With the transition from rest to mild dynamic exercise there is a sudden, rapid increase in heart rate (HR). Thereafter, HR increases in proportion to work rate until maximal HR and oxygen consumption are achieved. This brief review addresses current hypotheses concerning the reflex control of heart rate during exercise by the arterial baroreflex and reflexes elicited by activation of afferents within the active skeletal muscle. Previous conclusions drawn regarding the importance of these reflexes have ranged from no significant role to being intimately important in normal HR responses to exercise. The principal objective of this review is to describe how the techniques of activation and analysis of reflex responses can markedly affect the conclusions drawn regarding their relative role in the control of HR during exercise. For more detailed discussion of cardiovascular control during exercise, the reader is referred to other reviews(20,34,36,37,40,41).
The arterial baroreflex is the primary reflex involved in the moment-to-moment control of arterial blood pressure (AP). In response to changes in AP, the arterial baroreflex elicits changes in HR and systemic vascular conductance in order to return AP toward normal levels. The relationship between AP and HR is typically sigmoidal in nature and the slope of this relationship is an index of the gain or sensitivity of the reflex(38).
The effect of dynamic exercise on the gain of the arterial baroreflex has been the subject of controversy for some time. One hypothesis is that since HR and AP increase during dynamic exercise, arterial baroreflex gain must diminish during exercise otherwise the baroreflex would oppose the increase in pressure. Evidence supporting this point is that in baroreceptor denervated dogs HR and AP are little changed from normal levels during steady-state moderate to heavy exercise (16,47). However, during mild exercise AP decreases and is very unstable after baroreceptor denervation(51,52). In addition, with the transition from rest to moderate exercise the time course of changes in HR, cardiac output, and AP are slower after baroreceptor denervation (10). A potentially confounding issue is that after chronic baroreceptor denervation, plasticity may occur in the central integrating pathways possibly altering the efficacy of other reflexes which may participate in the adjustments to exercise (26,27).
The most compelling evidence for reduced baroreflex gain during exercise in humans comes from the work of Sleight and colleagues(2,31). These investigators induced changes in arterial pressure via bolus infusion of vasoactive drugs and observed the reflex chronotropic responses. They concluded that whereas at rest bradycardia occurred with increase in AP, during dynamic exercise the responses were virtually abolished at work rates wherein HR ≥ 150 bpm. In contrast, Melcher and Donald (17) observed in dogs that similar chronotropic and AP responses occurred at rest and during mild to heavy exercise when pressure was manipulated within the isolated carotid sinuses. These investigators concluded that dynamic exercise did not affect the strength of carotid baroreflex control of either the heart or peripheral vasculature.
In addition to the different species studied, two major differences exist between the studies described above. The studies on humans utilized bolus infusion of vasoactive drugs to elicit rapid, transient changes in AP and the chronotropic responses were analyzed in terms of the changes in the electrocardiogram R wave interval (RRI). The studies on dogs utilized the isolated carotid sinus technique and analyzed the responses in terms of the changes in HR. Can these differences in the method of analysis and/or technique of baroreflex activation explain the opposite conclusions, or do the opposite conclusions reflect a “species difference”?
HR versus RRI. HR and RRI are often thought of as reciprocal yet interchangeable. That is, if HR increases, RRI decreases. However, a reciprocal relationship is not linear. Figure 1 shows the curvilinear inverse relationship between HR and RRI. Whereas, if HR increases RRI decreases, the magnitude of the change is intimately dependent on the baseline level of HR (or RRI). For example, if at rest in response to a 10 mm Hg increase in arterial pressure HR decreases 10 bpm from a baseline level of 60 bpm (RRI = 1000 ms), baroreflex sensitivity, calculated as the ratio of the change in HR or RRI to the change in AP, would equal 1 bpm·mm Hg-1 in terms of HR, or 20.0 ms·mm Hg-1 in terms of RRI. If during moderately heavy exercise (baseline HR = 165 bpm, RRI = 363.6 ms) the same 10 mm Hg increase in AP induces the same 10 bpm bradycardia, in terms of HR, baroreflex sensitivity is unchanged (again 1 bpm·mm Hg-1) whereas, in terms of RRI, baroreflex sensitivity is reduced by nearly 90%, from 20.0 ms·mm Hg-1 at rest to 2.3 ms·mm Hg-1 during exercise. Thus, the same data can yield completely opposite conclusions when analyzed in terms of HR versus RRI. When analyzed in terms of HR, baroreflex sensitivity is unchanged whereas, in terms of RRI, baroreflex chronotropic responses are almost completely abolished(28).
Is the difference in conclusions regarding the effect of exercise on baroreflex sensitivity solely due to differences in the method of analysis or do other factors contribute to this disparity? The studies on humans(2,31) provide sufficient primary data to reanalyze the RRI data in terms of HR. Reanalysis in terms of HR still shows that baroreflex sensitivity is reduced, but not abolished, during exercise. Thus, the method of analysis is not the sole reason for the fundamentally different conclusions.
Transient versus steady-state analysis. The studies on humans(2,31) used bolus infusions of vasoactive drugs to elicit rapid, transient changes in arterial pressure (and HR or RRI). In contrast, the studies on dogs (17) used steady-state changes in pressure within the vascularly isolated carotid sinuses. Does the transient versus steady-state approach affect the results?
The rapid, transient changes in AP that occur with bolus infusion of vasoactive drugs or with other techniques such as rapid neck suction/pressure, induce changes in HR virtually solely via changes in parasympathetic tone(5,31). In both humans and dogs at rest the heart is under predominately parasympathetic control with little, if any, tonic sympathetic activity. Thus, baroreflex-mediated bradycardia could occur only via increases in parasympathetic activity since little sympathetic tone exists to be withdrawn; however, tachycardia could be accomplished via both parasympathetic inhibition and sympathetic activation(28). Coleman (3) observed in resting rats that the autonomic mechanisms mediating baroreflex chronotropic responses are intimately dependent on the method of baroreflex activation. With rapid changes in AP only parasympathetic responses are observed. The techniques eliciting transient changes in AP do not allow sufficient time for observation of the slower sympathetic component (54). This is especially important in investigating baroreflex responses during exercise. In this setting both tonic parasympathetic and sympathetic tone may exist. O'Leary and Seamans (28) concluded that in dogs at rest the heart is under predominantly parasympathetic control with little if any tonic sympathetic activity whereas, during moderate dynamic exercise functional, tonic activity of both parasympathetic and sympathetic nerves to the heart exists. Thus, during moderate to heavy dynamic exercise baroreflex bradycardia and tachycardia could occur via changes in activity of both arms of the autonomic nervous system if sufficient time is allowed to observe the slow sympathetic component. O'Leary and Seamans (28) used the steady-state technique of baroreflex activation in dogs (constant infusion of vasoactive drugs at varying doses to elicit steady-state changes in AP and HR) and observed that during moderate exercise blockade of either autonomic component tended to reduce baroreflex HR sensitivity(28). Since dynamic exercise shifts efferent mechanisms of baroreflex induced bradycardia from solely parasympathetic at rest to combined parasympathetic activation/sympathetic inhibition during exercise, it is not surprising that baroreflex sensitivity would be reduced (even if analyzed as HR rather than RRI) if the reflex is activated by rapid, transient changes in arterial pressure during exercise. In this setting substantial baroreflex bradycardia occurs via sympathetic inhibition which cannot be observed with transient changes in AP. Whereas, the relative role of the parasympathetic component in the baroreflex responses appears to decrease from rest to moderate exercise (28), the gain of baroreflex chronotropic responses is unchanged if steady-state responses are analyzed in terms of HR. Thus, the RRI data from humans obtained via bolus infusion of vasoactive drugs still shows attenuated, but not abolished, baroreflex sensitivity when reanalyzed in terms of HR likely because the method utilized for baroreflex activation prevented observation of a significant sympathetic component. Conversely, the steady-state HR data obtained in dogs(17,28) which showed no change in baroreflex sensitivity between rest and exercise, when reanalyzed in terms of RRI still shows appreciable baroreflex sensitivity, albeit reduced from values at rest. This still remaining baroreflex sensitivity during exercise when analyzed in terms of RRI likely exists because the steady-state technique was used which allowed observation of the important sympathetic component. Although when analyzed as RRI the marked baseline effect still remains despite using steady-state methods of baroreflex activation, e.g., Figure 1.
Thus, the disparate conclusion regarding the effect of exercise on baroreflex control of the heart likely stems from the differences in both the method of analysis, HR versus RRI, and the method of inducing baroreflex responses, transient versus steady-state; most likely the species difference is not markedly important. However, one could consider whether HR or RRI is a useful index of arterial baroreflex gain. The arterial baroreflex senses and controls arterial pressure. The reflex elicits changes in heart rate and contractility to modulate cardiac output (parenthetically, if stroke volume is known the calculated change in cardiac output will be the same using either HR or RRI) and the baroreflex induces changes in vasomotor tone to modulate peripheral vascular conductance. Thus, since HR is not the variable sensed by the baroreflex but is a component of the efferent responses to maintain pressure, it is logically questionable whether the changes in HR should be used to quantify baroreflex function (see Ludbrook;(12,14). Ideally, the ability of the baroreflex to regulate pressure should be the key feature of interest. Although the efferent mechanisms utilized by the baroreflex may be of great interest, i.e., cardiac output versus peripheral vascular conductance, a fundamental question is whether exercise alters baroreflex control of arterial pressure. An important point is that the baroreflex control of HR is similar to that of pressure, i.e., no change in baroreflex sensitivity rather upward resetting of the baroreflex function curves (17,30,32). That is, the same conclusion is reached using HR as systemic arterial pressure: no change in baroreflex sensitivity between rest and exercise. When analyzed as HR, the chronotropic responses yield conclusions consistent with those reached using the variable that is sensed and controlled by the arterial baroreflex, arterial pressure; this is a strong argument for the use of HR over RRI.
Arterial baroreflex resetting. In their classic study, Melcher and Donald (17) showed that the slope of the relationship between isolated carotid sinus pressure and systemic arterial pressure was unchanged between rest and mild to heavy dynamic exercise; rather, the baroreflex function curves were reset to a higher pressure.Figure 2 schematically illustrates resetting of the arterial baroreflex. With the transition from rest to exercise, the operating point of the arterial baroreflex is increased to a higher level. Rowell and O'Leary (36) hypothesized that the combination of central command and activation of muscle afferents caused the rightward and upward shift in the baroreflex function curves. However, the mechanisms mediating baroreflex resetting have yet to be determined.
Subsequent to the study by Melcher and Donald (17), the results from several investigations using a variety of species strongly support the concept that the operating point of the arterial baroreflex is reset to a higher pressure during exercise(4,30,32,51). DiCarlo and Bishop(4) observed in rabbits that during exercise exaggerated tachycardia and sympathetic activation occurred when the normal increase in arterial pressure was attenuated via infusion of a vasodilator at the initiation of exercise. Potts et al. (32) showed in humans that the relationship between carotid sinus transmural pressure and HR was shifted upward and to the right during exercise. In that study, 5-s periods of neck suction/pressure were used and it is unclear whether steady-state was achieved. This period of time is likely sufficient to achieve full expression of the parasympathetic component but may not be sufficiently long enough to observe steady-state sympathetic components. Papelier et al.(30), using similar techniques but with a more prolonged pulsatile stimulus, 20 s at each step change in carotid sinus transmural pressure, concluded that carotid arterial baroreflex control of HR and AP is progressively reset as work load increases.
A potential consequence of arterial baroreflex resetting is that the timing of baroreflex activation relative to the initiation of exercise may also markedly impact on the magnitude of baroreflex mediated responses. Most of the studies demonstrating baroreflex resetting were performed during steady-state exercise wherein HR and AP were elevated from the levels at rest(17,30,32). The results of DiCarlo and Bishop(4) indicate that baroreflex resetting occurs rapidly, at least within 10 s of the initiation of exercise. However, often AP does not immediately increase at the initiation of exercise and may decrease transiently (51). If the operating point of the baroreflex is immediately reset upward at the start of exercise without a concurrent increase in the prevailing level of AP, then baroreflex responses to hypotensive stimuli may diminish because the prevailing AP may now reside on the flatter, lower gain portion of the baroreflex stimulus-response relationship. The results of Ludbrook and Graham (13) support this concept. These investigators observed that the reflex increases in HR and AP in response to carotid occlusion were attenuated at the initiation of exercise versus that which occurred at rest. They concluded that resetting of the baroreflex operating point occurs faster than the change in AP such that baroreflex gain in response to a hypotensive stimulus becomes transiently depressed. Presumably, as time progresses during exercise and AP increases, the prevailing pressure moves closer to the baroreflex operating point and baroreflex gain increases to levels approximating that at rest. At the initiation of exercise HR often increases above the levels observed during steady-state. This transient overshoot in HR may be due to rapid baroreflex resetting. If the operating point of the baroreflex immediately increases at the start of exercise without an immediate increase in the prevailing AP, then a large baroreflex error signal transiently exists. As time progresses AP increases closer to the baroreflex operating point, thus the error signal is reduced and HR declines from the higher transient level toward the somewhat lower steady-state value. Krasney et al. (10) observed that the HR overshoot at the initiation of exercise is attenuated after arterial baroreceptor denervation. Thus, the arterial baroreflex may be a part of the afferent mechanisms mediating the HR responses to exercise; that is, during exercise if the prevailing pressure is lower than the baroreflex operating point, then an error signal exists that would be partially corrected by the arterial baroreflex. As a component of the baroreflex efferent responses, the baroreflex could then decrease parasympathetic tone and increase sympathetic tone to the heart, thus aiding in the tachycardic response to exercise.
Skeletal muscle contains group III and IV neuronal afferents that are sensitive to changes in the metabolic and mechanical environment of the muscle. Activation of these metabo- and mechano-receptors induces reflex pressor responses, termed the muscle metaboreflex and mechanoreflex, respectively. During exercise, these afferents may become activated with changes in interstitial concentration of metabolites and the increase in muscle tension and thus activation of muscle afferents may contribute to the cardiovascular responses to exercise. Whereas the exact metabolites responsible for activation of these afferents remain unclear, accumulation of the metabolites is related to oxygen delivery (43). A significant fraction of the metaboreceptors are also mechanically sensitive and conversely, a significant number of mechanoreceptors alter their response characteristics with changes in the metabolic environment(8).
Muscle metaboreflex. Much of the information on the muscle metaboreflex has been obtained via the technique of post-exercise skeletal muscle ischemia. In this setting, the circulation to active skeletal muscle is arrested at or shortly before the cessation of dynamic exercise or static muscle contractions thereby entrapping metabolites within the muscle and maintaining activation of muscle metaboreceptors. Differences in the recovery patterns of various cardiovascular variables (i.e., AP, HR, sympathetic nerve activity, etc.) are then observed(1,6,35,39,49,50,53). Several studies have shown that during post-exercise muscle ischemia, AP, and muscle sympathetic nerve activity (MSNA; sympathetic nerve activity to resting skeletal muscle that is directly measured in humans via insertion of a microelectrode into a peripheral sympathetic nerve fascicle) remain elevated for as long as the occlusion is sustained; however, HR decreases with a pattern similar to that normally occuring during the recovery from exercise without muscle ischemia. This has led several investigators to conclude that HR and AP (or more appropriately cardiac output and peripheral vascular conductance) are controlled differently by the muscle metaboreflex(6,35,36,50).
In contrast to the responses observed during the recovery from exercise, if the muscle metaboreflex is activated during exercise (e.g., by reducing blood flow to the active muscle), marked increases in both AP and HR occur(22,23,42,43,55). Indeed, data from Wyss et al. (55) indicate that in dogs a significant portion of the pressor response to graded muscle ischemia during exercise is due to the reflex increase in cardiac output. Thus a major discrepancy exists; when the muscle metaboreflex is activated during post-exercise ischemia significant metaboreflex HR responses are not evident whereas, when this reflex is activated during exercise, significant tachycardia is clearly evident and an important component in the pressor response.
What is the cause of the opposite conclusions regarding metaboreflex control of HR? Recently, we investigated the autonomic mechanisms mediating the reflex tachycardia. Experiments were performed in conscious dogs instrumented to control perfusion to the hindlimbs during treadmill exercise(22). Muscarinic blockade did not affect the magnitude of the metaboreflex HR or AP response (Fig. 3); the relationship between hindlimb perfusion and HR was shifted upward with no change in metaboreflex sensitivity. However, beta-adrenergic blockade markedly reduced both the HR and AP responses to muscle ischemia. Thus, the muscle metaboreflex-induced tachycardia occurs primarily via increases in sympathetic activity, and this increase in HR contributes importantly to the pressor response. Apparently, this reflex has little control over parasympathetic activity.
During post-exercise ischemia AP and MSNA remain increased above the levels prior to exercise whereas HR rapidly returns to resting levels. Is there a difference in the control of sympathetic activity to the heart versus peripheral vasculature during post-exercise muscle ischemia? If not, why does HR decrease normally during post-exercise muscle ischemia when MSNA remains elevated? We investigated these questions by maintaining skeletal muscle ischemia for 1 min after the cessation of exercise before and after muscarinic or beta-adrenergic blockade (22). In control experiments, HR decreased and AP remained elevated during post-exercise muscle ischemia as has been observed previously. In contrast, after muscarinic blockade both HR and AP remained elevated during post-exercise ischemia. After beta-adrenergic blockade, the tachycardic response to muscle ischemia was markedly reduced and HR decreased during post-exercise ischemia. These data strongly indicate that like sympathetic activity to the peripheral vasculature, sympathetic activity to the heart is maintained during post-exercise muscle ischemia. However, at the cessation of exercise parasympathetic activity increases. Increases in parasympathetic activity can abolish the tachycardic effect of sustained sympathetic activity (11,46).
At least two possible mechanisms may mediate the increase in parasympathetic tone at the cessation of exercise despite sustained metaboreflex activation. Strong evidence exists that at the initiation of exercise HR increases rapidly due to a reduction in parasympathetic tone. Activation of central command (i.e., responses due to the volition to exercise) may mediate this rapid decrease in parasympathetic tone(36,48). Thus, at the cessation of exercise, the HR response attributed to central command is reduced substantially allowing for an abrupt increase in parasympathetic tone. In addition, during post-exercise muscle ischemia AP is elevated above normal levels. If the arterial baroreflex is reset during exercise, then during the recovery from exercise the baroreflex operating point could return the level at rest. In this setting, the elevated AP, now possibly above the baroreflex operating point, would serve as an added stimulus for arterial baroreflex bardycardia. Since the muscle metaboreflex has weak, if any, control over parasympathetic tone(22), an increase in parasympathetic tone via the baroreflex would be unchecked by the sustained metaboreflex activation. Scherrer et al. (39) demonstrated that if the pressor response to post-exercise ischemia is attenuated via infusion of a vasodilator, some sustained tachycardia is evident, indicating that the arterial baroreflex may participate in the increased parasympathetic tone during post-exercise muscle ischemia. Sheriff et al. (42) and O'Leary et al. (23) demonstrated that the strength and mechanisms of the metaboreflex are intimately dependent on the extent of arterial baroreceptor activation. Thus, at the cessation of exercise, parasympathetic tone rises abruptly via the reduction in central command, activation of the arterial baroreflex, or by other unknown mechanism(s). This increase in parasympathetic tone obscures the tachycardic effect of the metaboreflex-induced sustained sympathetic activity to the heart and HR decreases. Therefore, the muscle metaboreflex does induce reflex changes in sympathetic activity to the heart. The conclusion that HR and AP are controlled differently during exercise likely stems from differences in both the reflex control of sympathetic versus parasympathetic tone and the method of metaboreflex activation.
Does the muscle metaboreflex participate in the HR responses to normal dynamic exercise as it likely does to moderate static contractions? This is unknown. Several studies have shown that during mild exercise substantial reductions in muscle perfusion are required before increases in HR or AP are observed (22,23,42,43,55). Thus, during mild exercise the muscle metaboreflex is probably not tonically active. Presumably, there is a large margin of flow reserve before metabolites are produced in sufficient quantity to activate the reflex. In support of this concept, Kozelka et al. (9) observed in dogs that lesions in the spinal dorsolateral sulcus and dorsolateral funiculus (tracts which relay muscle afferent information to higher centers) did not affect the HR or AP responses to mild treadmill exercise whereas after the lesions the pressor response to ischemic exercise (occlusion of the left iliac artery for 2 min during exercise) was virtually abolished. However, during moderate exercise reflex increases in HR and AP are observed with any reduction in muscle perfusion (29,43,55). This indicates that the reflex may be tonically active. However, in these studies it is impossible to differentiate between whether the reflex normally exists just at threshold during moderate exercise and becomes activated with small reductions in flow or in contrast, whether the reflex is already active during moderate exercise and small reductions in flow further activate the reflex. If moderate exercise does activate the muscle metaboreflex, then this reflex may participate in the HR and AP responses to exercise. Clearly, the muscle metaboreflex may induce the exaggerated sympathetic activation seen during moderate dynamic exercise in patients with peripheral vascular disease or ventricular dysfunction in which perfusion of active skeletal muscle is compromised.
Muscle mechanoreflex. Activation of skeletal muscle mechanoreceptors in anesthetized animals induces an increase in HR, AP, and ventricular contractility(15,19,20,44,45). Recently, Matsukawa et al. (15) showed that cardiac sympathetic nerve activity in anesthetized cats increases abruptly during static muscle contraction reaching a peak value within 10 s. Maximal increases in HR and AP occurred later, 40 and 60 s after initiation of contraction, respectively. The cardiac sympathetic nerve activation was related to the tension developed. Thus, at the initiation of static contractions reflex, increases in HR can occur via mechanoreceptor induced sympathetic activation. Since mechanoreceptor discharge quickly returns toward control levels during sustained static contractions (7,18), it is unlikely that these afferents contribute importantly to the maintained tachycardia during the latter stages of sustained static contractions(15); in this setting likely muscle metaboreceptors are markedly activated. In contrast to the studies in anesthetized animals, experiments in conscious humans revealed that activation of muscle mechanoreceptors via lower body positive pressure induced a reflex increase in AP, however, little change in HR occurred. Keep in mind, that these studies were conducted at rest when parasympathetic tone is high and is capable of obscuring the chronotropic effect of moderate increases in sympathetic activity; a setting similar to that during post-exercise muscle ischemia described above. What role the muscle mechanoreflex plays in steady-state dynamic exercise is not well understood. Inasmuch as after parasympathetic blockade little if any tachycardia occurs with the transition from rest to mild exercise (24,33), it is unlikely that muscle mechanoreceptors are markedly activated in this setting, assuming that like the muscle metaboreflex the muscle mechanoreflex acts predominately via sympathetic activation. The results of Kozelka (9) (spinal lesion experiments described above) also indicate that muscle afferents do not participate in the cardiovascular adjustments to mild exercise. With more strenuous dynamic exercise activation of muscle mechanoreceptors may contribute to the progressive increase in sympathetic tone, but this remains unknown.
Summary and Synthesis
The objective of this review was to demonstrate that the conclusions drawn regarding the roles of the arterial baroreflex and muscle metabo- and mechano-reflexes during exercise may be intimately dependent on the techniques utilized for activation and analysis of the reflexes.
The following summarizes one scheme for cardiovascular control during exercise based on the points raised above and adapted and modified from Rowell and O'Leary (36). At the initiation of exercise HR increases rapidly due to inhibition of parasympathetic tone. The inhibition of parasympathetic tone is probably due to activation of central command. However, if the arterial baroreflex is reset to a higher operating point, the baroreflex may also participate in the inhibition of parasympathetic tone in order to correct any difference between the prevailing level of pressure and the baroreflex operating point. In this setting neither the muscle metaboreflex nor the muscle mechanoreflex are markedly activated in normal subjects. As work load increases, HR increases due to further parasympathetic inhibition and concomitant sympathetic activation. The increase in sympathetic tone could occur due to the arterial baroreflex (via further baroreflex resetting), the muscle metaboreflex (if this reflex is tonically active during moderate exercise which is unknown) or muscle mechanoreceptor activation. The further parasympathetic inhibition could occur via the increased level of central command or arterial baroreflex resetting. During moderate exercise both significant sympathetic and parasympathetic tone to the heart exists. As exercise approaches maximal levels, parasympathetic activity wanes and sympathetic activity increases such that at maximal oxygen consumption little parasympathetic tone remains and sympathetic activity is greatly elevated. It is important to note that during severe exercise HR is at or near maximal levels. Thus, any further pressor response (i.e., to a fall in baroreceptor activity or further muscle afferent activation) could only occur via peripheral vasoconstriction in that cardiac output is already at maximal levels. Inasmuch as skeletal muscle receives the vast majority of the cardiac output, a further marked pressor response could only occur via vasoconstriction of the active skeletal muscle(21,25).
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