Special Section: Physical Activity and Hypertension
Blood Pressure Regulation during Exercise Loring B. Rowell
This brief review examines five problems concerning arterial blood pressure regulation during exercise. These are: 1. A history and summary of evidence that baroreflexes are, or are not, active during exercise. 2. *hat might be other “regulators” of blood pressure during exercise? The characteristics of a blood pressure-raisingreflex from ischemic and active skeletal muscle (muscle chemoreflex) is reviewed along with a putative role for centrally generated motor command signals (central command). 3. How blood pressure is maintained during exercise. The importance of regional vasoconstriction, particularly in active skeletal muscle, is reviewed. 4. How well matched are cardiac output and total vascular conductance? Does demand for muscle blood flow outstrip cardiac pumping capacity? 5. Reflex control of blood pressure by both baroreflexes and muscle chemoreflexes. The importance of baroreflexes and evidence for resetting is reviewed. A new hypothesis is stated. Key words: arterial baroreflexes; chemoreflexes; central command; sympathetic activity; regional blood flow; reflex resetting. (Annals of Medicine 23: 329-333,
1991)
History: Are Baroreflexes Operative during Exercise? Arterial baroreflexes were once thought to provide the stimulus for autonomic neural control of blood pressure and heart rate during exercise. The idea was that the muscle vasodilation accompanying exercise caused a sudden fall in blood pressure and that blood pressure was raised again by the arterial baroreflex. This reflex was seen as vital not only in restoring blood pressure but also in maintaining it during exercise in the face of an enormous rise in total vascular conductance. Eventually this idea was challenged on the basisof two observations. First, there is usually nofall in blood pressure at the onset of exercise or at the time when the exercise load is suddenly increased; in both cases blood pressure usually increases immediately. The second objection to the idea was that in response to exercise, blood pressure is raised to levels exceeding those present before the stress. Infinite gain or sensitivity would be required of any reflex that could correct a signal error by 100 %-or in the case of blood pressure, exceeding 100 %. From the Departments of Physiology and Biophysics and of Medicine (Cardiology), University of Washington, School of Medicine, Seattle, WA, U S A . Address and reprint requests: Loring B. Rowell, M.D., Departments of Physiology and Biophysics and of Medicine (Cardiology), University of Washington, School of Medicine, Seattle, WA 98195, USA.
Asecond challenge to the notion that arterial baroreflexes are important controllers of the circulation during exercise centered on the blood pressure responses of animals after arterial baroreceptor denervation. Some of these studies were recently reviewed (1, 2). In some experiments, denervation of the arterial baroreceptorscaused no obvious deficit in blood pressure control once a stable response to exercise had been achieved. Although steady-state levels of blood pressure during exercise appeared not to be affected by chronic denervation, the initial blood pressure responses were profoundly altered in some studies (see Refs. 3-5). Blood pressure fell suddenly at the start of exercise. The magnitude of the fall (approximately 20 to 60 mmHg) depended on the severity of exercise, as did the duration of the decline. If exercise was relatively mild, pressure remained depressed throughout exercise. Blood pressure rose within 1-2 min to pre-exercise levels if exercise was moderately heavy (4, 5). Also, a marked overshoot in blood pressure was seen when exercise stopped (4,6,7). In short, control of blood pressure at either the onset or at the end of exercise is not normal in animals without arterial baroreceptors (denervation was assumed to be complete). However, pressure control after these two transient periods of adjustment were complete appeared to be normal. A third challenge to the importance of baroreflex control of blood pressure during exercise came from studies on human subjects. The “sensitivity of the arterial baroreflex” was assessed during rest and exercise by observing the
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reflex bradycardia in response to a rise in arterial pressure caused by sudden injection of a bolus of phenylephrine(8). The change in the slope of the line relating the ECG, R-R intervalto the increase in blood pressure was equated with a change in the sensitivity of the entire baroreflex (i.e., not just the heart rate arm of the reflex). Those who used this definition of sensitivity found that baroreflex function is markedly depressed by exercise (or any other stress that raised heart rate). The more severe the exercise, the flatter the slope of the R-R interval-blood pressure relationship. The opposite conclusions about baroreflex sensitivity were reached by other groups and were based on virtually the same data, but instead of R-R interval, the change in heart rate was used to assess baroreflex sensitivity (9, 10). Exercise had no effect on the heart rate responseto a given change in bloodpressure. The fallacy in the former approach is that for any given change in heart rate, the corresponding change in R-R interval becomes lessas the initial heart rate gets higher, as with increasing exercise levels. This is simply the mathematical consequence of using interval rather than rate (1, 2). Another potential problem with either approach (i.e., heart rate or interval) is that basing the determination of sensitivity of the entire reflex on only its heart rate component can lead to the wrong conclusion. Changes in blood pressure are the consequenceof changes in both heart rate and total peripheral resistance and either may dominate a response so that neither variablecan by itself reflect changes in the sensitivity of the entire reflex (1, 2). For reasons outlined above, we inherited for about two decades a legacy of disbelief in the importanceof baroreflex control of blood pressure during exercise.
Alternatives: Other “Regulators” of Blood Pressure during Exercise There are alternative mechanisms by which arterial blood pressure could be raised and maintained during exercise without input from baroreceptors. In fact, the baroreflex could simply be one of several tonically active controllers of blood pressure. Were all of these redundant controllers to operate through high-gainfeedback loops, then removal of one of them would not be expected to exert much effect on bloodpressure. At this time, we know of only one other reflex that has high gain (similar to that of arterial baroreflexessee below) and which also has large and lasting effects on blood pressure; it is called the “muscle chemoreflex” (2). In 1937, Alam and Smirk (11) showed that accumulation of metabolites in skeletal muscle (done by occluding the muscle circulation)caused a marked rise in blood pressure, both during and after exercise, for as long as metabolites remained trapped within the muscle. These powerful pressure-raising reflexes arise from chemosensitive afferent nerve fibers (group 111 and group IV) within skeletal muscle in response to ischemia (12). Studies on chronically instrumented conscious dogs revealed that stepwise increments in arterial blood pressure occurredas hindlimbmuscle blood flow was experimentally reduced in graded fashion while these animals voluntarily exercised at loads of different intensities (13, 14). A distinct thresholdforthis muscle chemoreflex existsat low intensities of exercise; substantial reductions in muscle blood flow occurred before the pressor response was triggered (13,
14). The rise in pressure ( I 4) and increase in sympathetic nervous activity (15) appear to be triggered in coincidence with a fall in oxygen delivery below a critical level at which lactate and hydrogen ion concentration starts to rise in the muscle (15) or in its venous drainage (14, 16). Thus, at low rates of exercise, this pressor reflex can be viewed as an emergency measure directedtoward restoringmuscle blood flow when it falls below a critical level. For example, in patientswho experience spontaneous reductions in muscle blood flow due to intermittent claudication during exercise, the resultant muscle ischemiatriggers a rise in blood pressure prior to the onset of pain (17). At higher levels of exercise, the muscle chemoreflex has no threshold so that there is no margin for error in muscle blood flow as there is during milder exercise. In this setting, the reflex appears to be tonically active so that any small mismatch between muscle blood flow and metabolism would cause sufficient change in the concentration of hydrogen ion, lactate, and possibly other metabolites in the muscle to activate local chemosensitivenerve fibers. Their augmented firing “informs” the central nervous system about the adequacy of muscle perfusion. The efferent arm of this reflex, the sympathetic nervous system, increases vasoconstrictor outflow, heart rate, and blood pressure so as to restoremuscleblood flow and reduce the concentration of muscle metabolites (2, 12, 13). Thus, the muscle chemoreflex could serve as an important flow-sensitive (rather than pressure-sensitive), pressure-raising reflex during moderate to severe exercise (18). The strength or gain of this reflex has been determined in exercising dogs by relating the reflex-induced rise in systemic arterial blood pressure (minus the small rise due to mechanical effects of partial terminal aortic occlusion) divided by the fall in femoral arterial blood pressure below a chronicallyimplantedvascular occluder (13, 14, 19). This is equivalent to measuringthe gain or sensitivity of the carotid sinus baroreflexby measuringthe reflex change in systemic arterial blood pressure that results from a given change in pressure within the isolated carotid sinus (e.g., Refs. 5, 7). At the mild to moderate levels of exercise investigatedso far, the muscle chemoreflex has approximately the same gain as the carotid sinus baroreflex (determined in similar fashion) (5, 7). The muscle chemoreflex is able to correct approximately two-thirds (open-loopgain = -2) of a deficit in perfusion pressure and restore muscle blood flow toward a level that would significantly reduce accumulation of muscle metabolites (13, 14, 19). It is not known if the sensitivity of the reflex increases at high levels of exercise intensity. Another alternative means of raising blood pressure during exercise is by the centrallygeneratedcardiovascular motor and somatomotor signals originatingin basal ganglia, cerebellum, and spinal cord motor centers (2, 20). These and other areas involved in the organization of motor function activate in parallel both somatomotor neurons as well as the neurons involved in autonomic control of the cardiovascular system. These centrally generated motor command signals (called central command”) could cause the immediate rise in blood pressure observed at the onset of exercise, and could also contribute to much of the elevation in blood pressure seen during static exercise. The rise in blood pressure accompanying both mild dynamic as well as static exercise is not prevented by the sensory blockade (periduralanesthesiain normal subjects [21]), nor is it lost in patientswithout sensationbecause of neuropathy
Blood Pressure Regulation during Exercise (22, 23). Furthermore, attempts to elicit static contractions after complete neuromuscular blockade are still accompanied by about one-half of the normal rise in blood pressure despite lack of any muscle contraction (24). The muscle chemoreflex was absent (21, 22, 24) or at least greatly attenuated (23) in all of these studies. Available evidence indicates that the magnitude of the central command and the rise in blood pressure is directly related to the number of motor units activated during a normal voluntary contraction (12,20). Graded doses of the neuromuscular blocker curare have been administered to produce increasing degrees of motor weakness. The increased “effort” and motor unit recruitment required to maintain a given static contraction force was always accompanied by a greater rise in blood pressure (20,25,26). An interesting puzzle is why denervation of arterial baroreceptors (in studies cited earlier) leads to a sudden fall in blood pressure at the onset of exercise if central command is the process by which the normally rapid elevation in pressure occurs. A possible explanation is that at the onset of exercise, central command may rapidly shift the operating point of the baroreflex to a higher level and this sudden central resetting of the reflex explains the rise in blood pressure normally seen when exercise begins. A possible explanationfor the subsequent restorationof blood pressure after it falls in baroreceptor-denervatedanimals is that reduced muscle perfusion activates the muscle chemoreflex. This recovery of pressure does not occur during milder exercise (5), probably because the level of exercise is so low that the threshold for the muscle chemoreflex is not reached (2).
Blood Pressure during Exercise: How is it Maintained? During mild to moderate exercise in normal subjects, blood pressure is well maintained by increasing heart rate and cardiacoutput. As its durationand severityincrease,exercise is accompanied by vasoconstriction in many organs, especially the splanchnic region and kidneys (27). The importance of regional vasoconstriction is evident in cardiacpatientswho can raise musclevascularconductance far beyond the heart’s reduced ability to pump sufficient blood to maintain pressure. Up to a point, blood pressure is well-maintainedin these patientsby intensevasoconstriction in visceral organs, skeletal muscle, and other regions (28, 29). Loss of vasoconstrictionwould lead to a precipitous fall in blood pressure in these patients (40-50 mmHg or more depending on maximal cardiac output) (27). Despite the ability of normal young people to raise cardiac output to 25 I/min or more, and of endurance athletes who reach maximal cardiacoutputsexceeding 40 I/min,all of these individuals (patientsto athletes) show the same pattern and magnitude of regional vasoconstrictionwhen they are compared at the same relative work intensities.That is, at any given fraction of the maximal oxygen uptake, all show virtually the same degree of regional vasoconstriction. The importance of this vasoconstrictionto blood pressure regulation was assumed to be directly related to the magnitude of maximal cardiac output (27). That is, the calculated fall in blood pressure associated with a loss of all this regional vasoconstriction was based on that vasoconstriction being directed only to nonexercising regions (total flow approximately 3 I/min
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being reduced to 600-900 I/min in all groups (2, 27). Unknown at the time was the fact that active muscle is also an important target of this vasoconstrictor outflow (see below) and release of this vasoconstrictioncould have far more profound effects on blood pressure than those previously calculated (above). Although it was originally assumedthat sympatheticvasoconstrictoroutflowwas diff usely distributed to most organs, muscle was thought to be unresponsive because of a “functional sympatholysis”;i.e., muscle metabolitesblunted or abolished constrictor effects of norepinephrine.It is now clear that active skeletal muscle showsvigorous vasoconstrictorresponsesover physiological ranges of sympathetic nerve stimulation (30, 31). Tonic vasoconstriction in active muscle during even moderate exercise was recently observed by increasing carotid sinus transmuralpressure(neck suction a t 4 0 mmHg). A release of tonic vasoconstriction in the active legs accounted for most of the fall in arterial pressure when neck suction was applied (31a). The following section builds on the precedinginformation and developsthe idea that vasoconstrictionin active muscle might become a key factor in controlling blood pressure during severe exercise in normal subjects as well as in cardiac patients.
How Well Matched are Cardiac Output and Vascular Conductance? As long as bloodflow and vascular conductanceare properly balanced, blood pressure is well maintained. Some mammals, for example dogs and horses, have cardiac pumping capacities that exceed those of humans by nearly threefold (see Ref. 32). Dogs, in comparison to humans, show much less regional vasoconstriction in visceral organs (33) (particularly in kidneys [34]) or in active muscle (30), and little release of norepinephrine from sympathetic nerves during exercise (release is mainly from the adrenal medulla) (35). In contrast, the large increases in sympathetic nervous activity (SNA) (as indicated by neuronal leakage of norepinephrine) and regional vasoconstriction observed in humans suggest that the balance between blood flow and musclevascular conductancemay become precariousduring severe exertion. We now have three lines of evidence suggesting that humans can reach a point at which control of blood pressure requires vasoconstriction in active muscle in addition to the maximal vasoconstriction seen in visceral organs. The evidence can be summarizedas follows. First, during severe exercise with large muscle groups, addition of more muscles to the task (e.g., arms added to leg exercise) causes vasoconstriction in the active muscle (36). Second, muscle appears to be the major site for norepinephrine release during severe exercise. Addition of arms to severe leg exercise (as above) markedly increases the spillover of norepinephrinefrom active leg muscle (37), but there is now uncertaintyas to whether there is additionalvasoconstriction in the legs (37). Third, measurement of blood flow in small muscle groups- i.e., too small to tax the pumping capacity of the heart - suggests that blood flow per kg of muscle might reach levels that could never be provided by the heart were 10-1 5 kg of muscle maximally active (38,39), but not all muscles may have such high peak blood flows. The final question to be answered is how blood pressure
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might be controlled during severe exercise when the limits of cardiac function are approached.
Reflex Control of Blood Pressure during Severe Exercise - Baroreflexes, Chemoreflexes, or Both? Several lines of experimental evidence reveal that control of blood pressure by baroreflexes is as effective during exercise as it is at rest. The experiments showing this have looked at the systemic blood pressure response to a change in carotid sinus pressure so that the entire baroreflex is evaluated, not just the heart rate response (which incidentally is blunted during heavy exercise) (see Refs. 1, 2). In humans a given change in carotid sinus transmural pressure (by positive or negative pressure applied to the neck) causes similar changes in systemic blood pressure during rest and exercise (31a, 40,41). Melcher and Donald (5) and Walgenbach and Donald (7) manipulated blood pressure in the surgically isolated carotid sinuses of intact dogs during voluntary exercise. The stimulus-response curves for the carotid sinus reflex showed an upward shift in systemic blood pressure at any given carotid sinus pressure (controlled by the investigators) but no change in the sensitivity of the reflex in relation to severity of exercise. When Walgenbach and Donald (7) kept mean pressure constant (there were no pulsations) in the isolated carotid sinus (aortic baroreceptors had been denervated) and subjected their dogs to graded increases in work intensity, heart rate and cardiac output rose normally but without a compensatory increase in total vascular conductance. As a consequence, systemic arterial blood pressure rose markedly with each increment in workload and cardiac output. The current interpretation of these findings is that arterial baroreflexes are centrally reset to a higher operating level with increasing work intensity. That is, in these experiments the system was fooled by the constant carotid sinus pressure, interpreting this as a failure to reset the reflex to higher pressures. Thus, systemic arterial blood pressure was driven upward to extremes during the system’s unsuccessful attempts to raise carotid sinus pressure. Thus, one reason for the higher blood pressure during exercise is that the baroreflex (perhaps through the action of central command) seems to “seek” a higher pressure. Another cause, or possibly the dominant cause, for the rise in blood pressure during severe exercise might be the activation of muscle chemoreflexes when muscle perfusion is below a level at which metabolism is no longer fully aerobic. Recall that this reflex is closely associated with a release of hydrogen ion and lactate from active muscle (14-1 6). If both baroreflexes and chemoreflexes are active, the question is how they interact. As pointed out earlier, muscle chemoreflexes and arterial baroreflexes have similar gains or sensitivities, and both are powerful reflexes. Upward resetting of the baroreflex supports, rather than opposes, the rise in blood pressure with exercise and the chemoreflexes serve only as pressureraising reflexes. The two reflexes have recently been shown to oppose each other (19). Experiments like those of Wyss et al. (13) and Sheriff et al. (14) were carried out on dogs before and after the animals had complete surgical sinoaortic denervation (19). The open-loop gain of the muscle chemoreflex increased from a control value of greater than 2 (approximately 70 ‘lo correction) to 5.2 or 83 Yocorrection
of any error in muscle perfusion pressure. This means that muscle chemoreflexes are attenuated by approximately 60 ‘loby the arterial baroreflexes. The threshold of the muscle chemoreflex, seen during mild exercise, was not affected by baroreceptor denervation, meaning that this threshold does not exist because of successful opposition of the muscle chemoreflex by the arterial baroreflex at low workloads. Thus, the arterial baroreflexes appear to keep muscle chemoreflexes in checkduring moderate exercise when the threshold for the chemoreflex is exceeded and is therefore assumed to be tonically active. Without this opposition even small mismatches between muscle blood flow and metabolism could quickly elicit hypertension. We still do not know how these two powerful reflexes interact during severe exercise. The sensitivity of neither reflex by itself during severe exercise is known. So far no evidence suggests that chemoreflexes become more powerful with increasing severity of exercise; however, tests have so far been confined only to exercise loads that are relatively low for dogs. As maximal exercise is approached in humans, lactate release from muscle increases exponentially. This suggests that the changes in muscle perfusion needed to trigger the chemoreflex will become increasingly smaller, and thus this reflex would become more powerful as long as opposition by the baroreflex did not increase as well. Baroreflex sensitivity could remain nearly constant if the baroreflex is reset upward to higher and higher pressures as exercise intensity increases. Conversely, without resetting the carotid sinus reflex would become less and less sensitive as arterial pressure rose (the consequenceof moving to aflatter region of its sigmoidalshaped stimulus-response curve). Thus, depending on how the gain of the arterial baroreflexes might change, muscle chemoreflexes could become the most powerful controllers of arterial pressure during severe exercise. This could have major importance in patients with limited ability to raise cardiac output during exercise. In this setting a powerful reflex is needed to overwhelm a rise in vascular conductance that could easily trigger a precipitous fall in blood pressure.
Epilogue In a recent review, Rowell and O’Leary (42) postulated that the primary regulatory error corrected during exercise is a mismatchbetween cardiac output and vascular conductance (a blood pressure error) that activates the arterial baroreflex and raises blood pressure. The main idea is that at the onset of exercise central command raises heart rate by vagal withdrawal and resets the baroreflex to a higher operating pressure. The key to the hypothesis is that a blood pressure error will occur whenever the rise in cardiac output at the onset of exercise is not rapid enough to raise blood pressure immediately to the new and higher baroreflex operating point. At low levels of exercise cardiac output can be raised exclusively and rapidly by vagal withdrawal; there is no pressure error and no rise in sympathetic nerve activity to either the heart or blood vessels. Conversely, a blood pressure error and increased sympathetic nerve activity will occur whenever the rise in heart rate must be achieved primarily by increased sympathetic activity.The reason is that sympathetically mediatedchanges in cardiac output are slower than those mediated vagally,
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and consequently vasoconstriction is needed to complete the necessary rise in blood pressure, This could explain why sympathetic activity does not increase in normal exercising humans until heart rate reaches approximately 100 beats/ min: that is. when raDid vaaal withdrawal is complete.
20. Hobbs SF. Central command during exercise: parallel activation of the cardiovascular and motor systems by descending command signals. In Smith OA, Galosy RA, Weiss SM, eds. Circulation, neurobiology and behavior. New York: Elsevier, 1982: 217-31. 21. Freund PR, Rowell LB, Murphy TM, Hobbs SF, Butler SH. Blockade of the pressor response to muscle ischemia by sensory nerve block in man. Am J Physioll979; 236: H433-
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1 Ludbrook J. Reflex control of blood pressure during exercise. Ann Rev Physiol 1983; 45: 155-68. 2 RowellLB. Human circulation:regulationduringphysicalstress. New York: Oxford University Press, 1986. 3. Krasney JA, Levitzky MG, Koehler RC. Sinoaortic contribution to the adjustment of systemic resistance in exercising dogs, J Appl Physiol 1974; 36: 679-85. 4 Ardell JL, Scher AM, Rowell LB. Effects of baroreceptor denervation on the cardiovascular response to dynamic exercise. In: Sleight P, ed. Arterial baroreceptorsand hypertension. Oxford: Oxford University Press, 1980: 31 1-7. 5 Melcher A, Donald DE. Maintained ability of carotid baroreflex to regulate arterial pressure during exercise. Am J Physiol 1981; 241 : H838-49. 6 McRitchie RJ, Vatner SF, Boettcher D, Heyndrickx GR, Patrick TA, Braunwald E. Role of arterial baroreceptors in mediating cardiovascular response to exercise. Am J Physiol 1976; 230: 85-9. 7 Walgenbach SC, Donald DE. Inhibition by carotid baroreflex of exercise-induced increases in arterial pressure. Circ Res 1983; 52: 253-62.
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