whether increments in FBF were confined to skin and whether vasoconstriction of resting muscle is sustained throughout prolonged leg exercise.
l
regional indicator
forearm to this
accorn-
panied by increases in heart rate (HR), arterial blood pressure, and vasoconstriction in most nonactive regions. There is usually cutaneous vasoconstriction during the first few minutes of exercise, followed by a rise in cutaneous blood flow, presumably accompanying the rise in internal temperature (l-3, 11, 23, 26). When exercise is prolonged, vasoconstriction is maintained or increased in splanchnic (19) and renal (10) regions. However, other large vascular beds such as skin and nonworking skeletal muscle have not been thoroughly investigated during prolonged exercise. There are several indications that cutaneous blood flow might be progressively increased during prolonged exercise. Christensen and LNielsen (5) noted progressive increments in finger blood flow and volume during 30 min of leg exercise. However, it is unknown whether flow to nonacral regions, which are presumably under different control than acral regions (9), show a similar response. Kamon and Belding (12) noted gradual increments in “effective” dermal blood flow (calculated from heat uptake) in the forearm and hand during one hour of exercise. Similarly,
METHODS
Subjects were five normal men, aged 20-30 yr. All had participated in similar experiments previously, at which time they had been given thorough physical examinations and found to be in good health. Each subject was thoroughly acquainted with all aspects of the experiment before his informed consent was obtained. All experiments were conducted in a room maintained at 24 rt 1°C. Subjects were dressed only in shorts and shoes. Each experiment consisted of a 5- to lo-min period of upright, seated rest followed by 55-60 min of continuous exercise on a bicycle ergometer at a constant work load chosen to yield heart rates of approx. 130 beats/min during 920
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FOREARM
BLOOD
FLOW
DURING
PROLONGED
EXERCISE
the first 1’0 min of exercise. For experiments involving antipyrine washout, the control period was 20-25 min. This choice of work load prevented HR from reaching maximal values, but was of an intensity known to elicit marked vasoconstriction in visceral organs (17). Work load was 600 kpm/min for one subject and 750 kpm/min for the other four subjects. For a given experiment, FBF in one or both arms or FBF in one arm and MBF in the other arm were measured throughout the control, exercise, and recovery periods. Total FBF was measured by plethysmography in all subjects using a mercury-in-Silastic circumference gauge of Whitney’s design (24). Methods for obtaining plethysmograms during exercise and for calculation of FBF from plethysmographic curves have been previously described (4, 11). Briefly, a special arrangement of slings (one on each wrist) supported the relaxed forearm above venostatic level with forward and upward pull SO that the gauge and the arm moved together in translation. Such an arrangement usually gave high-quality records during upright exercise, examples of which are shown in Fig. 1. FBF was measured twice per min for 4 of every 5 min throughout each study while circulation to the hand was arrested. Forearm MBF was measured in four subjects from the clearance of [1251]antipyrine injected into a forearm muscle as previously described (6, 20). A single injection of 5 PCi in 0.05-0.08 ml sterile distilled water was made through a l-cm long, 30-gauge (0.3 mm) needle into the brachioradialis muscle while the subject was seated at rest on the bicycle. A small, light-weight scintillation detector (Harshaw, x x 9i in. thallium-activated NaI crystal) was attached to the forearm. The base of the 16-cm-long probe was lightly bound to the wrist by wrapping it with a 3-in.wide elastic bandage. The center of the crystal was positioned directly over the site of injection. This end of the probe was held to the arm by tape and collodion to prevent any movement of the crystal with respect to the depot. The probe was attached in this way to avoid compressing tissues beneath the probe so that MBF would not be restricted by these attachments. [1251]antipyrine activity was measured by feeding the output from the scintillation detector into a pulse height analyzer with settings appropriate for 1251 discrimination and counting the number of pulses each 10 s with a laboratory computer (Digital Equipment Corporation PDP 8E). Activity of [1251]antipyrine was then displayed as the natural logarithm of counts/s every 10 s.
921 MBF was computed every 2 min as A(log, counts/s)/& (assuming the partition coefficient between tissue and blood for antipyrine is one ( 13)). We delayed the beginning of exercise until the 15- to 20-min period of hyperemia which normally follows the [12jI]antipyrine injection had ended, as judged by stable MBF over two or more 2-min intervals. After such stability had been achieved, exercise began. To ensure that this technique could follow a rise in MBF, we had each subject contract his brachioradialis muscle several times immediately following the period of leg exercise (3 subjects) or just prior to the end of exercise (1 subject), while we continued to measure [1251]antipyrine clearance (see Fig. 3). T es9 measured with a thermocouple probe positioned at the level of the left atrium, and HR were measured throughout each experiment. HR and Tes were each sampled once per second and subsequently converted to 30-s averages RESULTS
Major findings of this study were: I) a progressive rise in FBF throughout the one hour of exercise, and 2) a fall in forearm MBF at the beginning of exercise which was sustained throughout the work period. Figure 2 shows results for FBF, Tes , and HR from a representative subject for the control, exercise, and recovery periods. Figure 3 shows [1251]antipy rine activity and calculated forearm MBF for these three periods, again from one subject. Averages for all measured responses are shown in Fig. 4. Values from each subject were averaged over each lo-min interval and the values from all subjects averaged for this composite. Average values for FBF from the first 10 min of exercise varied only slightly from control levels (overall fall FBF rose in average of - 0.1 ml/ 100 ml min). Thereafter, increments of 3.09, 2.64, 1.52, 0.27, and 0.74 ml/100 ml* min, respectively, over each succeeding lo-min interval, or a total average rise of 8.26 ml/ 100 ml min. Thus, the major fraction of the rise in FBF occurred over the lo- to 40-min interval, with only small changes occurring before or afterwards. l
l
150 -
too
HI?,
bpm
-
;;;;
FBF,
ml/1OOml~min
16IZ-
* OO
1. Plethysmographic records taken at 50 min of exercise indicating quality of curves usually seen when both arms were used for plethysmography during exercise. LFBF = left forearm blood flow; RFBF = right forearm blood flow. FIG.
I IO
20
I 30
I 40
1 50
1 60
I 70
J
80
minutes
FIG. 2. Heart rate (HR), esophageal temperature (T& and left and right forearm blood flows (FBF) from 1 subject during upright rest, 59 min of upright exercise at 750 kpm/min, and recovery.
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922
J. M.
(F
MBF, ml/l00mldn
6
Ln counts /min
JOHNSON
AND
L. B. ROWELL
average of 120 beats/min for O-10 min of exercise to 148 beats/min for the 50- to 60-min interval. Similarly, T,, rose from a resting control value of 37.09”C to 37.16, 37.65, 37.75, 37.79, 37.85, and 37.92”C for the six lo-min intervals of exercise. During the initial lo-min interval of exercise, T,, showed a fall, followed by a fast rise (see Fig. 2) so that the average values were not greatly different from control although a major portion of the rise in T,, occurred during the first 10 min of exercise. DISCUSSION
8-
‘0
I 20
I IO
I I 40 50 minutes
I 30
I 60
1 70
80
90
FIG. 3. Lower: clearance curve from an injection of 5 &i [1251]antipyrine into forearm muscle during rest, exercise, and recovery. Upper: muscle blood flow (MBF) calculated from disappearance of [1251]antipyr ine. Subject exercised his forearm between 84 and 88 min. Increased MBF at that time indicates [Y]antipyrine clearance was not diffusion limited. 150 120 90 60 Tea,
%
38
37.5
ITI
37
MBF, 4-
I ml/
T
1
I
0. ml/l00ml
min
l2r
IO -
9 v
a-
T,
6-
4-
2-
06
control
o-lo
lO-20 minutes
20-30 of exercise
30-40
40-50
SO-60
FIG. 4. Averages and standard errors for HR, Tes, MBF, for control and each lo-min portion of prolonged exercise subjects. Abbreviations as in previous figures.
and FBF from all
That these changes in FBF are confined to the skin is supported by the [1251]antipyrine clearances from forearm muscle (see Fig. 3). Average control MBF was 3.84 ml/ 100 ml of muscle per min and fell to 2.13 ml/ 100 ml min during the first 10 min of exercise. Thereafter, MBF showed a further slight fall. MBF averaged 1.75, 1.27, 1.50, 1.40, and lo-min 1.66 ml/ 100 ml min over the five succeeding intervals, respectively. HR increased with the time of exercise. HR rose from an l
l
.
*
100 ml.min
4
FBF,
The finding that FBF rises progressively throughout prolonged exercise is in accord with the previous findings that finger blood flow (5) and “effective” dermal blood flow of the hand and forearm (12) tend to rise throughout exercise. The finding of a sustained fall in forearm MBF throughout prolonged exercise indicates that the progressive rise in FBF is confined to the skin and that resting skeletal muscle does not eventually vasodilate and contribute to the fall in blood pressure. Progressively rising cutaneous blood flow coupled with the previous findings of falling cutaneous venous tone during exercise (18, 27) indicates that skin is a major site of falling peripheral resistance and rising peripheral blood volume. Although these results do not prove that the downward drift in arterial and central venous pressures and in stroke volume attending prolonged exercise are due to progressive increments in cutaneous blood volume, our data are consistent with such a notion. The question whether areas other than skin could contribute to the fall in peripheral resistance or to the redistribution of blood volume remains unanswered. While it has been shown that both the splanchnic (19) and renal (6) vascular beds have a sustained or increased vasoconstriction with prolonged exercise, it is unknown whether blood flow to active skeletal muscle is constant throughout prolonged exercise. Unfortunately, current methods for measurement of active MBF are not well suited to answering this question. What might be the magnitude of the rise in whole body SkBF during prolonged work? Extrapolation from FBF values are, of course, risky since one has to presume that forearm skin is quantitatively representative of skin over the whole body. In this regard, we estimated the increment in total SkBF during whole body direct heating at rest to be 7.8 l/min (16). This estimate is based upon the increase in cardiac output plus the observed fall in blood flow to other regions during whole body heating at rest. In our subjects, whose average body surface area is commonly about 1.8 m2 and whose average arm circumference is about 27 cm, one would predict on the basis of the surface area of 100 ml of forearm that FBF in those studies should rise by 20 ml/ 100 mlmin. This, in fact, was about the average increment in FBF observed for this level and duration of heating (6). Assuming that such a correspondence is not fortuitous and prevails for forearm vascular responses during prolonged exercise, one would predict on the basis of the average increase in FBF of 8 ml/ 100 ml min an increase in total SkBF of about 3 l/min. Clearly, such an increase in SkBF is greater than what one would expect from previous observations showing nearly constant (8, 22) cardiac output during prolonged exercise. Furthermore, additional vasoconstric_
.
I
l
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FOREARM
BLOOD
FLOW
DURING
PROLONGED
EXERCISE
tion with prolonged exercise in the splanchnic (19) and renal (10) regions would contribute only a few hundred noted in forearm ml/min to skin. The vasoconstriction muscle, if representative of all resting skeletal muscle, would also contribute an additional blood flow to skin of only a few hundred ml/min. The only remaining regional circulation which could provide significant blood flow redistribution to skin by vasoconstriction would be working skeletal muscle. Again, available techniques are not adequate to reveal a I- to 2-l/min reduction in blood flow to working skeletal muscle during prolonged exercise. We do know that sympathetic outflow increases in some regions during this stress, at least as suggested by increments in HR and in splanchnic and renal vascular resistances. However, we do not know in man whether such sympathetic outflow is directed to working skeletal muscle as well. If it is, then previous findings in dogs (7) that even markedly vasodilated active skeletal muscle will respond to increased vasoconstrictor activity could be of significance. Presently, however, we know of no evidence which suggests a reduction in active MBF under the conditions of prolonged exercise. Regardless of the source or magnitude of the increase in SkBF, the relationship of the increase to T,, was somewhat surprising. During the first lo-20 min of exercise there were only small changes in FBF whereas during the same period most of the change in T,, had occurred. During the last 40 min of exercise, there was little or no change in T,, while there were major increments in FBF. In some subjects there appeared to be no correlation between FBF and T,,. Figure 5 shows FBF plotted versus T,, throughout exercise for one subject. This subject, as well as others, showed a significant forearm vasodilatation during a period of essentially conwe found that during 7-10 min of stant T,,. Previously, exercise at an elevated skin temperature, the FBF-T,, slope was significantly reduced by upright exercise, as compared to supine rest (11). However, such slopes from the current experiment were higher than those usually observed at rest. The lowest slope observed during prolonged exercise was 25 ml/l00 ml .rnin “C when only the period of forearm vasodilatation is considered. Even so, the final levels of FBF observed during prolonged exercise were less than levels previously observed for the same internal temperature at rest (6, 11, 25). Thus, the previous conclusion that skin is relatively vasoconstricted by upright exercise (11) is upheld by the current experiment, albeit the conclusion that the FBF-T,, slope is affected is not. Such a finding suggests that during exercise T,, might not be a proper index of thermoregulatory drive for cutaneous vasodilatation. That is, there may be important thermosensitive centers whose temperatures significantly lag behind that of T,, during exercise. Certainly increments in SkBF during whole body direct heating at rest have been shown to correlate well with T,, (25). Whether such a relationship persists during exercise deserves further study. If T,, is an adequate index of the thermoregulatory drive for cutaneous vasodilatation during exercise, these results
923 F BF,
ml/ IOOml~min
0
RFBF
I
I
37
37.5 Tes, OC
I
38
FIG. 5. LFBF (filled circles) and RFBF (open circles) plotted Tee throughout 60 min of exercise. Note period of rising FBF with change in Tes. Abbreviations as in Fig. 2.
vs. no
indicate one or a combination of several. possible mechanisms. First, there may be a shift in the thermoregulatory set point (as implied by Nielsen (15)), with exercise such that cutaneous vasodilatation does not begin until T,, has risen by about 0.5”C. However, such a mechanism would not explain a rising SkBF with a constant T,,. Alternatively, increased vasoconstrictor outflow accompanying prolonged exercise at a cool skin temperature may yield an FBF-T,, relationship which no longer has the linear relationship seen at rest (25) or during exercise at a high skin temperature (11). Also, vasoconstrictor outflow to skin or the responsiveness of skin to sustained vasoconstrictor outflow may not be sustained but may tend to fall as exercise is prolonged. This latter situation would probably yield a progressive rise in SkBF at a constant thermal drive for vasodilatation (and constant T,,). Clearly, this experiment was not designed to discriminate between these possible mechanisms. In conclusion, it has been shown that forearm SkBF shows a progressive upward rise during prolonged exercise, whereas resting forearm MBF shows a sustained vasoconstriction. Such a finding is consistent with the hypothesis that the progressive fall in arterial and central venous pressures and in stroke volume and the rise in HR attending prolonged exercise is due to a gradual displacement of blood volume and blood flow to skin. However, others have suggested that altered cardiac function (8, 22) might also attend prolonged exercise and contribute to these changes. We gratefully acknowledge the assistance of Mrs. Evelyn C. Steen, R.N., Mr. Michael McKeag, and Ms. Pam Stevens. This work was supported by National Heart and Lung Institute Grant HL-16910. A part of this study was conducted through the Clinical Research Facility of the University of Washington supported by National Institutes of Health Grant RR-37. Received
for publication
20 March
1975.
REFERENCES 1. BEVEG~RD, capacity Physiol.
B. S., AND J. T. SHEPHERD. Reactions of resistance and vessels in forearm and hand to leg exercise. J. AppZ. 21: 123-132, 1966.
2.
BISHOP, J. M., K. W. DONALD, S. H. TAYLOR, WORMALD. The blood flow in the human arm during exercise. J. Physiol., London 137 : 294-308, 1957.
P. N. supine leg
AND
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924 3. BLAIR, D. A., W. E. GLOVER, AND I. C. RODDIE. Vasomotor responses in the human arm during leg exercise. Circulation Res. 9: 264-274, 196 1. G. L., C. R. WYSS, AND L. B. ROWELL. Control of 4. BRENGELMANN, forearm skin blood flow during periods of steadily increasing skin temperature. J. APPZ. Physiol. 35: 77-84, 1973. Investiga5. CHRISTENSEN, E. H., M. NIELSEN, AND B. HANNISDAHL. tions of the circulation in the skin at the beginning of muscular work. Acta Physiol. &and. 4 : 162-l 70, 1942. R., G. L. BRENGELMANN, L. B. RO~ELL, AND C. 6. DETRY, J.-M. WYSS. Skin and muscle components of forearm blood flow in directly heated resting man. J. AppZ. Physiol. 32 : 506-511, 1972. 7. DONALD, D. E., D. J. ROWLANDS, AND D. A. FERGUSON. Similarity of blood flow in the normal and sympathectomized dog hind limb during graded exercise. Circulation Res. 26 : 185-199, 1970. 8. EKLUND, L. G. Circulatory and respiratory adaptation during prolonged exercise. Acta Physiol. &and. SuppZ. 292, 1967. 9. Fox, R. H., AND 0. G. EDHOLM. Nervous control of the cutaneous circulation. Brit. Med. Bull. 19 : 1 lo- 114, 1963. 10. GRIMBY, G. Renal clearances during prolonged supine exercise at different loads. J. AppZ. Physiol. 20: 1294-1298, 1965. 11. JOHNSON, J. M., L. B. RO~ELL, AND G. L. BRENGELMANN. Modification of the skin blood flow-body temperature relationship by upright exercise. J. AppZ. Physiol. 37 : 880-886, 1974. 12. KAMON, E., AND H. S. BELDING. Dermal blood flow in the resting arm during prolonged leg exercise. J. AppZ. Physiol. 26 : 317-320, 1969. 13. LINDBJERG, I. F. Disappearance rate of 133xenon, 4-iodo-antipyrine-1311 and 1311- from human skeletal muscles and adipose tissue. Stand. J. CZin. Lab. Invest. 19 : 120-128, 1967. during work at 14. NIELSEN, B., AND M. NIELSEN. Body temperature different environmental temperatures. Acta Physiol. Stand. 56 : 120-129, 1962. der Korpertemperatur bei Muskel15. NIELSEN, M. Die Regulation arbeit. Skand. Arch. Physiol. 79 : 193-230, 1938. 16. ROWELL, L. B. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54 : 75-l 59, 1974.
J.
M.
JOHNSON
AND
L. B. ROWELL
L. B., J. R. BLACKMON, R. H. MARTIN, J. A. MAZZA17. RO~ELL, RELLA, AND R. A. BRUCE. Indocyanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man. J. CZin. Invest. 43 : 1677-1690, 1964. 18. RO~ELL, L. B., G. L. BRENGELMANN, J.-M. R. DETRY, AND C. WYSS. Venomotor responses to rapid changes in skin temperature in exercising man. J. AppZ. Physiol. 30 : 64-74, 197 1. L. B., K. K. KRANING II, T. 0. EVANS, V. W. KENNEDY, 19. ROWELL, J. R. BLACKMON, AND F. KUSUMI. Splanchnic removal of lactate and pyruvate during prolonged exercise in man. J. AppZ. Physiol. 21: 1773-1783, 1966. L. B., C. R. WYSS, AND G. L. BRENGELMANN. Sustained 20. ROWELL, human skin and muscle vasoconstriction with reduced baroreceptor activity. J. AppZ. Physiol. 34: 639-643, 1973. Esophageal, rectal and muscle 21. SALTIN, B., AND L. HERMANSEN. temperature during exercise. J. APPZ. Physiol. 21: 1757-l 762, 1966. response to prolonged 22. SALTIN, B., AND J. STENBERG. Circulatory severe exercise. J. AppZ. Physiol. 19: 833-838, 1964. 23. WENGER, C. B., M. F. ROBERTS, J. A. J. STOLWIJK, AND E. R. NADEL. Forearm blood flow during body temperature transients produced by leg exercise. J. APPZ. Physiol. 38 : 58-63, 1975. R. J. The measurement of volume changes in human 24. WHITNEY, limbs. J. Physiol., London 12 1: l-27, 1953. J. M. JOHNSON, L. B. ROWELL, 25. WYSS, C. R., G. L. BRENGELMANN, AND M. NIEDERBERGER. Control of skin blood flow, sweating and heart rate: role of skin vs. core temperature. J. A@Z. Physiol. 36: 326-733, 1974. Partition of blood 26. ZELIS, R., D. T. MASON, AND E. BRAUNWALD. flow to the cutaneous and muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. Circulation Res. 24: 799-806, 1969. AND J. T. SHEPHERD. Effect of 27. ZITNICK, R. S., E. AMBROSIONI, temperature on cutaneous venomotor reflexes in man. J. APPZ. Physiol. 31: 507-512, 1971.
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Forearm
in U.S.A.
skin and muscle
prolonged
vascular
responses to
leg exercise in man
JOHN M. JOHNSON AND LORING B. ROWELL Department of Physiology and Biophysics, and Department of Medicine, University of Washington School of Medicine, Seattle, Washington 9819.5
JOHNSON, JOHN M., AND LORING B. ROWELL. Forearm skin and muscle zlascular responses to prolonged leg exercise in man. J. Appl. Physiol. 39(6) : 920-924. 1975.-To determine the cutaneous and resting skeletal muscle vascular responses to prolonged exercise, total forearm blood flow (FBF-plethysmography) (5 men) and forearm muscle blood flow (MBF-[1251]antipyrine clearance) (4 men) were measured throughout 55-60 min of bicycle exercise (600-750 kpm/min). Heart rate (HR) and esophageal temperature (T,,) were also measured throughout exercise. FBF showed only small changes during the first 10 min followed by progressive increments during the lo-40 min interval and smaller rises thereafter. For the full 60 min of exercise, there was an average increase in FBF of 8.26 ml/ 100 ml min. MBF showed an initial fall with the onset of exercise (on the average from 3.84 to 2.13 ml/l00 ml mmin) which was sustained or fell further as exercise continued, indicating that increments in FBF were confined to skin. Much of the increase in FBF occurred despite essentially constant T, + Results suggest that the progressive decrements in central venous pressure, stroke volume, and arterial pressure previously seen during prolonged exercise are due in part to progressive increments in cutaneous blood flow and volume.
Wenger et al. (23) measured forearm blood flow (FBF) increments during 30 min of leg exercise. It is unknown whether this increase was confined to skin or whether increments in contributed
THE
blood flow; temperature clearance; blood flow
FIRST
FEW
MINUTES
of
regulation; distribution
dynamic
plethysmography;
exercise
are
muscle response.
blood
flow
(MBF)
might
have
A further indication that cutaneous blood flow might progressively rise during prolonged exercise is the finding that central venous pressure, stroke volume, arterial pressure, and total peripheral resistance all show progressive reductions (8, 12). Th ese alterations indicate a peripheral shift of blood volume which might be displaced primarily to skin. Although skin venous tone usually returns to nearcontrol values during the first few minutes of exercise (18, 27), further increments in skin venous volume would be achieved by increasing skin blood flow (SkBF). One indication that SkBF might not be progressively increased during prolonged exercise is the finding that esophageal temperature (T,,) which closely parallels cutaneous vasodilatation at rest (25), often reaches a plateau after approximately 15-20 min of moderate exercise (14, 21) The major question asked in this study was whether SkBF shows a progressive rise during prolonged exercise. To answer this question, we plethysmographically measured FBF throughout 60 min of upright exercise. A second major question was whether resting MBF shows a sustained reduction during prolonged work. We therefore measured the response of forearrn MBF from the clearance of [1251]antipyrine from resting forearm muscle. These measurements would indicate whether increments in FBF were confined to skin and whether vasoconstriction of resting muscle is sustained throughout prolonged leg exercise.
l
regional indicator
forearm to this
accorn-
panied by increases in heart rate (HR), arterial blood pressure, and vasoconstriction in most nonactive regions. There is usually cutaneous vasoconstriction during the first few minutes of exercise, followed by a rise in cutaneous blood flow, presumably accompanying the rise in internal temperature (l-3, 11, 23, 26). When exercise is prolonged, vasoconstriction is maintained or increased in splanchnic (19) and renal (10) regions. However, other large vascular beds such as skin and nonworking skeletal muscle have not been thoroughly investigated during prolonged exercise. There are several indications that cutaneous blood flow might be progressively increased during prolonged exercise. Christensen and LNielsen (5) noted progressive increments in finger blood flow and volume during 30 min of leg exercise. However, it is unknown whether flow to nonacral regions, which are presumably under different control than acral regions (9), show a similar response. Kamon and Belding (12) noted gradual increments in “effective” dermal blood flow (calculated from heat uptake) in the forearm and hand during one hour of exercise. Similarly,
METHODS
Subjects were five normal men, aged 20-30 yr. All had participated in similar experiments previously, at which time they had been given thorough physical examinations and found to be in good health. Each subject was thoroughly acquainted with all aspects of the experiment before his informed consent was obtained. All experiments were conducted in a room maintained at 24 rt 1°C. Subjects were dressed only in shorts and shoes. Each experiment consisted of a 5- to lo-min period of upright, seated rest followed by 55-60 min of continuous exercise on a bicycle ergometer at a constant work load chosen to yield heart rates of approx. 130 beats/min during 920
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on September 23, 2018. Copyright © 1975 American Physiological Society. All rights reserved.
FOREARM
BLOOD
FLOW
DURING
PROLONGED
EXERCISE
the first 1’0 min of exercise. For experiments involving antipyrine washout, the control period was 20-25 min. This choice of work load prevented HR from reaching maximal values, but was of an intensity known to elicit marked vasoconstriction in visceral organs (17). Work load was 600 kpm/min for one subject and 750 kpm/min for the other four subjects. For a given experiment, FBF in one or both arms or FBF in one arm and MBF in the other arm were measured throughout the control, exercise, and recovery periods. Total FBF was measured by plethysmography in all subjects using a mercury-in-Silastic circumference gauge of Whitney’s design (24). Methods for obtaining plethysmograms during exercise and for calculation of FBF from plethysmographic curves have been previously described (4, 11). Briefly, a special arrangement of slings (one on each wrist) supported the relaxed forearm above venostatic level with forward and upward pull SO that the gauge and the arm moved together in translation. Such an arrangement usually gave high-quality records during upright exercise, examples of which are shown in Fig. 1. FBF was measured twice per min for 4 of every 5 min throughout each study while circulation to the hand was arrested. Forearm MBF was measured in four subjects from the clearance of [1251]antipyrine injected into a forearm muscle as previously described (6, 20). A single injection of 5 PCi in 0.05-0.08 ml sterile distilled water was made through a l-cm long, 30-gauge (0.3 mm) needle into the brachioradialis muscle while the subject was seated at rest on the bicycle. A small, light-weight scintillation detector (Harshaw, x x 9i in. thallium-activated NaI crystal) was attached to the forearm. The base of the 16-cm-long probe was lightly bound to the wrist by wrapping it with a 3-in.wide elastic bandage. The center of the crystal was positioned directly over the site of injection. This end of the probe was held to the arm by tape and collodion to prevent any movement of the crystal with respect to the depot. The probe was attached in this way to avoid compressing tissues beneath the probe so that MBF would not be restricted by these attachments. [1251]antipyrine activity was measured by feeding the output from the scintillation detector into a pulse height analyzer with settings appropriate for 1251 discrimination and counting the number of pulses each 10 s with a laboratory computer (Digital Equipment Corporation PDP 8E). Activity of [1251]antipyrine was then displayed as the natural logarithm of counts/s every 10 s.
921 MBF was computed every 2 min as A(log, counts/s)/& (assuming the partition coefficient between tissue and blood for antipyrine is one ( 13)). We delayed the beginning of exercise until the 15- to 20-min period of hyperemia which normally follows the [12jI]antipyrine injection had ended, as judged by stable MBF over two or more 2-min intervals. After such stability had been achieved, exercise began. To ensure that this technique could follow a rise in MBF, we had each subject contract his brachioradialis muscle several times immediately following the period of leg exercise (3 subjects) or just prior to the end of exercise (1 subject), while we continued to measure [1251]antipyrine clearance (see Fig. 3). T es9 measured with a thermocouple probe positioned at the level of the left atrium, and HR were measured throughout each experiment. HR and Tes were each sampled once per second and subsequently converted to 30-s averages RESULTS
Major findings of this study were: I) a progressive rise in FBF throughout the one hour of exercise, and 2) a fall in forearm MBF at the beginning of exercise which was sustained throughout the work period. Figure 2 shows results for FBF, Tes , and HR from a representative subject for the control, exercise, and recovery periods. Figure 3 shows [1251]antipy rine activity and calculated forearm MBF for these three periods, again from one subject. Averages for all measured responses are shown in Fig. 4. Values from each subject were averaged over each lo-min interval and the values from all subjects averaged for this composite. Average values for FBF from the first 10 min of exercise varied only slightly from control levels (overall fall FBF rose in average of - 0.1 ml/ 100 ml min). Thereafter, increments of 3.09, 2.64, 1.52, 0.27, and 0.74 ml/100 ml* min, respectively, over each succeeding lo-min interval, or a total average rise of 8.26 ml/ 100 ml min. Thus, the major fraction of the rise in FBF occurred over the lo- to 40-min interval, with only small changes occurring before or afterwards. l
l
150 -
too
HI?,
bpm
-
;;;;
FBF,
ml/1OOml~min
16IZ-
* OO
1. Plethysmographic records taken at 50 min of exercise indicating quality of curves usually seen when both arms were used for plethysmography during exercise. LFBF = left forearm blood flow; RFBF = right forearm blood flow. FIG.
I IO
20
I 30
I 40
1 50
1 60
I 70
J
80
minutes
FIG. 2. Heart rate (HR), esophageal temperature (T& and left and right forearm blood flows (FBF) from 1 subject during upright rest, 59 min of upright exercise at 750 kpm/min, and recovery.
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922
J. M.
(F
MBF, ml/l00mldn
6
Ln counts /min
JOHNSON
AND
L. B. ROWELL
average of 120 beats/min for O-10 min of exercise to 148 beats/min for the 50- to 60-min interval. Similarly, T,, rose from a resting control value of 37.09”C to 37.16, 37.65, 37.75, 37.79, 37.85, and 37.92”C for the six lo-min intervals of exercise. During the initial lo-min interval of exercise, T,, showed a fall, followed by a fast rise (see Fig. 2) so that the average values were not greatly different from control although a major portion of the rise in T,, occurred during the first 10 min of exercise. DISCUSSION
8-
‘0
I 20
I IO
I I 40 50 minutes
I 30
I 60
1 70
80
90
FIG. 3. Lower: clearance curve from an injection of 5 &i [1251]antipyrine into forearm muscle during rest, exercise, and recovery. Upper: muscle blood flow (MBF) calculated from disappearance of [1251]antipyr ine. Subject exercised his forearm between 84 and 88 min. Increased MBF at that time indicates [Y]antipyrine clearance was not diffusion limited. 150 120 90 60 Tea,
%
38
37.5
ITI
37
MBF, 4-
I ml/
T
1
I
0. ml/l00ml
min
l2r
IO -
9 v
a-
T,
6-
4-
2-
06
control
o-lo
lO-20 minutes
20-30 of exercise
30-40
40-50
SO-60
FIG. 4. Averages and standard errors for HR, Tes, MBF, for control and each lo-min portion of prolonged exercise subjects. Abbreviations as in previous figures.
and FBF from all
That these changes in FBF are confined to the skin is supported by the [1251]antipyrine clearances from forearm muscle (see Fig. 3). Average control MBF was 3.84 ml/ 100 ml of muscle per min and fell to 2.13 ml/ 100 ml min during the first 10 min of exercise. Thereafter, MBF showed a further slight fall. MBF averaged 1.75, 1.27, 1.50, 1.40, and lo-min 1.66 ml/ 100 ml min over the five succeeding intervals, respectively. HR increased with the time of exercise. HR rose from an l
l
.
*
100 ml.min
4
FBF,
The finding that FBF rises progressively throughout prolonged exercise is in accord with the previous findings that finger blood flow (5) and “effective” dermal blood flow of the hand and forearm (12) tend to rise throughout exercise. The finding of a sustained fall in forearm MBF throughout prolonged exercise indicates that the progressive rise in FBF is confined to the skin and that resting skeletal muscle does not eventually vasodilate and contribute to the fall in blood pressure. Progressively rising cutaneous blood flow coupled with the previous findings of falling cutaneous venous tone during exercise (18, 27) indicates that skin is a major site of falling peripheral resistance and rising peripheral blood volume. Although these results do not prove that the downward drift in arterial and central venous pressures and in stroke volume attending prolonged exercise are due to progressive increments in cutaneous blood volume, our data are consistent with such a notion. The question whether areas other than skin could contribute to the fall in peripheral resistance or to the redistribution of blood volume remains unanswered. While it has been shown that both the splanchnic (19) and renal (6) vascular beds have a sustained or increased vasoconstriction with prolonged exercise, it is unknown whether blood flow to active skeletal muscle is constant throughout prolonged exercise. Unfortunately, current methods for measurement of active MBF are not well suited to answering this question. What might be the magnitude of the rise in whole body SkBF during prolonged work? Extrapolation from FBF values are, of course, risky since one has to presume that forearm skin is quantitatively representative of skin over the whole body. In this regard, we estimated the increment in total SkBF during whole body direct heating at rest to be 7.8 l/min (16). This estimate is based upon the increase in cardiac output plus the observed fall in blood flow to other regions during whole body heating at rest. In our subjects, whose average body surface area is commonly about 1.8 m2 and whose average arm circumference is about 27 cm, one would predict on the basis of the surface area of 100 ml of forearm that FBF in those studies should rise by 20 ml/ 100 mlmin. This, in fact, was about the average increment in FBF observed for this level and duration of heating (6). Assuming that such a correspondence is not fortuitous and prevails for forearm vascular responses during prolonged exercise, one would predict on the basis of the average increase in FBF of 8 ml/ 100 ml min an increase in total SkBF of about 3 l/min. Clearly, such an increase in SkBF is greater than what one would expect from previous observations showing nearly constant (8, 22) cardiac output during prolonged exercise. Furthermore, additional vasoconstric_
.
I
l
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FOREARM
BLOOD
FLOW
DURING
PROLONGED
EXERCISE
tion with prolonged exercise in the splanchnic (19) and renal (10) regions would contribute only a few hundred noted in forearm ml/min to skin. The vasoconstriction muscle, if representative of all resting skeletal muscle, would also contribute an additional blood flow to skin of only a few hundred ml/min. The only remaining regional circulation which could provide significant blood flow redistribution to skin by vasoconstriction would be working skeletal muscle. Again, available techniques are not adequate to reveal a I- to 2-l/min reduction in blood flow to working skeletal muscle during prolonged exercise. We do know that sympathetic outflow increases in some regions during this stress, at least as suggested by increments in HR and in splanchnic and renal vascular resistances. However, we do not know in man whether such sympathetic outflow is directed to working skeletal muscle as well. If it is, then previous findings in dogs (7) that even markedly vasodilated active skeletal muscle will respond to increased vasoconstrictor activity could be of significance. Presently, however, we know of no evidence which suggests a reduction in active MBF under the conditions of prolonged exercise. Regardless of the source or magnitude of the increase in SkBF, the relationship of the increase to T,, was somewhat surprising. During the first lo-20 min of exercise there were only small changes in FBF whereas during the same period most of the change in T,, had occurred. During the last 40 min of exercise, there was little or no change in T,, while there were major increments in FBF. In some subjects there appeared to be no correlation between FBF and T,,. Figure 5 shows FBF plotted versus T,, throughout exercise for one subject. This subject, as well as others, showed a significant forearm vasodilatation during a period of essentially conwe found that during 7-10 min of stant T,,. Previously, exercise at an elevated skin temperature, the FBF-T,, slope was significantly reduced by upright exercise, as compared to supine rest (11). However, such slopes from the current experiment were higher than those usually observed at rest. The lowest slope observed during prolonged exercise was 25 ml/l00 ml .rnin “C when only the period of forearm vasodilatation is considered. Even so, the final levels of FBF observed during prolonged exercise were less than levels previously observed for the same internal temperature at rest (6, 11, 25). Thus, the previous conclusion that skin is relatively vasoconstricted by upright exercise (11) is upheld by the current experiment, albeit the conclusion that the FBF-T,, slope is affected is not. Such a finding suggests that during exercise T,, might not be a proper index of thermoregulatory drive for cutaneous vasodilatation. That is, there may be important thermosensitive centers whose temperatures significantly lag behind that of T,, during exercise. Certainly increments in SkBF during whole body direct heating at rest have been shown to correlate well with T,, (25). Whether such a relationship persists during exercise deserves further study. If T,, is an adequate index of the thermoregulatory drive for cutaneous vasodilatation during exercise, these results
923 F BF,
ml/ IOOml~min
0
RFBF
I
I
37
37.5 Tes, OC
I
38
FIG. 5. LFBF (filled circles) and RFBF (open circles) plotted Tee throughout 60 min of exercise. Note period of rising FBF with change in Tes. Abbreviations as in Fig. 2.
vs. no
indicate one or a combination of several. possible mechanisms. First, there may be a shift in the thermoregulatory set point (as implied by Nielsen (15)), with exercise such that cutaneous vasodilatation does not begin until T,, has risen by about 0.5”C. However, such a mechanism would not explain a rising SkBF with a constant T,,. Alternatively, increased vasoconstrictor outflow accompanying prolonged exercise at a cool skin temperature may yield an FBF-T,, relationship which no longer has the linear relationship seen at rest (25) or during exercise at a high skin temperature (11). Also, vasoconstrictor outflow to skin or the responsiveness of skin to sustained vasoconstrictor outflow may not be sustained but may tend to fall as exercise is prolonged. This latter situation would probably yield a progressive rise in SkBF at a constant thermal drive for vasodilatation (and constant T,,). Clearly, this experiment was not designed to discriminate between these possible mechanisms. In conclusion, it has been shown that forearm SkBF shows a progressive upward rise during prolonged exercise, whereas resting forearm MBF shows a sustained vasoconstriction. Such a finding is consistent with the hypothesis that the progressive fall in arterial and central venous pressures and in stroke volume and the rise in HR attending prolonged exercise is due to a gradual displacement of blood volume and blood flow to skin. However, others have suggested that altered cardiac function (8, 22) might also attend prolonged exercise and contribute to these changes. We gratefully acknowledge the assistance of Mrs. Evelyn C. Steen, R.N., Mr. Michael McKeag, and Ms. Pam Stevens. This work was supported by National Heart and Lung Institute Grant HL-16910. A part of this study was conducted through the Clinical Research Facility of the University of Washington supported by National Institutes of Health Grant RR-37. Received
for publication
20 March
1975.
REFERENCES 1. BEVEG~RD, capacity Physiol.
B. S., AND J. T. SHEPHERD. Reactions of resistance and vessels in forearm and hand to leg exercise. J. AppZ. 21: 123-132, 1966.
2.
BISHOP, J. M., K. W. DONALD, S. H. TAYLOR, WORMALD. The blood flow in the human arm during exercise. J. Physiol., London 137 : 294-308, 1957.
P. N. supine leg
AND
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924 3. BLAIR, D. A., W. E. GLOVER, AND I. C. RODDIE. Vasomotor responses in the human arm during leg exercise. Circulation Res. 9: 264-274, 196 1. G. L., C. R. WYSS, AND L. B. ROWELL. Control of 4. BRENGELMANN, forearm skin blood flow during periods of steadily increasing skin temperature. J. APPZ. Physiol. 35: 77-84, 1973. Investiga5. CHRISTENSEN, E. H., M. NIELSEN, AND B. HANNISDAHL. tions of the circulation in the skin at the beginning of muscular work. Acta Physiol. &and. 4 : 162-l 70, 1942. R., G. L. BRENGELMANN, L. B. RO~ELL, AND C. 6. DETRY, J.-M. WYSS. Skin and muscle components of forearm blood flow in directly heated resting man. J. AppZ. Physiol. 32 : 506-511, 1972. 7. DONALD, D. E., D. J. ROWLANDS, AND D. A. FERGUSON. Similarity of blood flow in the normal and sympathectomized dog hind limb during graded exercise. Circulation Res. 26 : 185-199, 1970. 8. EKLUND, L. G. Circulatory and respiratory adaptation during prolonged exercise. Acta Physiol. &and. SuppZ. 292, 1967. 9. Fox, R. H., AND 0. G. EDHOLM. Nervous control of the cutaneous circulation. Brit. Med. Bull. 19 : 1 lo- 114, 1963. 10. GRIMBY, G. Renal clearances during prolonged supine exercise at different loads. J. AppZ. Physiol. 20: 1294-1298, 1965. 11. JOHNSON, J. M., L. B. RO~ELL, AND G. L. BRENGELMANN. Modification of the skin blood flow-body temperature relationship by upright exercise. J. AppZ. Physiol. 37 : 880-886, 1974. 12. KAMON, E., AND H. S. BELDING. Dermal blood flow in the resting arm during prolonged leg exercise. J. AppZ. Physiol. 26 : 317-320, 1969. 13. LINDBJERG, I. F. Disappearance rate of 133xenon, 4-iodo-antipyrine-1311 and 1311- from human skeletal muscles and adipose tissue. Stand. J. CZin. Lab. Invest. 19 : 120-128, 1967. during work at 14. NIELSEN, B., AND M. NIELSEN. Body temperature different environmental temperatures. Acta Physiol. Stand. 56 : 120-129, 1962. der Korpertemperatur bei Muskel15. NIELSEN, M. Die Regulation arbeit. Skand. Arch. Physiol. 79 : 193-230, 1938. 16. ROWELL, L. B. Human cardiovascular adjustments to exercise and thermal stress. Physiol. Rev. 54 : 75-l 59, 1974.
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L. B., J. R. BLACKMON, R. H. MARTIN, J. A. MAZZA17. RO~ELL, RELLA, AND R. A. BRUCE. Indocyanine green clearance and estimated hepatic blood flow during mild to maximal exercise in upright man. J. CZin. Invest. 43 : 1677-1690, 1964. 18. RO~ELL, L. B., G. L. BRENGELMANN, J.-M. R. DETRY, AND C. WYSS. Venomotor responses to rapid changes in skin temperature in exercising man. J. AppZ. Physiol. 30 : 64-74, 197 1. L. B., K. K. KRANING II, T. 0. EVANS, V. W. KENNEDY, 19. ROWELL, J. R. BLACKMON, AND F. KUSUMI. Splanchnic removal of lactate and pyruvate during prolonged exercise in man. J. AppZ. Physiol. 21: 1773-1783, 1966. L. B., C. R. WYSS, AND G. L. BRENGELMANN. Sustained 20. ROWELL, human skin and muscle vasoconstriction with reduced baroreceptor activity. J. AppZ. Physiol. 34: 639-643, 1973. Esophageal, rectal and muscle 21. SALTIN, B., AND L. HERMANSEN. temperature during exercise. J. APPZ. Physiol. 21: 1757-l 762, 1966. response to prolonged 22. SALTIN, B., AND J. STENBERG. Circulatory severe exercise. J. AppZ. Physiol. 19: 833-838, 1964. 23. WENGER, C. B., M. F. ROBERTS, J. A. J. STOLWIJK, AND E. R. NADEL. Forearm blood flow during body temperature transients produced by leg exercise. J. APPZ. Physiol. 38 : 58-63, 1975. R. J. The measurement of volume changes in human 24. WHITNEY, limbs. J. Physiol., London 12 1: l-27, 1953. J. M. JOHNSON, L. B. ROWELL, 25. WYSS, C. R., G. L. BRENGELMANN, AND M. NIEDERBERGER. Control of skin blood flow, sweating and heart rate: role of skin vs. core temperature. J. A@Z. Physiol. 36: 326-733, 1974. Partition of blood 26. ZELIS, R., D. T. MASON, AND E. BRAUNWALD. flow to the cutaneous and muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. Circulation Res. 24: 799-806, 1969. AND J. T. SHEPHERD. Effect of 27. ZITNICK, R. S., E. AMBROSIONI, temperature on cutaneous venomotor reflexes in man. J. APPZ. Physiol. 31: 507-512, 1971.
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