Autonomic adjustments to exercise in humans.

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Autonomic Adjustments to Exercise in Humans James P. Fisher,1 Colin N. Young,2 and Paul J. Fadel3,4* ABSTRACT Autonomic nervous system adjustments to the heart and blood vessels are necessary for mediating the cardiovascular responses required to meet the metabolic demands of working skeletal muscle during exercise. These demands are met by precise exercise intensity-dependent alterations in sympathetic and parasympathetic nerve activity. The purpose of this review is to examine the contributions of the sympathetic and parasympathetic nervous systems in mediating specific cardiovascular and hemodynamic responses to exercise. These changes in autonomic outflow are regulated by several neural mechanisms working in concert, including central command (a feed forward mechanism originating from higher brain centers), the exercise pressor reflex (a feed-back mechanism originating from skeletal muscle), the arterial baroreflex (a negative feed-back mechanism originating from the carotid sinus and aortic arch), and cardiopulmonary baroreceptors (a feed-back mechanism from stretch receptors located in the heart and lungs). In addition, arterial chemoreceptors and phrenic afferents from respiratory muscles (i.e., respiratory metaboreflex) are also capable of modulating the autonomic responses to exercise. Our goal is to provide a detailed review of the parasympathetic and sympathetic changes that occur with exercise distinguishing between the onset of exercise and steady-state conditions, when appropriate. In addition, studies demonstrating the contributions of each of the aforementioned neural mechanisms to the autonomic changes and ensuing cardiac and/or vascular responses C 2015 American Physiological Society. Compr Physiol 5:475-512, 2015. will be covered.

Introduction The autonomic nervous system plays a critical role in mediating the cardiovascular adjustments necessary to meet the metabolic demands of the exercising muscle, and as such is paramount for the performance and sustainment of physical activity. A reduction in the tonic suppressive influence of parasympathetic (vagus) nerve activity contributes to exercise-induced increases in heart rate (HR), ventricular contractility, stroke volume, and thus, cardiac output. Increases in HR and ventricular contractility are also evoked by activation of cardiac sympathetic nerve activity (SNA) and sympathetic stimulation of epinephrine release from the adrenal medulla. In addition, a sympathetically mediated vasoconstriction in nonexercising muscles and visceral organs (e.g., splanchnic circulation) facilitates the redistribution of cardiac output to the active skeletal muscles. At the same time, the normal ability of SNA to cause vasoconstriction is attenuated in the active muscles, in part due to an effect of muscle metabolites to diminish the vasoconstrictor response to α-adrenergic receptor activation (123,268). Such modulation, termed functional sympatholysis, may constitute a protective mechanism that optimizes muscle blood flow in the face of the increased sympathetic vasoconstrictor drive that occurs during exercise. However, sympatholysis is not complete and the increased SNA to active muscles does have a restrictive effect on blood flow, which is important for the maintenance of arterial blood pressure (BP) during exercise (337). Overall, the importance of the autonomic adjustments to exercise can be readily appreciated from the finding that patients with autonomic failure

Volume 5, April 2015

cannot maintain the lightest loads of dynamic exercise even if performed in the supine position to enhance central blood volume and venous return (199). The autonomic responses to exercise are dependent upon the type of exercise that is being performed. In general, exercise can be divided into two categories: dynamic and isometric (or static) (185, 221). Dynamic exercise involves rhythmical contractions that alter both muscle length and joint angle and involves intermittent changes in intramuscular force that occur in conjunction with the contraction and relaxation of the working muscles. This intermittent pumping action of skeletal muscle (i.e., muscle pump) contributes to increases in muscle blood flow. Isometric exercise on the other hand involves a sustained contraction with minimal change in muscle length or joint angle and includes a substantial development of intramuscular force. The large increases in intramuscular pressure are transferred to the vasculature and cause a decrease in * Correspondence

to [email protected] of Sport, Exercise & Rehabilitation Sciences, College of Life & Environmental Sciences, University of Birmingham, Birmingham, United Kingdom 2 Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA 3 Department of Medical Pharmacology & Physiology, University of Missouri, Columbia, MO, USA 4 Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA Published online, April 2015 (comprehensivephysiology.com) DOI: 10.1002/cphy.c140022 C American Physiological Society. Copyright 1 School

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Autonomic Adjustments to Exercise in Humans

Comprehensive Physiology

skeletal muscle blood flow. These contrasting contractile characteristics and the subsequent hemodynamic alterations contribute importantly to the differences in the cardiovascular responses evoked. While HR and BP increase with both dynamic and isometric exercise, there are distinct differences. At a constant work load, during dynamic exercise HR increases to a steady-state value, whereas during isometric exercise HR continually rises at a given work load until fatigue. However, perhaps the most notable difference between dynamic and isometric exercise is the pressor response, which occurs to a much greater extent during isometric exercise owing to the more immediate and large increases in SNA with this form of exercise, as discussed in detail later in this review. Studies designed to examine the autonomic responses to exercise have incorporated both dynamic and isometric exercise protocols. Handgrip and knee extensions performed as a percent of maximal voluntary contraction (% MVC) are the primary forms of isometric exercise used. The classic mode of dynamic exercise for investigation is cycling; however, laboratory studies investigating neural cardiovascular control during dynamic exercise more often use a rhythmical form of isometric exercise which incorporates intermittent isometric contractions separated by timed relaxation periods. A major advantage of this form of exercise is that it more readily allows for movement sensitive measurements such as muscle SNA (microneurography) or beat-to-beat blood flow (Doppler

ultrasound) to be obtained without the motion artifacts inherent to whole body dynamic exercise. Likewise, the use of dynamic and isometric exercise in human research protocols has been instrumental in teasing apart the contributions of the underlying neural mechanisms involved in evoking the autonomic and ensuing cardiovascular responses to exercise. Several neural mechanisms working in concert are responsible for the autonomic adjustments to exercise and through complex interactions precisely control the cardiovascular and hemodynamic changes in an intensity-dependent manner (Fig. 1). It is well accepted that central signals from the higher brain associated with the volitional component of exercise (i.e., central command) (264,362,378), peripheral signals arising from mechanically and metabolically sensitive afferents in contracting skeletal muscle (i.e., exercise pressor reflex) (162, 164, 219, 220, 315), and feedback from stretch receptors originating in the carotid and aortic arteries (i.e., arterial baroreflex) (75, 76, 78, 263, 265) are all involved. Less appreciated, but also important, are low-pressure mechanically sensitive stretch receptors located in the heart, great veins and blood vessels of the lungs that sense changes in central blood volume and pressure (i.e., the cardiopulmonary baroreflex) (41, 76, 78, 88, 163, 209). In addition, arterial chemoreceptors housed in the carotid and aortic bodies and phrenic afferents from respiratory muscles (i.e., respiratory metaboreflex) are also capable of modulating the autonomic responses to exercise. This review will focus on the contributions of the

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Schematic summarizing the mechanisms involved in mediating the autonomic adjustments to exercise. Neural signals originating from higher brain centers (i.e., central command), chemically sensitive receptors in the carotid and aortic bodies (i.e., arterial chemoreflex), stretch receptors in the carotid and aortic arteries (i.e., arterial baroreflex), mechanically and metabolically sensitive afferents from skeletal muscle (i.e., exercise pressor reflex), mechanically sensitive stretch receptors in the cardiopulmonary region (i.e., cardiopulmonary baroreflex) and metabolically sensitive afferents from respiratory muscles (i.e., respiratory metaboreflex) are processed within brain cardiovascular control areas that influence efferent sympathetic and parasympathetic nerve activity. The alterations in autonomic outflow elicited by these inputs during exercise evoke changes in cardiac and vascular function, as well as release of catecholamines from the adrenal medulla.

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sympathetic and parasympathetic nervous systems in mediating specific cardiovascular and hemodynamic responses to exercise. Studies demonstrating the contributions of the aforementioned neural mechanisms to the autonomic changes and ensuing cardiac and/or vascular responses will be covered. In addition, distinctions between the onset of exercise and steady-state conditions will be made, when appropriate. Of note, nonadrenergic hormonal contributions (e.g., Angiotensin II, Vasopressin) to the cardiovascular responses to exercise will not be covered nor will autonomic effects on metabolic and respiratory responses. Overall, the literature examining the autonomic nervous system and the mechanisms of neural cardiovascular control during exercise is vast. As such, it is not feasible to include all of the research within these fields in a single article and therefore, additional review articles are cited throughout to direct the reader to further work in these important areas. It should also be noted that this review was designed to focus primarily on studies in healthy humans and more recently published work with only brief mention to animal studies and historical data.

Autonomic Responses to Exercise Cardiac autonomic regulation Following a brief description of the organization of the autonomic neural control of the heart and the methods commonly used for its assessment in humans, the influence of exercise phase (e.g., onset, steady-state, and recovery), duration, intensity, and modality on cardiac autonomic control will be discussed.

Cardiac autonomic organization Parasympathetic and sympathetic efferent activity can modulate the chronotropic, inotropic, and lusitropic functioning of the heart. The cell bodies of the parasympathetic preganglionic neurons are situated in the nucleus ambiguus and dorsal motor nucleus of the medulla oblongata (154). The axons travel within the tenth cranial nerve (vagus nerve) and synapse at a postganglionic neuron located at the cardiac plexus. Sympathetic preganglionic cell bodies are located in the intermediolateral cell column of the spinal cord and the preganglionic fibers directed to the heart synapse at the stellate ganglion and upper thoracic ganglia (T1-T5). Postganglionic parasympathetic and sympathetic fibers synapse at the sinoatrial node, atrioventricular node, atria, and ventricles. The classical view of cardiac autonomic neurotransmission whereby parasympathetic efferents release acetylcholine onto muscarinic receptors and sympathetic efferents release norepinephrine onto β1 -receptors is well established (154). However, the importance of the complex pre- and postsynaptic interactions between parasympathetic and sympathetic fibers (e.g., excitatory facilitation and accentuated antagonism) (189) and the role of intrinsic and locally released neuromodulators (e.g., neuronal nitric oxide and neuropeptide


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Y) (18, 136) should not be overlooked. Although the rich sympathetic innervation of ventricles is widely recognized, as recently reviewed by Coote (39), there is accumulating evidence for dense parasympathetic innervation of this region and its functional significance in the control of ventricular rhythm, rate and contractility. In addition, a positive chronotropic response to α1 -adrenergic stimulation has been reported in young individuals (287). However, the importance of parasympathetic regulation of ventricular function and α1 adrenoreceptor chronotropism during exercise in health and disease remains to be elucidated.

Assessment of cardiac autonomic regulation The limited accessibility of cardiac autonomic efferents means that obtaining direct intraneural recordings from humans is not plausible, thus indirect assessments of cardiac autonomic control must be relied upon. The relative merits and faults of these experimental approaches have been discussed extensively elsewhere (32) and will only be briefly mentioned here. The use of pharmacological blocking agents provides a valuable means of dissecting the contributions of parasympathetic and sympathetic activity to cardiac regulation. Cardiac parasympathetic activity may be assessed by the administration of muscarinic receptor antagonists such as atropine sulfate or glycopyrronium bromide (also known as glycopyrrolate), with the latter being preferred in more recent investigations as its penetration of the blood-brain barrier is much lower, which decreases the likelihood of any potential confounding central effects (259). The pharmacological assessment of cardiac sympathetic activity may be achieved by the administration of β-adrenergic blockade. Although βblockade has been usually administered prior to exercise, a small number of studies in animals have initiated administration during exercise (22, 239), thus circumventing any confounding effects of a change in baseline HR. The potentially confounding effects of drug non-specificity (e.g., combined β1 - and β2 -adrenergic receptor blockers) and blockade completeness should be considered when interpreting pharmacological investigations of cardiac autonomic control during exercise. Also, while very useful in the assessment of HR regulation during exercise, the associated changes in diastolic filling time and thus preload, means that pharmacological examination of the inotropic effects of cardiac autonomic activity in vivo can be difficult. On the basis that cardiac SNA is proportional to the appearance of norepinephrine in the coronary venous effluent (coronary sinus); cardiac norepinephrine spillover rate can provide an accurate assessment of cardiac sympathetic firing (169). Norepinephrine spillover from the heart may be studied with the infusion of radio-labeled norepinephrine and appropriate catheterization and regional blood sampling (74). To the best of the authors’ knowledge, a comparable approach has not been used to assess cardiac acetylcholine spillover from the human heart, which would require appropriate control for the high catalytic activity

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of acetylcholinesterase (309). While the directness of this approach is a key strength, its invasiveness and the associated technical challenges limits it widespread use. Albeit much more indirect, time and frequency domain analysis of HR variability provides a noninvasive means of assessing cardiac autonomic activity (69). As power spectral analysis of fluctuations in R-R interval occurring around a respiratory frequency (i.e., high frequency, 0.15-0.40 Hz) and short-term time domain measures (e.g., root mean square of successive differences) of HR variability are virtually abolished by cholinergic-muscarinic blockade (69, 262) they are widely utilized to estimate cardiac parasympathetic activity. In contrast, low frequency (i.e., 0.04-0.15 Hz) R-R interval power is attenuated by both cholinergic and β-adrenergic blockade suggesting that the activities of the parasympathetic and sympathetic nerves contribute, and thus the interpretation of changes in low frequency power is complex (69, 169). The specific limitations associated with the use of HR variability to interrogate cardiac autonomic control during exercise have been discussed at length elsewhere (32). Patients who possess a functionally denervated heart as a consequence of spinal cord transection or heart transplantation also provide a valuable means of interrogating cardiac autonomic control in humans. Cardiac adrenergic innervation and activation can also be assessed with radio-scanning methods (74). This approach has been used to document heightened cardiac sympathetic activity in chronic heart failure patients and is also associated with elevated SNA directed to the skeletal muscle vasculature, reduced exercise capacity and future cardiac events in this population (387,388). Although providing a powerful research tool, limited studies have used this approach to evaluate cardiac SNA during acute exercise (10), possibly due to its expense and poor temporal resolution.

Cardiac autonomic regulation at exercise onset HR increases virtually instantaneously upon the initiation of exercise. The involvement of a reduction in cardiac parasympathetic activity (or “inhibition of the normal restraining action of the inhibitory centre”) in humans was suggested at the turn of the last century (26) although experimental support for this proposition is much more recent (343). Administration of atropine has been shown to significantly attenuate the initial increase in HR to a variety of exercise modalities, including isometric handgrip (98,194), isometric arm flexion (143), and leg cycling (80,271). Furthermore, HR variability derived indices of cardiac parasympathetic activity are decreased in early exercise (11, 22). In contrast, the magnitude of the cardiac acceleration at the onset of leg cycling is not diminished by prior β-adrenergic blockade, implying a minimal influence of sympathetic activity at this time (80, 271). Taken together these findings suggest that the early HR response to exercise is principally mediated by the withdrawal of cardiac parasympathetic activity, with the sympathetic contribution being manifest at a longer latency. This concept is supported by investigations showing a rapid reduction in HR resulting

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from stimulation of cardiac parasympathetic efferents and a more sluggish response to sympathetic nerve stimulation (∼3-6 s) (133). Contrary to the traditional view, Matsukawa and colleagues have advanced the hypothesis that it is an increase in cardiac SNA at the onset of exercise that principally causes the initial rise in HR. This view is supported by studies in conscious cats in which directly recorded cardiac SNA was shown to rapidly increase at the onset of treadmill exercise (by 168%-297% within ∼7 s) (346). However, reconciling these observations in cats with the human studies described above is challenging in the absence of direct cardiac sympathetic recordings in humans. Furthermore, alternative techniques for directly assessing cardiac SNA in humans do not offer sufficient temporal resolution to capture the kinetics of the onset response (e.g., cardiac plasma norepinephrine spillover). It has also been shown that tetraplegic subjects, in whom a complete cervical spinal cord lesion (C6-C7) has caused cardiac sympathetic denervation while cardiac parasympathetic innervation remains intact, display an attenuated increase in HR at the start of isometric arm exercise (329). Furthermore, the normal reduction in R-R interval high frequency spectral power is more sluggish in these patients during isometric exercise, compared to control participants (328). These observations have been taken as further evidence for the relative importance of SNA to the initial cardiac acceleration that accompanies exercise. However, an alteration in cardiac parasympathetic regulation as a consequence of a chronic adaptation to spinal lesion cannot be excluded.

Cardiac autonomic regulation during steady-state exercise There is an approximately linear relationship between HR and oxygen uptake during incremental dynamic exercise of a large muscle mass (180). It is generally considered that the relative contribution of cardiac parasympathetic withdrawal to this HR response is greatest at lower exercise workloads and becomes less significant as exercise intensity increases, particularly once HR exceeds ∼100 b·min−1 . Conversely, the relative contribution of cardiac sympathetic stimulation to the exercise-induced elevation in HR increases along with exercise workload. Indeed, administration of atropine diminishes the magnitude of the HR rise during low-to-moderate intensity exercise, whereas HR is unaffected by propranolol administration (80,194,271). In contrast, at higher exercise intensities βadrenergic blockade significantly attenuates the size of the HR response, thus suggesting a key role for heightened SNA and circulating catecholamines at such workloads (80, 194, 271). An exercise intensity-dependent reduction in high frequency power spectral density has also been described, indicative of progressive cardiac parasympathetic withdrawal (11). This is much more marked in the transition from rest to low-intensity exercise, than between moderate to high exercise intensity in healthy individuals (11). Such changes in autonomic modulation of the heart were absent in heart transplant patients


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possessing a denervated heart (11). Nevertheless, the relative contributions of cardiac parasympathetic activity and SNA to the HR response at differing dynamic exercise intensities continues to be debated (374). HR variability derived indices of cardiac parasympathetic activity have also been demonstrated to decrease during isometric exercise (149), although the magnitude of this reduction is less marked than observed during dynamic exercise and typically accompanied by a more modest increase in HR (128). As mentioned above, HR variability analyses do not permit a robust assessment of cardiac SNA, and to the authors’ knowledge, the influence of dynamic exercise intensity on cardiac norepinephrine spillover has not been comprehensively evaluated in healthy humans. However, Hasking et al. (129) has reported that cardiac norepinephrine spillover was markedly increased during moderate intensity leg cycling exercise (from 5 ± 2 to 73 ± 23 ng·min−1 ). During prolonged submaximal dynamic exercise at a steady-state workload, there is a progressive increase in HR, mirrored by a fall in stroke volume, such that cardiac output is maintained relatively stable (43, 66). This “cardiovascular drift” phenomenon is exacerbated when exercise is combined with heat stress and dehydration (111). Intriguingly, β1 -adrengeric blockade prevented the normal increase in HR observed after 15 min of leg cycling exercise (∼57% peak oxygen uptake, thermo-neutral conditions) and consequently stroke volume did not fall, likely as a consequence of the relatively longer diastolic filling time (100). Whether cardiac norepinephrine spillover increases over the time course of such exercise is unclear, however in dogs performing prolonged steady-state submaximal treadmill exercise the progressive increase in HR was accompanied by a progressive reduction in HR variability determinants of cardiac parasympathetic activity (182). An increase in core temperature may explain the autonomic contribution to the drift in HR noted during prolonged submaximal exercise (100, 157), although increased central command and skeletal muscle afferent feedback likely also contribute (178). The heart appears to retain at least some parasympathetic control at high exercise intensities. Indeed, atropine administration elicits a robust increase in HR in dogs performing heavy-intensity treadmill exercise (239) and respiratory mediated fluctuations in HR are still evident (22). However, the lack of an increase in HR with atropine administration during exhaustive dynamic exercise and the absence of appreciable HR variability in humans, suggests that cardiac parasympathetic withdrawal is complete at these workloads (272). An early study by Robinson et al. (272) reported that cardiac parasympathetic blockade reduced maximal oxygen uptake, although this observation was not substantiated by later investigations (65). As recently reviewed, an extensive body of work has evaluated the contribution of cardiac SNA to maximal exercise performance using a variety of human and animal models (343). The most relevant studies with respect to the focus of the present review are those employing β-adrenergic blockade in humans. Several of these studies have reported a reduction in maximal oxygen consumption and exercise


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capacity (9, 72, 336); however, this has not been a universal finding with no effect of β-adrenergic blockade often reported (65, 196, 269). Part of the reason for these equivocal findings may relate to the training status of the participants studied. Joyner et al. (159) demonstrated that β-adrenergic blockade with propranolol had little effect on maximal oxygen uptake in untrained subjects (≈45 mL·min−1 .kg−1 ) whereas in aerobically trained individuals (≈63 mL·min−1 .kg−1 ) a notable reduction in maximal oxygen uptake was observed. While, the importance of a direct cardiac effect is clear from the reported reduction in maximal cardiac output, indirect mechanisms may also contribute (e.g., metabolic and hormonal alterations) particularly when nonspecific β-adrenergic antagonists have been utilized. Along with a reduction in intrinsic HR, a reduction in β-adrenergic sensitivity contributes to the well-established reduction in maximal HR with age (33) that makes a significant contribution to the age-related lowering of maximal oxygen consumption (134). Maximal HR is often estimated as 220—age (93), but may underestimate maximal HR in older individuals and on the basis of extensive meta-analyses and laboratory-based investigations alternative regression equations have been derived (e.g., Tanaka equation; 208 × 0.7— age) (270, 333). An inability of HR to increase appropriately in proportion to the metabolic demands of exercise has been termed “chronotropic incompetence” and has been linked with an impairment in β-adrenergic sensitivity (37, 71). It may be defined in a number of ways, but the failure to attain ≥80% of HR reserve during an incremental maximal exercise test is most commonly used (28). Importantly, chronotropic incompetence is associated with exercise intolerance and is an independent predictor of mortality in clinical (e.g., heart failure) and healthy populations (28, 71). It should be noted that while alterations in cardiac autonomic control may be implicated in chronotropic incompetence the underlying mechanisms remain incompletely understood. At the immediate cessation of exercise the initial recovery of HR is quite abrupt, but this is generally followed by a more gradual decline occurring over minutes, the specific kinetics of which are dependent on the intensity and duration of the prior exercise (130, 150). HR recovery is delayed in heart transplant patients (292) indicative of a contribution of cardiac autonomic efferent activity in this process. The rapid recovery of HR following exercise has been attributed to the rapid restoration of cardiac parasympathetic activity, since it is virtually abolished by atropine administration, but unaffected by β-adrenergic blockade (87, 150). Furthermore, endurance trained athletes in whom cardiac parasympathetic activity is elevated demonstrate a more rapid recovery of HR (150). The secondary more gradual decline in HR following exercise may be attributable to a slower restoration of the remaining cardiac parasympathetic activity and reduction in cardiac sympathoexcitation (11), which sustains a modest elevation in cardiac output, thus preserving perfusion pressure in the face of peripheral vasodilatation. HR recovery kinetics have been shown to have prognostic value, with a poor

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recovery (e.g., a fall in peak exercise HR by 60% peak workload) where increases in muscle SNA were observed. Ray et al. (266) reported that during one legged kicking muscle SNA was reduced below baseline when exercise was performed in the upright position, and unchanged during supine exercise. As discussed in more detail below, these findings point to the important modulatory role played by venous return, central blood volume, and thus cardiopulmonary baroreceptor loading status to the muscle SNA responses at the onset of low-intensity dynamic exercise, but at higher exercise intensities this sympatho-inhibitory effect is obscured by other sympatho-excitatory mechanisms (e.g., exercise pressor reflex and central command). Collectively, studies examining SNA responses at the onset of exercise support a nonuniform sympatho-excitation that likely assists in initiating the appropriate cardiovascular adjustments to exercise. In this regard, the reported immediate increases in SNA to the kidney and skin would be important for redistribution of blood flow to active muscles upon the


initiation of exercise. At the same time, lack of an increase or an inhibition of muscle SNA would facilitate vasodilation and increased blood flow within active skeletal muscles. Lastly, the increase in cardiac SNA would elevate HR (along with reduced parasympathetic nerve activity) and cardiac contractility contributing to increases in cardiac output, which would be preferentially distributed to active skeletal muscle due to the aforementioned peripheral SNA responses. While this differential sympathetic activation pattern at the onset of exercise seems reasonable and appropriate, it is important to note that some studies have indicated an immediate and sustained exercise-induced increase in lumbar SNA to skeletal muscle in conscious rats (56) and unanesthetized decorticate cats (121).

Peripheral sympathetic activity during steady-state exercise In contrast to the onset of exercise, there is substantial evidence that SNA increases in an intensity dependent manner during sustained levels of dynamic exercise in humans. Indeed, for the most part, studies using direct muscle SNA recordings, plasma norepinephrine as well as norepinephrine spillover have all suggested that sympathetic activation

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becomes progressively greater as exercise intensity and duration is increased (24,103,146,186). Galbo et al. (103) reported a progressive increase in venous norepinephrine concentration during graded treadmill exercise at workloads above 50% maximal oxygen uptake (VO2 max). Likewise, arterial and venous norepinephrine concentrations were found to progressively increase during incremental leg cycling (24, 186, 334, 341). An exercise intensity dependent and marked elevation in whole body norepinephrine spillover was also observed, to which a large contribution was attributable to the kidney (188,341). However, Seals et al. (300) reported a strong relationship between plasma norepinephrine and muscle SNA during graded intensity two-arm cycling, but notably, at low workloads neither norepinephrine nor muscle SNA were increased. In addition, more recent work by Ichinose et al. (146) demonstrated that during 6-min stages of graded leg cycling from very mild to exhaustive exercise an initial decrease in directly recorded muscle SNA at low workloads was followed by progressive increases reaching an approximate 265% elevation from baseline during exhaustive exercise (Fig. 5). These data clearly demonstrate that profound increases in muscle SNA can occur with dynamic exercise. Aside from exercise intensity, the duration of exercise has a major impact on the temporal pattern and degree of sympatho-excitation. In this regard, Davy and colleagues (52) reported an increase in plasma venous norepinephrine after 10 min of treadmill walking at approximately 65% peak oxygen uptake (VO2 peak) that increased further as exercise continued. Furthermore, progressive increases in norepinephrine have been reported during 3 h of treadmill running at 60% of VO2 peak (103). It is important to note that both the intensity and duration of exercise will combine to dictate the overall sympathetic response. For example, during 30 min of sustained leg cycling performed at 25% of maximum workload, plasma norepinephrine concentration and wholebody norepinephrine spillover were increased by 15 min of exercise and then plateaued to remain elevated throughout (188). In contrast, 30 minutes of exercise performed at 65% of maximum workload evoked a much larger increase in plasma norepinephrine concentration and whole-body norepinephrine spillover that progressively increased throughout the exercise period. A similar progressive increase in sympathetic activation was observed using direct muscle SNA recordings obtained during 30 min of upright cycling at 40% VO2 max (285). Thus, in describing the sympathetic response to dynamic exercise the duration and intensity need to be considered as both contribute importantly to the degree of sympathetic activation. An important distinction that requires consideration is whether sympathetic responses are being measured in active or inactive skeletal muscle beds. Indeed, many of the studies examining sympathetic responses to exercise in humans, particularly those using direct recording of muscle SNA, have assessed the inactive limb. Furthermore, whole body norepinephrine measures represent a marker combining active and inactive beds. This becomes quite important

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Figure 5 Muscle SNA responses to a bout of incremental leg cycling ranging in intensity from very mild to exhausting. Raw recordings of arterial BP and muscle SNA (MSNA) during rest, very mild, mild, moderate, heavy, and exhausting exercise and recovery in a representative subject from Ichinose et al. (146). After an initial decrease in MSNA from rest during very mild exercise, MSNA was increased progressively as exercise intensity increased. Reprinted, with permission, from (146).


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because the limited data available suggests that the active limbs may be the major targets of the increase in sympathetic activation. For example, it has been reported that 60% of norepinephrine release during submaximal dynamic exercise comes from the skeletal muscle circulation (73). In addition, the classic work of Savard and colleagues (291) demonstrated that norepinephrine spillover was greater from the active leg compared to the inactive during one legged knee extension exercise undertaken at 50% and 100% of maximum workload. Although the concept that there is greater SNA to active skeletal muscle is intriguing and seems reasonable as this may be needed to offset local metabolically mediated vasodilation, not all studies have reported a difference between active and inactive SNA during exercise. In this regard, Hansen et al. (124) reported similar increases in directly measured muscle SNA in the active and inactive limb during ischemic unilateral static toe extension at 20% MVC. The reason for the lack of a difference in muscle SNA between the exercising and nonexercising limbs in this study is not clear but may relate to the exercise modality employed, the low exercise intensity, and/or the small muscle mass engaged. Indeed, although ischemic, a mild intensity was used in this study, and when matched for relative exercise intensity, sympathetic activation will be greater when a larger compared to smaller muscle mass is engaged (23). However, even though the size of the contracting muscle mass reportedly increases the magnitude of the resultant SNA and BP response, this association is complex and likely affected by a multitude of factors including but not limited to skeletal muscle fiber type, exercise mode, and local blood flow (229, 297), as reviewed elsewhere (88). In summary, the existing literature provides clear evidence for intensity and duration-dependent increases in muscle SNA to both the active and inactive limbs during isometric and dynamic exercise in humans. This is accompanied by increased norepinephrine spillover from the cardiac (129,368), renal (129,341), and splanchnic (208) vasculature. Nevertheless, regional differences in the temporal pattern of the sympathetic activation and the impact that both intensity and duration have on the sympathetic response have to be carefully considered when examining studies reporting SNA during exercise. In the following sections of this review, we will discuss the neural mechanisms underpinning the parasympathetic and sympathetic adjustments to exercise.

Neural Cardiovascular Control Mechanisms Central command In 1886, Zuntz and Geppert proposed the existence of a cortical control mechanism that simultaneously activated respiratory centers and voluntary locomotor pathways. This feed forward parallel activation of locomotor and respiratory neural circuits was further advanced to incorporate the cardiovascular responses to exercise (156, 180, 181). Originally termed “cortical irradiation” (181) and later “central command”


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(113), this concept refers to descending neural signals that elicit skeletal muscle contraction and concomitantly activate central nervous system centers involved in the control of autonomic neural outflow to the cardiorespiratory system. It is now clear that an individual’s perception of effort contributes to the magnitude of central command during exercise, independent of the actual force produced (Fig. 6). However, it is important to note that effort sense is a complex variable that can be influenced by numerous stimuli (e.g., pain), which provide afferent feedback to cardioregulatory centers of the brain (377, 378). Thus, in addition to the traditional feed-forward concept (180, 181, 390), it is likely that central command also involves feedback mechanisms (377, 378), and in this regard multiple brain sites (116). Due to the complexity of central command, the identification of specific brain region(s) responsible for evoking autonomic adjustments has remained elusive. However, putative locations for central command have been identified in animals using direct electrical or chemical stimulation of neural structures including the Fields of Forel, motor cortex, insular cortex, mesencephalic, and hypothalamic areas (1, 15, 68, 314, 332, 362). The advancement of neuroimaging techniques has provided an opportunity for translation of these findings to humans and the insular and anterior cingulate cortices have been suggested as human brain regions that are activated by central command during exercise (45, 168, 234, 235, 339, 379, 380). More recently, direct electrical stimulation of midbrain areas during neurosurgery (e.g., deep brain stimulation) in awake humans has been used to enhance our understanding of potential central command areas (16, 117, 118, 338) (Fig. 7). While constrained by electrode placement and a patient population (e.g., chronic pain), these novel studies have indicated that the thalamus, subthalamic nucleus, substantia nigra, periaqueductal gray, and periventricular gray may all be involved in determining the cardiovascular response to exercise. Collectively, although these studies identify specific regions of interest, the development of an integrated neurocircuitry model of central command remains an open area of investigation. The influence of the exercise phase, duration, intensity, and modality on this complex neural mechanism is discussed below.

Central command at exercise onset The idea of a central neural signal driving cardiovascular responses during exercise arose from early observations that HR increased in anticipation of and immediately at the onset of exercise—a response that was suggested to be too rapid to be explained by reflex mechanisms in the contracting skeletal muscle (29, 108, 156, 180, 181). These initial observations, intuitively, albeit indirectly, suggested a fast feed-forward neural mechanism, and were supported by subsequent studies demonstrating an increase in HR within the first beat during static arm contraction (143) and large muscle dynamic exercise (153, 231, 382). A more definitive role for central command in the initial HR response to exercise has been

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Figure 6 Imagined and actual handgrip exercise elicits similar cardiovascular responses. Heart rate, mean arterial blood pressure, and rating of perceived exertion during actual (left) and imagined (right) handgrip exercise. Subjects were categorized into low (n = 4) and high (n = 5) hypnotizability groups. Muscle electromyographic recordings demonstrated no measurable increases in force during imagined handgrip, not shown. The data are presented as mean ± SD. ∗ P < 0.05 low versus high hypnotizability. Reprinted, with permission, from (379).

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Electrophysiology recordings from the periaqueductal gray suggest that this neural region is involved in mediating the cardiovascular adjustments to exercise. Three patients had stimulation electrodes placed in the periaqueductal gray for the treatment of chronic neuropathic pain. Local field potentials (LFP) were collected from the periaqueductal gray during resting conditions, anticipation of exercise, cycling at 15 W (30-60 s) and recovery from exercise. (A) Original LFP recordings from the periaqueductal gray. (B) Magnetic resonance image illustrating electrode placement in the periaqueductal gray. (C) Mean power spectral density from all three subjects. (D) Normalized spectral changes (rest = 1.0) divided into frequency bands. ∗ P < 0.05, ∗∗ P < 0.01, ∗∗∗ P < 0.001 versus rest. Reprinted, with permission, from (118).

provided from studies using passive cycling exercise (382) and partial motor paralysis (153, 301) to alter the level of central command influence. According to the latter approach, partial neuromuscular blockade decreases the contractile ability of the paralyzed muscles and thus, a greater neurally generated signal is required to maintain the same level of absolute force (i.e., exaggerated central command input). In this regard, the initial rise in HR in response to voluntary contractions is unaffected by partial neuromuscular blockade (i.e., same HR response with less absolute muscular force developed), suggesting that the rapid tachycardic response is related to voluntary effort, rather than feedback from the contracting skeletal muscle (153, 301). These findings are in line with classic work in cats in which stimulation of locomotor brain regions elicited stimulation-dependent increases in cardiovascular variables, despite lack of muscle contraction due to deep anesthesia or paralysis (57, 67, 363). Thus, it is well accepted that the initial rapid increase in HR at the onset of exercise is due to descending central nervous system input, although as discussed later, reflex inputs contribute quickly. Due to the latency of parasympathetic and


sympathetic influences on HR, the general assumption has been that central command-induced cardiac vagal withdrawal mediates the increase in HR at the onset of exercise. Indeed, vagal blockade with atropine blunts the rapid rise in heart in response to static contractions (98,108,143). However, recent evidence suggests a potential role for early increases in cardiac sympathetic outflow during spontaneous motor activity in a feline model (346), although the translational applicability of these findings to humans remains yet to be determined. In contrast to cardiac autonomic control, relatively few investigations have examined a direct role for central command mediated peripheral vascular regulation at the onset of exercise. However, BP increases in anticipation of exercise, relative to the perceived level of effort necessary, which is consistent with a centrally mediated mechanism (116). Using brief (3 s) maximal isometric contractions, Iwamoto et al. (153) demonstrated that the exercise induced increase in BP was attenuated, but not eliminated, following partial neuromuscular blockade. That is, central command, in the absence of reflex skeletal muscle feedback, contributed in part to the rise in BP. These findings are consistent with work in cats in

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which pharmacological blockade of skeletal muscle stretch activated ion channels did not influence early increases in BP during spontaneous muscle contractions (i.e., central command induced pressor response) (201). However, the autonomic contribution to potential central command induced early increases in BP has yet to be fully determined, although in support of a sympathetic contribution, BP and renal SNA have been shown to increase prior to and at the onset of static exercise (206), locomotion (277), grooming (203) and treadmill exercise (237) in animals. Although not specifically designed to examine the onset of exercise, work from Victor and colleagues using brief rhythmic handgrip exercise and partial neuromuscular blockade lends some additional insight (355). Short 3-s handgrip contractions below 50% MVC were shown to have no influence on muscle SNA. However, under intense conditions (75% MVC) every muscular contraction was accompanied by a synchronized burst of muscle SNA and this synchronization persisted following partial curization, although muscular force development was minimized. These observations highlight the potential for central command to increase muscle SNA at the onset of exercise, albeit likely only at high intensities. In contrast, central command appears crucial for controlling skin SNA, due to the rapid increases observed prior to and at the immediate onset of exercise (267, 344, 358, 359, 384). At the onset of dynamic muscular contractions a rapid increase in active skeletal muscle vasodilatation occurs, concomitant with a decrease, increase or no change in BP depending on the exercise modality and intensity (174). While the cause of this rapid vasodilation remains unresolved and has been attributed to a number of factors including the muscle pump and vascular compression, vasodilatory or metabolic factors, myogenic responsiveness, and sympathetic vasoconstrictor withdrawal, the concept of a sympathetically mediated vasodilatory mechanism (e.g., cholinergic) has remained contentious in humans. Cholinergic (muscarinic) blockade has been shown not to influence the hyperemic response at the onset of rhythmic handgrip exercise (308); findings that are consistent with the observation that there are no obvious sympathetic cholinergic vasodilator fibers in human skeletal muscle (25, 348). Furthermore, the increase in forearm blood flow in response to an attempted maximal contraction is minimal following limb paralysis with pipecuronium, an agent that blocks postsynaptic nicotinic receptors with no effect on acetylcholine release, suggesting that acetylcholine spillover from other areas (e.g., motor nerves) is not involved in skeletal muscle vasodilation in humans (63, 372). In contrast, Secher and colleagues (303) demonstrated that BP was stable at the onset (first 6 s) of a control bout of low-intensity dynamic exercise, but with partial curarization BP decreased, suggesting that the augmentation of central command stimulates a peripheral neurogenic vasodilatory mechanism. More recent examinations using a novel technique of motor imagery of exercise to stimulate central command have suggested that a neural signal induces vasodilation in skeletal muscle (152). However, the transient increase in lower limb

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vascular conductance evoked by an isometric contraction of the contralateral calf muscle is no different when performed either volitionally or electrically evoked, suggesting that central command is not requisite for this rapid vasodilatory response (89). Despite conflicting findings in humans, a number of observations in animal models demonstrate that stimulation of certain neural regions can produce skeletal muscle vasodilation (1, 15, 70, 142, 202, 204) and that the increases in blood flow and vascular conductance at the onset of muscular contractions are blocked to a similar extent with either ganglionic blockade or atropine (177). Overall, while a role for central command in mediating the peripheral vascular responses at the onset of exercise has been demonstrated in humans, further investigations are warranted, including considerations for the specific autonomic contributions relative to the exercise modality, muscle mass, and intensity.

Central command during steady-state exercise As highlighted above, a primary strategy used to study the potential role of central command during exercise in humans has been neuromuscular blockade. Freychuss (97) reported that an unsuccessful attempt to isometrically contract the forearm muscles, following complete neuromuscular blockade, was still accompanied by an increase in HR and BP, albeit approximately 50% of the normal response. In line with this, partial neuromuscular blockade to augment the level of central command has generally resulted in an exaggerated cardiovascular response during static and dynamic exercise (13, 106, 187, 224, 250, 261, 351) (Fig. 8). Although such a relationship is not as clear during high intensity isometric contractions (107, 184) and maximal dynamic exercise (104). Studies employing additional strategies to modulate central command input such as electrical stimulation of resting skeletal muscle (180), hypnosis (49, 339, 370, 379, 380), muscle tendon vibration (113, 155, 246), and patients with unilateral limb weakness (151, 385) or sensory neuropathies (61) have also demonstrated a role for central command in mediating the cardiac acceleration and increases in BP in response to exercise. For example, Williamson et al. (379) showed that the HR and BP responses to actual and imagined (i.e., hypnosis with no force produced) handgrip exercise were identical, supporting the concept that central command mediated responses are dictated by the perception of effort (Fig. 6). Although less extensively investigated, the increase in cardiac output during exercise appears to be mediated in part by central command, primarily due to modulation of HR (192,250,326,383), although discrepant findings have been reported (13, 151). The traditional concept has been that the central command-induced increase in HR during exercise is due to parasympathetic withdrawal. Indeed, muscarinic, but not nonselective β-adrenergic, blockade, reduces the central command-induced tachycardia during exercise with partial curization (224, 354). However, this area may warrant further investigation in humans given recent findings that central command has been shown to primarily influence cardiac


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command in mediating skin SNA responses to exercise. In contrast, as mentioned above, using direct recordings of muscle SNA in experiments designed to isolate the reflex effects of skeletal muscle metaboreceptor afferents, Mark and colleagues suggested that central command has a minimal influence on sympathetic outflow to the skeletal muscle vasculature during low- to moderate-intensity static and dynamic exercise (198, 354). Furthermore, the magnitude of the rise in muscle SNA during contractions following partial neuromuscular blockade is minimal (351). Collectively, these findings suggest that central command is crucial for increasing efferent skin SNA during exercise, but has a modest effect on skeletal muscle sympathetic outflow at low to moderate exercise levels, although a more prominent role may be apparent during high intensities of exercise (355).

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Augmenting the level of central command with partial neuromuscular blockade exaggerates the cardiovascular responses to static handgrip exercise. Mean arterial blood pressure and heart rate at rest, during a 2 min handgrip contraction at 15% maximal voluntary contraction (dashed lines) and for 2 min of recovery. The data are presented as the mean from 12 healthy subjects (5 female). • control, ◦ contraction with tubocurarine that the subjects were able to maintain for 2 min, contraction with tubocurarine that the subjects were not able to maintain throughout the 2 min exercise period. P < 0.05 resting and exercise values during tubocurarine are different from control. Reprinted, with permission, from (224).

sympathetic nerve activation (345, 346) versus parasympathetic nerve activity (160) in cats. In regards to BP, Mitchell et al. (224) demonstrated that α- or β-adrenergic blockers alone or in combination with muscarinic blockade do not block the central command induced elevation in exercising BP during partial neuromuscular blockade. These findings illustrate a redundancy in the autonomic control of BP via central command signals, although additional investigations are needed. Exaggerated elevations in plasma catecholamine concentrations have been found when central command is increased during static (250) and dynamic (104) exercise with partial neuromuscular blockade, implying a role for central command mediated sympathetic activation. Indeed, elevations in skin SNA during handgrip exercise with neuromuscular blockade were shown to be similar to the responses during a control contraction despite the decrease in force development and feedback from skeletal muscle afferents (358). These findings highlight the importance of central


The contribution of a reflex originating in skeletal muscle to the cardiorespiratory response to exercise was recognized toward the end of the 19th century (156, 390); however, it was the work of Alam and Smirk (5, 59) that unequivocally established the importance of afferent feedback from skeletal muscle in evoking the pressor response to exercise in humans (Fig. 9). Since this seminal work, an abundance of research has been devoted to understanding this neural reflex mechanism emanating from skeletal muscle, including the identification of its afferent and efferent components, which have collectively been termed the “exercise pressor reflex” (209). During exercise both mechanically and metabolically sensitive sensory fibers provide feedback via the dorsal horn of the spinal cord to brainstem cardiovascular areas in response to mechanical and metabolic stimuli, respectively (41, 163, 165, 209). The muscle mechanoreflex is mainly comprised of thinlymyelinated group III afferent neurons whose receptors are primarily activated by mechanical deformation as induced by changes in pressure or stretch (318, 381). Thus, the muscle mechanoreflex is primarily activated at the immediate onset of muscle contraction coincident with a distortion of the mechanoreceptors’ receptive field. Indeed, group III afferents have been shown to fire with an abrupt and profound burst of impulses at the onset of muscle contraction (162, 219). In contrast, the afferent fibers of the muscle metaboreflex are mostly unmyelinated group IV neurons whose receptors are primarily chemically sensitive and stimulated by metabolites produced by contracting skeletal muscle (163, 222). Therefore, the muscle metaboreflex is thought to require a sufficient period of time before it responds due to the delay in production of metabolites by contracting skeletal muscle (198). However, this separation in activation of these exercise pressor reflex afferent neurons is not absolute as group III and IV fibers exhibit polymodal qualities such that some group III fibers respond to metabolic changes while some group IV fibers respond to mechanical distortion (219). In addition, both fiber types can be sensitized (191, 275) or desensitized (275) by changes in the metabolic milieu of the muscle

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interstitium. Overall, there is substantial research demonstrating that during muscle contraction, activation of both mechanically and metabolically sensitive afferent fibers contribute importantly to the autonomic responses to exercise and as such, play a major role in mediating the neural cardiovascular adjustments to exercise.

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Original report identifying a BP-raising reflex originating in skeletal muscle in humans. (A) Schematic showing preparation for the experimental protocol used in which a cuff was placed around the exercising forearm to perform ischemic exercise, while a cuff on the opposite arm was used to measure arterial BP. (B) Shows part of the seminal results from this study documenting the mild increase in BP during freely perfused rhythmic exercise (top panel) in comparison to the massive increase in systolic BP during and after exercise when the forearm was made ischemic by cuff inflation to supra-systolic pressure. Reprinted, with permission, from (220).

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As noted in the previous section, there is substantial work in humans attributing the immediate HR increase at the onset of exercise (e.g., the shortening of the first R-R interval) to a central command mediated reduction in cardiac parasympathetic activity (153, 181, 301, 382). However, pronounced increases in HR at the onset of muscular contraction can be induced in the absence of central command. Krogh and Lindhard (180) demonstrated in 1917 that percutaneous electrical stimulation can evoke a muscular contraction accompanied by an increase in HR, but only after the first R-R interval. As central command is bypassed during an electrically stimulated contraction the resultant HR response is attributable to muscle afferent feedback. Although, a “muscle-heart” reflex was proposed by Hollander and Bouman (143) with a latency of 550 ms during either voluntary or electrically stimulated exercise, these investigators may have inadvertently stimulated the skeletal muscle afferents directly (153). Isometric contractions evoked by ventral root stimulation in anesthetized rats has also been shown to produce a rapid decrease in cardiac parasympathetic activity (213) and increase in sympathetic activity (205, 345, 346). al-Ani et al. (6) reported that when cardiac parasympathetic activity is increased during expiration the magnitude of the HR response to electrically evoked upper arm flexion is greater than when contractions are performed during inspiration, thus indicating that feedback from skeletal muscle afferents can inhibit cardiac parasympathetic tone. Mechanically sensitive group III skeletal muscle afferents are known to be robustly activated at the onset of an electrically evoked muscular contraction (163), and as such the rapidity of the cardiac autonomic responses described above suggests a predominant role for these afferents. However, the use of electrically evoked contractions does not permit the relative contribution of mechanically and metabolically sensitive muscle afferents to be dissected. Passive limb movement and external compression have been employed to experimentally activate mechanically sensitive muscle afferents, without engaging those that are metabolically activated. The relative strengths and weaknesses of the approaches used to investigate the influence of human muscle mechanoreceptors on cardiac autonomic control have been reviewed in detail elsewhere (163). Passive hindlimb stretch in cats evokes an increase in HR associated with transient cardiac sympathetic nerve activation and a more sustained reduction in parasympathetic activity (205, 226). Studies in humans utilizing medical anti-shock trousers to compress the limbs (381) and passive muscle stretch (17) have reported no effect on HR. However, HR was shown to increase


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during 4 s of passive leg cycling movements (231), while Williamson et al. (382) demonstrated that when passive leg cycling movements were combined with percutaneous electrical stimulation and triggered early enough in the cardiac cycle (first one-third) an instantaneous increase in HR was elicited. Subsequent to this Coote and colleagues (109, 110) demonstrated that passive calf muscle stretch evoked a transient HR increase that was accompanied by a reduction in HR variability and abolished with prior administration of glycopyrrolate (Fig. 10). Thus, despite some evidence to the contrary, it appears that activation of mechanically sensitive muscle afferents in humans can increase HR via inhibition of cardiac parasympathetic activity. However, it is pertinent to note that of the mechanically sensitive group III muscle afferents that respond to tendon stretch, only ∼50% have been shown to respond during an isometric muscle contraction (132). The influence of the muscle mechanoreflex on peripheral SNA is arguably less well understood than its influence on cardiac autonomic control. Animal studies have identified that the muscle mechanoreflex increases renal (175, 352) and muscle (140) SNA. In humans, Herr et al. (135) reported that muscle SNA increases at the onset of isometric quadriceps contractions at 25% maximum voluntary contraction with a latency of 4-6 seconds. While the short latency of this response is indicative of a muscle mechanoreflex effect, a contribution from central command and/or the muscle metaboreflex cannot be excluded. Isolated muscle mechanoreflex activation in humans, induced by passive dynamic forearm stretch, has been reported to evoke a slight transient increase in muscle SNA with a latency of 1 to 3 s (46). Thus, it appears that the muscle mechanoreflex evokes rapid, albeit modest, autonomic alterations at the level of both the heart and skeletal muscle vasculature, and thus contributes to the initial cardiac and hemodynamic responses to exercise in healthy humans.


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Skeletal muscle mechanoreflex during steady-state exercise Following an initial burst of activity at the onset of a tetanic contraction the discharge rate of mechanically sensitive group III skeletal muscle afferents typically decreases if the contraction is nonfatiguing (163, 217). However, the discharge rate of these afferents rises or falls with a respective increase or decrease in isometric tension, and their discharge can become synchronized to electrically evoked intermittent isometric tetanic contractions (163, 217). Furthermore, during low-intensity dynamic exercise induced by mesencephalic locomotor region stimulation in cats muscle mechanoreceptor activity becomes synchronized with step cycle (2). Such observations highlight the potential importance of muscle mechanoreceptors to autonomic control not only at the onset of exercise, but also during steady-state dynamic exercise at a low intensity. However, studies in humans using lower body positive pressure have suggested that intense mechanoreceptor stimulation is needed to evoke a mechanoreflex mediated increase in muscle SNA (101, 102). Overall, additional research is needed to delineate the contribution of mechanoreflex to muscle SNA, particularly during dynamic exercise. During a fatiguing isometric contraction at a constant tension the activity of muscle mechanoreceptors typically increases, possibly due to the accumulation of metabolic byproducts within the muscle (165). This sensitization effect is also evident from studies showing that mechanoreceptor discharge is potentiated by ischemia or substances such as bradykinin, arachidonic acid, ATP, or cyclooxygenase products (3, 165, 228). Work examining the potential importance of muscle mechanoreceptor sensitivity on autonomic control in humans is limited. Fisher and colleagues (84) investigated whether the HR and BP responses to passive calf stretch were potentiated when performed during postexercise ischemia, a period in which the concentration of metabolites within the muscle is elevated. The magnitude of both the HR and BP response to passive stretch was the same irrespective of whether muscle metabolites were elevated or not. In contrast, Cui et al. (47) reported that when static passive wrist extension stretch was applied during postexercise ischemia following fatiguing handgrip exercise significant increases in muscle SNA and BP were evoked, whereas no change in muscle SNA or BP were observed when wrist extension was conducted under free-flow conditions. Although, no HR response to static passive wrist extension was observed under either condition, the sensitization effect on muscle SNA and BP was subsequently shown to be diminished following cyclooxygenase inhibition (48). The reason for the conflicting findings of Fisher et al. (84) and Cui et al. (47) may relate to differences in muscle group (calf, forearm), exercise mode (nonfatiguing, fatiguing) or method used to induce passive stretch. Collectively, these observations imply that the accumulation of metabolites within the skeletal muscle during steadystate exercise can sensitize the mechanically sensitize skeletal muscle afferents, most likely leading to an increase in muscle

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Activation of group III and IV skeletal muscle afferents during dynamic exercise induced by stimulation of the mesencephalic locomotor region in cats. Cumulative histograms for 24 group III afferents (A) and 10 group IV afferents (B) before, during, and after dynamic exercise. The exercise period is denoted by horizontal bars. These findings demonstrate that low-intensity dynamic exercise stimulated both Group III and IV skeletal muscle afferents. Imp, impulses. Reprinted, with permission, from (2).

SNA and BP, while the effect on cardiac autonomic control appears minimal.

Skeletal muscle metaboreflex at exercise onset While the thin fiber skeletal muscle afferents respond to mechanical distortion and therefore, typically respond immediately at the onset of muscular contraction, those responsive to metabolic perturbation respond with a longer latency (163). These observations, along with the time delay for the accumulation of most metabolites during exercise, means the contribution of muscle metaboreceptors to autonomic regulation is generally believed to be minimal at the onset of exercise. However, the studies of Kaufman and colleagues have illustrated that both group III and group IV skeletal muscle afferents are engaged during short duration (60 seconds) low-intensity dynamic exercise and that their discharge is coupled to the rhythmical contraction of the working muscles (2, 3) (Fig. 11). These direct afferent recordings suggest that the Group IV afferents have the potential to contribute to the autonomic responses in early exercise, prior to the generation of a substantial metabolic “error signal.” Nevertheless, central command is traditionally viewed as setting the initial autonomic response to exercise, and if the exercise pressor reflex is involved at exercise onset it would likely be through mechanically sensitive group III afferents. A caveat to this viewpoint is that studies in humans isolating the contribution

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of muscle metaboreceptors to the initial autonomic responses to exercise are lacking. This likely has to do with the complexity of onset kinetics in regards to neural interactions and the robust nature of the cardiovascular responses with the initiation of exercise.

Skeletal muscle metaboreflex during steady-state exercise The first attempt to experimentally isolate the contribution of the skeletal muscle metaboreflex to the cardiovascular response to exercise was made by Alam and Smirk (5). In a landmark study, subjects performed rhythmic forearm and calf contractions, first under free-flow conditions and second with circulation to the limb occluded such that they were ischemic both during and following exercise (see Fig. 9). The postexercise ischemia maneuver trapped the exercise-induced metabolites within the previously active muscle, thus preserving their stimulatory effect on metabolically sensitive skeletal muscle afferents in the absence of the muscle mechanoreflex or central command. This maneuver, first performed with direct muscle SNA measures by Allyn Mark, Gunnar Wallin, and colleagues, has been used in numerous studies to investigate the muscle metaboreflex in humans. Consistently, during postexercise ischemia, the exercise-induced increase in BP and muscle SNA remain robustly elevated (see Fig. 4) (198), whereas the HR response appears to depend


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significantly on the muscle mass and/or exercise modality studied (4, 96). Indeed, HR returns toward baseline levels during postexercise ischemia following rhythmic or isometric handgrip (87, 198, 230), static leg extension (149), and isometric calf plantar flexion (89). In contrast, HR is elevated above baseline during postexercise ischemia following rhythmic calf plantar flexion (4) and cycling (96, 128) with both legs. Such findings imply that the autonomic control of the heart is differentially modified during these maneuvers. In addition, the intensity of the preceding exercise and thus, magnitude of metaboreceptor activation during postexercise ischemia can also play a role in the degree to which HR is affected by the muscle metaboreflex. This is likely due to the intensity dependence of cardiac sympathetic activation via the metabolically sensitive afferents (87). As the muscle metaboreflex activation is a potent stimulus of the sympathetic nervous system it is seemingly incongruous that in many circumstances HR remains at baseline values during postexercise ischemia (87,149,198,230). Part of the explanation for this seems to be the loss of the powerful inhibitory input from central command (224) and muscle mechanoreflex (110) to cardiac parasympathetic preganglionic nuclei upon the cessation of exercise. In addition, the excitatory input to these nuclei is likely increased as a consequence of arterial baroreceptor stimulation resulting from the robust elevation (A)

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in BP during postexercise ischemia. As originally demonstrated in dogs (238), and more recently in humans (87), the activation of cardiac parasympathetic activity at this time can overpower a potential sympathetically mediated elevation in HR. Indeed, O’Leary (238) reported that during postexercise ischemia following treadmill exercise in canines HR returned toward baseline levels under control (no drug) conditions, whereas with the administration of atropine to block cardiac parasympathetic activity HR remained at the level observed during exercise. Thus with the cardiac parasympathetic activity removed a sympathetically mediated elevation in HR elicited by the muscle metaboreflex was seemingly revealed. In humans, cholinergic muscarinic blockade with glycopyrrolate unmasked an elevation in HR during postexercise ischemia following low intensity handgrip (87). This direct pharmacological evidence (Fig. 12) supported earlier work showing increases in HR variability derived indices of both cardiac parasympathetic (230) and sympathetic (149) nerve activity during postexercise ischemia in humans. As mentioned above, an elevation in HR with postexercise ischemia is observed following some modes of exercise. We have reported a modest HR elevation during postexercise ischemia subsequent to moderate intensity handgrip (40% maximum voluntary contraction for 2 min) that was eliminated with β-adrenergic blockade (87) (Fig. 12).

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Thus, it appears that strong activation of the muscle metaboreflex may increase cardiac SNA to an extent that can overcome a reactivation of cardiac parasympathetic activity. Intriguingly, HR variability analysis indicates that elevations in HR during postexercise ischemia following leg cycling are associated with reductions in cardiac parasympathetic activity (128). However, pharmacological investigations have shown that this HR elevation persists with either muscarinic or β-adrenergic blockade, implying a redundancy in the sympathetic and parasympathetic control of the heart under these conditions (83). The role of the muscle metaboreflex in cardiac autonomic control has also been evaluated by the occlusion or partial occlusion of perfusion to the exercising skeletal muscles. Unlike postexercise ischemia, however, this maneuver engages the muscle metaboreflex whilst central command and muscle mechanoreceptors are also activated. Experimental hypoperfusion in exercising dogs (238) and humans (83) can evoke a robust increase in HR that is attenuated by βadrenergic blockade and not affected by cardiac parasympathetic blockade. However, as β-adrenergic blockade does not entirely block this response (83, 238) and as HR variability derived estimates of cardiac parasympathetic activity are reduced during leg cycling with restricted flow (128), the ability of the muscle metaboreflex to inhibit cardiac parasympathetic activity cannot be entirely ruled out. Intriguingly, increases in HR during electrically evoked cycling exercise in individuals with spinal cord injury (no afferent feedback) are attenuated by the inflation of thigh cuffs to restrict blood flow to and from the active limbs (173). This perhaps indicates a role for blood borne factors released from active skeletal muscle on the HR responses to exercise. Rather than the augmentation of skeletal muscle afferent activation during exercise an alternative approach is to pharmacologically block or inhibit their activity. Administration of an epidural anesthetic to partially block skeletal muscle afferent feedback has been used in a number of investigations (82, 95, 99, 223, 302, 316). While a diminished HR and BP response to exercise can result (223), indicative of the importance of skeletal muscle afferents to the normal cardiovascular response to exercise, this has not been a consistent finding, possibly due to variations in the depth of analgesia and confounding effects on efferent neuromuscular control (302). Likewise, this may have to do with the mode of exercise. Although epidural anesthesia caused clear reductions in HR and BP responses to static handgrip (223), a blunting of the BP but not the HR response has been shown during dynamic exercise (172, 326). An important caveat to epidural anesthesia usage is the muscle “weakness” induced likely means that central motor drive and thus central command are enhanced to produce a fixed workload. However, this limitation may be circumvented by the pharmacological agonism of spinal opioid receptors, thus modulating the ascending activity of skeletal muscle afferent feedback without affecting central motor drive (386). In exercising dogs, intrathecal administration of the opiate agonist morphine virtually abolishes the

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HR and BP responses to unilateral iliac arterial occlusion (253), while agonism of spinal opioid receptors also attenuates the exercise reflex pressor in cats (141). In humans it has been reported that HR and BP is reduced during leg cycling at moderate-to-high workloads following lumbar intrathecal administration of fentanyl, a morphine analogue and selective μ-opioid receptor agonist, to partially block lower limb muscle afferents (7, 247). Similar results were recently reported during single leg knee extensor exercise following fentanyl administration (8). However, the autonomic basis for such changes remains to be determined. Nevertheless, the available evidence indicates that the major effect of metabolically skeletal muscle afferents on HR occurs via an increase in cardiac SNA whereas the effect on cardiac parasympathetic activity is more minor (83, 87, 149, 230, 238). Unlike the more subtle influence the metaboreflex has on cardiac SNA, there is unequivocal data to support the robust effect metaboreceptors have in increasing muscle SNA. Numerous studies using postexercise ischemia to isolate the muscle metaboreflex or experimental restriction of active muscle perfusion to augment muscle metaboreflex activation, have demonstrated large intensity-dependent increases in muscle SNA and BP. However, the specific chemical product(s) that activate metabolically sensitive muscle afferents remains controversial (162, 164, 219, 220, 315). This literature has been reviewed in detail by others, but some discussion is warranted due to the robust nature in which the metaboreflex stimulates muscle SNA. Several of the metabolites produced by muscular work that have been targeted as candidates for the activation of the muscle metaboreflex during exercise in humans include, but are not limited to lactic acid, potassium, adenosine, arachidonic acid, diprotonated phosphate, prostaglandins, and hydrogen ion (81, 91, 122, 274, 311, 331, 350, 375). However, equivocal results have been reported for most of these candidates with studies supporting and refuting the involvement of each substance to some degree. For example, studies using individuals who produce minimal amounts of lactic acid due to a myophosphorylase enzyme deficiency (i.e., McArdle’s disease) have indicated that the BP and muscle SNA responses to static handgrip are markedly attenuated compared to normal healthy subjects (79, 260) suggesting that the production of lactic acid is requisite for the full expression of the muscle metaboreflex (Fig. 13). However, even within this unique patient population disparate results have been reported (356, 357), although it should be noted that Kaufman and colleagues have demonstrated a major role for lactic acid in stimulating skeletal muscle afferents through acidsensing ion channel receptors (ASIC) (131, 210). In regards to the latter, there is an accumulating body of research examining the receptors responsible for activating metabolically sensitive skeletal muscle afferents with a role for transient receptor potential vanilloid 1 receptors, purinergic receptors and the CB1 cannabinoid receptor along with ASIC receptors (120, 190, 376). There is also now research focusing on the central integration of this afferent information. However,


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Sympathoexcitatory responses to fatiguing static handgrip at 30% MVC in patients with McArdle’s disease, who cannot produce lactic acid due to a myophosphorylase deficiency, and age, sex, and bodyweight matched controls. (A) Original muscle SNA (MSNA) record from a patient with McArdle’s disease and a control subject with a similar time to fatigue. (B) Summary data showing MSNA, mean arterial pressure (MAP) and HR responses during fatiguing handgrip followed by postexercise forearm ischemia and recovery. The MSNA response to exercise was severely blunted in the McArdle’s patients compared to controls. ∗ P < 0.05 versus controls. Reprinted, with permission, from (79).

these studies are beyond the scope of this review and the interested reader is directed to some excellent recent reviews (162, 164, 219, 220, 315). In an intriguing recent study, Pollak et al. (252) infused metabolites known to be produced during exercise into the abductor pollicis brevis muscle of the hand of healthy humans. Although the sensations of skeletal muscle fatigue and pain were the main outcome variables of this study, rather than cardiovascular or autonomic responses, this approach holds great promise to further probe the metabolite(s) responsible for stimulating skeletal muscle afferents and evoking the exercise pressor reflex mediated cardiovascular response. Interestingly, the infusion of individual metabolites at maximal amounts evoked no fatigue or pain and it was only when a combination of metabolites was infused did the subjects report sensations of fatigue or pain. These findings suggest that it is a combination of substances that excite metabolically sensitive skeletal muscle afferents. Indeed, as the research in this area continues, this is the most probable scenario to evolve in regards to the cardiovascular responses evoked by the muscle metaboreflex, and there is likely also, redundancy that exists among the metabolites capable of stimulating skeletal muscle afferent fibers. Emerging evidence also indicates that metabolically sensitive afferent fibers emanating from respiratory muscles may play a role in increasing sympathetic outflow during exercise. Indeed, unmyelinated nerve fibers are present in the phrenic nerve (62) and prolonged heavy intensity exercise in rats has been shown to elevate diaphragm lactic acid concentrations


(and likely other metabolites) several fold above basal levels (94). In anesthetized animals, type IV phrenic afferents are activated during fatiguing diaphragm contractions (139), whereas chemical stimulation of phrenic afferents elicits increases in HR, BP, and reduces blood flow in renal and mesenteric arterial vascular beds (145). Thus, a respiratory metaboreflex could be activated during prolonged highintensity exercise in which a fatiguing diaphragm and other respiratory muscles lead to an accumulation of metabolic byproducts (53, 119). However, isolating the effect of a respiratory metaboreflex, particularly during exercise, is technically challenging in humans. A series of studies pioneered by Dempsey and colleagues utilized a novel approach in which a mechanical ventilator was used to reduce the amount of respiratory muscle work during exercise, and thus, the stimulation of the respiratory metaboreflex. Interestingly, an increase in active skeletal muscle blood flow was found when diaphragm fatigue was prevented during maximal exercise (125, 126), whereas no changes in leg blood flow and vascular resistance was seen during respiratory muscle unloading at submaximal exercise intensities (373). While the autonomic mechanisms involved in these changes remains unclear, vasoconstriction in active skeletal muscle of dogs due to stimulation of phrenic afferents with lactic acid was prevented by combined α- and β-adrenergic blockade (273). Moreover, under resting conditions, fatiguing the respiratory muscles leads to increases in muscle SNA (317) and decreases leg blood flow and vascular conductance (305,306). Thus, although more indepth investigations are needed, the respiratory metaboreflex

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Figure 14 Schematic illustration depicting the afferent and efferent neural responses of the arterial baroreceptors. Reductions in BP in the carotid sinus and aortic arch are sensed by the baroreceptors eliciting decreases in afferent nerve firing. This reduction in neural input to the brainstem causes an increase in sympathetic neural outflow to the heart and vasculature, while at the same time decreasing parasympathetic nerve activity to the heart. Collectively, these reflex-mediated adjustments are designed to correct the decrease in pressure sensed by the baroreceptors and bring BP back to its original value. The converse occurs when the baroreceptors are exposed to an increase in BP. Adapted, with permission, from (76).

appears to mediate increases in sympathetic vasoconstrictor outflow at high-intensities of exercise, likely as a means to redirect exercising muscle blood flow to fatiguing respiratory muscles.

Arterial baroreflex The arterial baroreflex plays a major role in the autonomic and ultimately BP adjustments that accompany acute cardiovascular stressors, including exercise. A number of animal and human investigations have been performed in an effort to identify the components of the baroreflex arc, establishing the basis for our current understanding of arterial baroreceptor anatomy, neural processing and function (197, 278, 304). Briefly, the carotid and aortic baroreceptors are comprised of unencapsulated free nerve endings located at the medialadventitial border of arteries in the carotid sinus bifurcation and aortic arch (278, 304) that function as the sensors in a negative feedback control system (138). Alterations in BP cause a conformational change in the baroreceptors leading to changes in afferent neuronal firing. A branch of the glossopharyngeal nerve, the Hering nerve, carries impulses from the carotid baroreceptors, while small vagal branches carry impulses from the aortic baroreceptors. These afferent signals converge centrally within the NTS of the medulla oblongata. When BP is elevated, the baroreceptors are stretched and this deformation causes an increase in afferent neuronal firing, which results in a reflex-mediated increase in parasympathetic

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nerve activity and decrease in SNA. Conversely, when BP is lowered, afferent firing is reduced, resulting in a decrease in parasympathetic nerve activity and an increase in SNA. In both cases, the autonomic adjustments will affect both the heart and the blood vessels altering cardiac output and vascular conductance, respectively (76,158,263), and returning BP to its original set point value (138) (Fig. 14). Although initially debated, the fundamental role of the arterial baroreflex to the autonomic adjustments to exercise is now well established. It has been demonstrated in both animals (40,364,365) and healthy subjects (19,76,249,258,263) that during exercise the arterial baroreflex continues to regulate BP by resetting to operate around the exercise-induced elevation in BP. Moreover, there is convincing evidence that a properly functioning arterial baroreflex is requisite for an appropriate neural cardiovascular response to exercise (54, 293, 312, 342, 365). In this regard, previous studies have reported that acute baroreceptor denervation leads to an exaggerated increase in BP in exercising dogs (51, 365, 366). Similarly, in humans who have surgically denervated carotid baroreceptors, not only is resting BP variability elevated, but the BP response to exercise is exaggerated (312, 342). An emerging concept, described in detail by Michael Joyner (158), is that the baroreflex acts to partially restrain the BP response to exercise by buffering increases in SNA produced by activation of central command and the exercise pressor reflex (14, 35, 158, 307). This concept is substantiated by the greater increase in muscle SNA and HR observed during


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handgrip in young healthy subjects when arterial baroreflex activation is prevented by pharmacologically clamping BP at resting values and negating the exercise-induced rise in BP (293). Thus, impaired arterial baroreflex function (i.e., decreased sensitivity or gain) can lead to altered neural cardiovascular responses during exercise indicating that an operational baroreflex is necessary for the appropriate autonomic and cardiovascular response to exercise. Overall, there is considerable research demonstrating that the arterial baroreflex contributes importantly to the autonomic responses to exercise and as such, plays a major role in mediating the neural cardiovascular adjustments to exercise.

Arterial baroreflex at exercise onset While, much more is known about arterial baroreflex regulation under steady-state exercise conditions, a functional arterial baroreflex appears necessary for evoking the appropriate central cardiovascular and peripheral circulatory adjustments in the transition from rest to exercise (54). The magnitude of R-R interval lengthening in response to carotid baroreceptor stimulation in the decerebrate cat is attenuated by electrically evoked hindlimb contraction (213) or selective activation of group III and IV skeletal muscle afferents (214). In contrast, the magnitude of the fall in HR in response to aortic depressor nerve stimulation in decerebrate cats was similar at rest and the onset of both electrically evoked muscle contraction and muscle stretch (227). However, the bradycardic response to aortic depressor nerve stimulation was transiently attenuated at the onset of volitional isometric exercise in conscious cats, but restored later in exercise (177, 200, 227). Taken together these findings suggest that the activation of central command and/or skeletal muscle afferents can inhibit baroreflex regulation of HR via the parasympathetic nerves at the onset of exercise. Limited work has examined whether arterial baroreflex function is modified in humans during the transition from rest to exercise. We noted a transient attenuation of the magnitude of the fall in HR in response to carotid baroreceptor loading (neck suction, −60 mmHg) at the immediate onset (∼1 s) of high intensity handgrip (45%-60% MVC), but not during lowmoderate intensity handgrip (15%-30% MVC). Attribution of the blunted baroreflex responsiveness observed to either the activation of central command or the muscle mechanoreflex is not presently possible, as the activation of both would be expected to be graduated with exercise intensity. However, in an attempt to understand the mechanism involved we performed carotid baroreceptor loading (neck suction, −60 mmHg) during the anticipation of isometric handgrip exercise. Intriguingly, we noted a blunting of the magnitude of the reduction in HR evoked by neck suction when delivered immediately prior to handgrip (Fig. 15). Given the lack of muscle mechanoreflex or metaboreflex activation at this time one presumes a central mechanism is responsible, although interestingly this effect was only observed in the first two of 4 trials, indicative of a habituation response. Although, it


Figure 15

Anticipation of exercise blunts carotid baroreflex mediated HR responses. Summary data showing the HR responses to neck suction (NS) at −60 Torr performed at rest and in anticipation of isometric handgrip exercise during four repeat trials. This anticipatory period was used to isolate feedforward central command input in the absence of any feedback from skeletal muscle. To create an anticipatory period, subjects were instructed that immediately after the cessation of NS they must take hold of the handgrip dynamometer and start exercising as rapidly as possible at 45% MVC and sustain the contraction for 1 min. Although a clear blunting of carotid-cardiac responses was observed in the first two trails, a habituation in the response was found. ∗ represents P < 0.05 versus rest. Unpublished observations made by the authors.

is interesting to note that passive calf stretch to selectively activate the muscle mechanoreflex has also been shown to attenuate the HR response to carotid baroreceptor loading in humans (−30 mmHg, neck suction) (110). Finally, it remains to be determined whether such modulation of arterial baroreflex responses at the onset of exercise in humans is attributable to a reduced baroreflex sensitivity (i.e., reduced maximal gain) (200, 215) or rapid resetting of the baroreflex function curve (254, 255). However, work by Dicarlo and Bishop (54) in conscious rabbits identified the importance of an immediate baroreflex resetting in mediating the increases in renal sympathetic outflow, BP, and HR at the onset of exercise. Thus, a rapid baroreflex resetting appears requisite to the initiation of the autonomic response to exercise and subsequent hemodynamic and cardiovascular adjustments.

Arterial baroreflex during steady-state exercise During steady-state dynamic exercise the arterial baroreflex stimulus-response relationship is reset to function about the established BP and in general, the baroreflex maintains its ability to regulate BP as effectively as during rest (19,40,216,249,258). It was Bevegard and Shepherd (19) who initially reported that carotid baroreflex regulation was maintained during exercise in humans. These investigators demonstrated that HR, BP, and vascular conductance responses to simulated carotid sinus hypertension with the application of neck suction were similar during exercise compared to those observed at rest. Subsequently, Melcher and Donald

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Centering point Heart rate, muscle SNA, or mean arterial pressure

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Figure 16 A schematic summary of carotid baroreflex resetting that occurs from rest to heavy exercise. In general, the carotid baroreflex function curve for HR, muscle SNA, and MAP is progressively reset from rest to heavy exercise. However, the functional characteristics of the stimulus-response curve differ depending on the dependent variable studied. See text for details.

(216) constructed full stimulus-response curves of the isolated carotid baroreceptors in chronically instrumented exercising dogs and were the first to demonstrate that the baroreflex function curve was reset by exercise to operate around the prevailing BP without a change in reflex sensitivity. Potts et al. (258) confirmed these findings in humans using the variable pressure neck chamber to simulate carotid hypotension (neck pressure) and hypertension (neck suction). These investigators demonstrated that the carotid baroreflex was reset during upright dynamic leg cycling to functionally operate around the exercising BP without a change in sensitivity. Numerous studies followed that have confirmed and extended these initial findings, demonstrating that baroreflex resetting occurs in direct relation to the intensity of exercise from rest to maximum (Fig. 16) (77,105,106,232,233,242,249). Although the variable pressure neck chamber, which selectively describes carotid baroreflex function, has been the primary method used to examine exercise resetting in humans, the assumption is made that the aortic baroreflex operates in parallel with the carotid baroreflex and therefore will similarly respond and reset with exercise (76, 263). Arterial baroreflex resetting during exercise has been demonstrated to occur due to the interactive effects of central command (106, 148, 212, 246) and sensory feedback from metabolically and mechanically sensitive skeletal muscle afferents [i.e., exercise pressor reflex; (90,105,148,212,316)]. Raven and colleagues undertook an important series of experimental studies in humans that discerned the roles for central command and the exercise pressor reflex in the exercise resetting of the baroreflex. This work, which was performed to test a hypothesis originally put forth by Rowell and O’Leary, has been comprehensively outlined in several reviews (76,78,263) and so will only be briefly covered here. Importantly, although it is clear that both the carotid-cardiac and carotid-BP (i.e., vasomotor) curves are reset with exercise to operate at the prevailing BP there are some differences in baroreflex control

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of HR and BP that deserve discussion. Indeed, studies have demonstrated that both central command and the exercise pressor reflex are capable of inducing a bi-directional rightward and upward shift of the carotid-BP curve through a facilitative interaction (76, 78, 263). Moreover, this exercise resetting occurs without a change in maximal gain or operating point gain such that the control of BP is well maintained. In contrast, while central command is capable of relocating the carotid-cardiac baroreflex stimulus-response curve both rightward and upward, it appears that input from the exercise pressor reflex contributes to a rightward shift only. In addition, although resetting of the carotid-cardiac baroreflex function curve during exercise is accompanied by a preservation of maximal gain (i.e., sensitivity), the gain at the operating point (i.e., point about which HR is regulated) is reduced. This is associated with movement of the operating point away from the centering point (i.e., region of maximal gain) and toward the reflex threshold (243). “Spontaneous” cardiac baroreflex sensitivity (cBRS), calculated from the dynamic fluctuations in BP and HR (e.g., sequence technique), is associated with the operating point gain and also decreases during dynamic exercise (86, 243, 288, 289). Ogoh et al. (243), using separate cholinergic (muscarinic) and β1 -adrenergic blockade, demonstrated that the reduction in spontaneous cBRS and operating point gain of the carotid cardiac baroreflex function curve during steady-state dynamic exercise were attributable to a reduction in cardiac parasympathetic activity. Since central command and the muscle mechanoreflex have been implicated in the withdrawal of cardiac parasympathetic activity during exercise (110,224), they may reasonably be considered as prime candidates for mediating exercise-induced changes in baroreflex sensitivity. Indeed, Iellamo et al. (148) reported that spontaneous cBRS was reduced during low intensity electrically evoked exercise under free-flow conditions, and given that central command was bypassed and muscle metaboreflex activation minimal, a role of the muscle mechanoreflex was postulated. On the other hand, Gallagher and colleagues (106) noted that partial neuromuscular blockade to enhance central command during exercise evoked a reduction in operating point gain of the carotid cardiac baroreflex function curve. Thus, it appears likely that input from both central command and muscle mechanoreceptors can contribute to the relocation of the operating point gain on the carotid cardiac baroreflex function curve during dynamic exercise and the resultant reduction in cBRS that has also been observed with spontaneous cBRS measures. In contrast, neither spontaneous cBRS (149) nor the gain at the operating point of the carotid cardiac baroreflex function curve are altered during isolated muscle metaboreflex activation with postexercise ischemia following handgrip (90). However, when the muscle metaboreflex is activated by hypoperfusing a large mass of dynamically exercising skeletal muscle in either canines (288, 289) or humans (127, 128), a reduction in spontaneous cBRS is observed. The reason for these apparently discrepant findings likely relates to differences among these protocols in the prevailing levels of


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cardiac autonomic activity and degree of input from neural control mechanisms. Indeed, during postexercise ischemia the loss of inhibitory input from central command and muscle mechanoreflex and/or baroreflex activation once exercise has ceased would lead to a relative increase in cardiac parasympathetic activity (230, 238) that could mask a muscle metaboreflex mediated reduction in cBRS as noted earlier in this review for metaboreflex-mediated HR responses. In addition, it remains a matter of debate whether the partial restriction of blood flow to the exercising muscle; (i) increases central command along with the muscle metaboreflex (179, 253), (ii) causes an attenuation of cBRS by directly reducing cardiac parasympathetic activity or via an indirect mechanism (225), and (iii) reduces the operating point gain or maximal gain of the full stimulus-response function curve. It is also possible that during exercise the accumulation of metabolites within the exercising skeletal muscles sensitizes mechanically sensitive muscle afferents that are known to modulate cardiac parasympathetic activity. However, Drew et al. (60) observed that the magnitude of the passive calf stretch mediated reduction in cBRS was no different when performed during post exercise ischemia following calf exercise at 0%, 30%, 50%, and 70% MVC to grade the concentration of metabolites within the muscle. Nevertheless, the presently available evidence implicates central command, the muscle mechanoreflex and the muscle metaboreflex in the exercise induced resetting of the carotid-cardiac baroreflex function curve and the accompanying reduction in operating point gain and spontaneous cBRS, although the relative contribution of each likely varies as a function of the exercise modality studied. In contrast to the extensive body of work examining the arterial baroreflex in terms of its sensitivity (i.e., gain), its temporal response pattern (i.e., latency) has received less attention. A delay in the latency of the peak cardiac baroreflex response has previously been reported during dynamic exercise in young individuals (193, 325), although this has not been a universal finding (256). Sundblad and Linnarsson (327) proposed that this delay resulted from an exercise-induced increase in sympathetic activation. More recently, pharmacological antagonism of cardiac parasympathetic control has been reported to prolong the latency of the peak carotid-HR response (85,167), thus raising the possibility that withdrawal of cardiac parasympathetic tone may account for the more sluggish cardiac-baroreflex responses during exercise. Studies in both animals and humans have also investigated the means by which the arterial baroreflex mediates changes in BP both at rest and during exercise. In other words, given that BP is the product of cardiac output and total peripheral resistance, how much does the arterial baroreflex rely on changes in HR and stroke volume (i.e., cardiac output) compared to total vascular resistance or conductance to modulate BP. Several studies that have examined the relative contribution of changes in cardiac output and total vascular conductance to carotid baroreflex-mediated changes in BP demonstrated that the capacity of the carotid baroreflex to regulate BP depends almost exclusively on its ability to


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alter total vascular conductance both at rest and during exercise (35, 241, 242). In fact, although at rest approximately 25% of the carotid baroreflex-mediated BP response could be attributed to changes in cardiac output, during exercise the ability of the carotid baroreflex to control BP was solely reliant on reflex-mediated changes in peripheral conductance (242). This critical reliance of the baroreflex on vascular changes was not significantly altered by subject posture (241). Similar findings indicating the dominance of alterations in vascular conductance contributing to carotid baroreflex-mediated changes in BP have been identified in the dog using bilateral carotid occlusion at rest and during treadmill exercise (35). Thus, the ability of the arterial baroreflex to regulate BP is critically dependent on alterations in vascular tone both at rest and during exercise. Considering that the neural stimulus from the arterial baroreflex to the vasculature is the sympathetic nervous system, an understanding of baroreflex control of sympathetic outflow is critical. Although technically challenging to directly assess sympathetic outflow in humans during physical activity due to the associated movement, the application of the microneurography technique to measure baroreflex control of muscle SNA during exercise has provided some very insightful and important information. In this regard, the functional characteristics of the baroreflex control of SNA have been shown to dynamically change throughout a given bout of exercise to allow for the effective modulation of BP (Fig. 17) (147,161). Ichinose et al. (147) reported that along with a progressive resetting of the muscle SNA-diastolic BP relationship during 3 min of handgrip, a time-dependent increase in muscle SNA baroreflex sensitivity occurred. These findings of dynamic temporal changes in the baroreflex control of muscle SNA have been extended to dynamic exercise as well however; the intensity of exercise may be of greater importance for inducing changes in muscle SNA baroreflex sensitivity (245). Indeed, in humans the carotid baroreflex control of muscle SNA appears preserved during moderate-intensity one-legged kicking and arm cycling exercise (77, 166, 245), whereas during moderate to high intensity leg cycling an increase in arterial baroreflex-muscle SNA gain has been observed (146). In general agreement, the sensitivity of the arterial baroreflex control of renal SNA has been shown to be increased during high-intensity (90% maximal HR) treadmill exercise in conscious rats (218). Collectively, these studies indicate a progressive resetting of the baroreflex control of SNA to operate around the exercise-induced elevations in BP with a maintained or increased sensitivity depending on the intensity of the exercise performed. Thus, the arterial baroreflex control of sympathetic outflow is well maintained throughout a bout of exercise.

Cardiopulmonary baroreflex Mechanically sensitive receptors situated in the heart (atria, ventricles), lungs, and great veins provide feedback to medullary vasomotor centers via unmyelinated vagal afferents

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Callister et al. (30) specifically evaluated the muscle SNA (radial nerve at elbow) responses to 1 min of upright leg cycling at submaximal workloads ranging from approximately 10% to 80% of peak aerobic power (Fig. 18). Irrespective of workload, a marked reduction in muscle SNA was observed during the preparation for and at the onset of exercise, while muscle SNA did not increase until 40 to 60 s of exercise at the highest workload. While the suppression of muscle SNA in anticipation of exercise may be related to the mild cognitive effort or arousal associated with the task (31), as described in detail below, the inhibition of muscle SNA at the onset of dynamic exercise is likely linked to a loading of the cardiopulmonary baroreceptors.

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Figure 17 Progressive resetting of the arterial baroreflex control of muscle SNA (MSNA) in the transition from rest to steady-state two arm cycling exercise. (A) Summary data showing the average operating points (•) with the corresponding mean linear regression lines relating MSNA burst incidence and diastolic BP at rest, unloaded exercise (EX), initial 50% EX, and later 50% EX. (B) Group summary data for the slopes of the linear regression lines between MSNA burst incidence and diastolic BP (i.e., arterial baroreflex sensitivity). These findings indicate that baroreflex control of MSNA is well maintained throughout dynamic exercise in humans, progressively being reset to operate around the exercise-induced elevations in BP without any changes in reflex sensitivity. See text for further details. Reprinted, with permission, from (245).

(C-fibers) in response to changes in central venous pressure and volume (197). The loading of these cardiopulmonary receptors exerts a reflex inhibition of sympathetic adrenergic activity to several vascular beds and conversely their unloading evokes a marked increase in SNA. The experimental approaches utilized to evaluate cardiopulmonary baroreceptor function have been reviewed in detail elsewhere (197) and will be discussed sparingly here.

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The observation that HR is typically lower during dynamic exercise performed in a supine position compared to an upright position provided an early indication that changes in central blood volume and cardiopulmonary loading may influence the cardiovascular response to steady-state exercise in humans (320). The earliest studies specifically examining the functional significance of the cardiopulmonary baroreflex on the autonomic adjustments to exercise during exercise in humans typically employed handgrip exercise. Walker et al. (1980) reported that low intensity isometric handgrip evoked a vasoconstriction in the nonexercising forearm that was threefold greater when handgrip was combined with mild lower body negative pressure (LBNP, −5 mmHg) to unload the cardiopulmonary baroreceptors (367). Further, the increase in forearm vascular resistance was significantly greater during combined LBNP and handgrip, than the algebraic addition of the response to LBNP alone plus handgrip alone. Thus it was contended that the cardiopulmonary baroreceptors tonically inhibit sympathetic vasoconstriction during isometric handgrip. However, these findings and this conclusion were disputed by subsequent investigations (290, 294, 296) that observed no interaction between either the forearm vasculature or sympathetic responses to LBNP and isometric handgrip. The reasons for these discrepant findings are unclear, but are suggested to relate in part to the level of LBNP, and thus cardiopulmonary unloading, utilized (12). While isometric handgrip has a limited effect on either preload (central venous pressure) or left-ventricular enddiastolic volume in young healthy individuals (319), dynamic exercise with a relatively large muscle mass evokes a much greater increase in left ventricle preload, stroke volume, and contractility (367). Thus, it would be reasonable to expect cardiopulmonary vagal afferents to provide a marked inhibition of SNA during dynamic exercise. Despite reports that acute or chronic cardiopulmonary denervation has no effect on the cardiovascular responses of canines running on a treadmill


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Figure 18 Original records showing muscle SNA (MSNA; radial nerve) and BP at baseline (control) and during the preparation and initiation of leg cycling exercise at 33 W (panel A) and 166 W (panel B). A notable reduction in MSNA is evident during the preparation and initial stages of exercise at both workloads. Reprinted, with permission, from (30).

(51, 364), observations in rats (36) and rabbits (55, 236) support a role for cardiac afferents in the neural control of the peripheral circulation during exercise. In humans, Saito et al. (286) observed that muscle SNA, obtained using the microneurography technique at the median nerve (elbow), was reduced below baseline during low intensity leg cycling (20% VO2 max), but increased at higher intensities (60% and 75% VO2 max). A muscle pump-mediated enhancement of venous return, cardiac filling pressure, and thus cardiopulmonary baroreceptor loading, in the absence of a powerful concomitant sympatho-excitatory drive from central command or the exercise pressor reflex, may account for the fall in muscle SNA at the lower workload compared to higher intensities. In agreement, Ray et al. (266) reported that both central venous pressure increased and muscle SNA fell during dynamic knee-extension exercise when subjects were in an upright-seated position, but remained unchanged from baseline when subjects were supine, once again indicative of the importance of cardiac filling pressure and central blood volume on the sympathetic adjustments to dynamic exercise in humans. Following pioneering studies in animals examining the role of the cardiopulmonary baroreceptors during exercise (51, 364), Mack et al. (195) reported that the forearm vascular responses to LBNP were similar at rest and during leg cycling exercise in humans. Subsequently, Ogoh et al. (240) manipulated cardiac filling volumes with both LBNP and infusion of 25% human serum albumin and observed no differences between the forearm and systemic vascular


responses evoked at rest and exercise. One presumes that the ability of the cardiopulmonary baroreflex to modulate muscle SNA is also unchanged from rest to exercise, but this remains to be determined. Nevertheless, the available evidence indicates that the cardiopulmonary baoreflex remains functional in exercising humans but is reset to operate around an increased central venous pressure or central blood volume (195, 240). Moreover, cardiopulmonary loading during exercise results in a diminished upward and rightward resetting of the carotid-vasomotor baroreflex function curve (244, 361). Several studies have also indicated that unloading of the cardiopulmonary baroreceptors heightens the gain of the carotid baroreflex both at rest and during exercise (20, 21, 176, 251, 257), although this has not been a universal finding (64, 330). The interaction between the cardiopulmonary baroreflex and the arterial baroreflex during exercise has recently been reviewed (78). Finally, the functional significance of the cardiopulmonary baroreceptors may become particularly important when whole-body exercise is accompanied by heat stress and/or dehydration (44,112). Secondary to the notable increase in cutaneous perfusion and reduction in plasma volume through sweating under these conditions, central blood volume, stroke volume and cardiac output are reduced, while HR and plasma norepinephrine concentration are markedly increased (44,112,276). A resultant reduction in perfusion and oxygen delivery to the exercising skeletal muscle is likely a major factor in the development of fatigue during maximal aerobic exercise (44,112). The complex effect of thermal stress on the integrative control of the cardiovascular

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system during exercise has been the subject of several excellent recent reviews (44, 112). In summary, while the involvement of the cardiopulmonary baroreflex in autonomic and hemodynamic regulation is perhaps not as well understood or as widely appreciated as central command, the exercise pressor reflex and the arterial baroreflex, there is ample evidence to indicate that it plays an important functional role. Indeed, the initial inhibition of muscle SNA at the onset of dynamic leg exercise may be attributed to the increase in venous return and subsequent elevations in central venous pressure and cardiopulmonary baroreceptor load. As exercise continues, this effect would be overcome by stimulation of skeletal muscle afferents and the greater central command input during higher intensity exercise contributing to increases in muscle SNA to active and inactive skeletal muscle.

Arterial chemoreflex Chemically sensitive receptors located primarily in the carotid bodies, and to a lesser extent in the aortic bodies, sense changes in the chemical composition of the bloodstream and relay afferent information to medullary regions via the carotid sinus and vagus nerve, respectively. This afferent information subsequently modulates the respiratory and autonomic systems in a homeostatic effort. The carotid body is highly vascularized and the sensing of PO2 , PCO2 , and pH is thought to primarily occur via type I (i.e., glomus) cells, which form chemical synapses with the carotid sinus nerve (137, 211).


However, the neurotransmission that determines the afferent signal to the medulla is complex and includes inhibitory and excitatory inputs from numerous type I cells, chemical and electrical intercellular communication among type I and between other cell types (e.g., type II cells), pre- and postsynaptic neuromodulation, as well as efferent sympathetic and parasympathetic innervation of the carotid body (183). In addition to the classical modulators, the carotid chemoreflex also responds to a vast number of circulating chemical stimuli (183) and is influenced by blood flow and shear stress (58). Moreover, medullary chemoreceptors also modulate efferent respiratory and autonomic pathways by responding to changes in the chemical milieu of the extracellular and cerebrospinal fluid, and the sensitivity of the central and peripheral chemoreceptors is likely interdependent upon each other (313). It is well accepted that the chemoreflex is intimately involved in resting autonomic, cardiovascular and ventilatory regulation (211). However, during exercise, the influence of the chemoreflex has primarily focused on respiratory adjustments, which are reviewed in detail elsewhere (92, 211), and investigations on chemoreflex-mediated cardiovascular control are sparse. Recently, Stickland, Dempsey, and colleagues conducted a series of experiments to examine the role of the chemoreflex in modulating SNA and blood flow during exercise. Pharmacological (intravenous dopamine) or physiological (acute hyperoxia) methods to inhibit the chemoreflex increased femoral blood flow and vascular conductance during rhythmic leg exercise, but had no influence under resting conditions in healthy humans (321) (Fig. 19). In addition, a

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Transient inhibition of the carotid chemoreflex with inhaled hyperoxia increases exercising leg blood flow and vascular conductance. End-tidal O2 (PET,O2), femoral artery blood flow and femoral vascular conductance during transient inhaled hyperoxia at rest (left) and during two-legged knee extension exercise (right). ∗ P < 0.05 versus baseline. Reprinted, with permission, from (321).

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reduction in muscle SNA was reported in response to transient hyperoxia during moderate intensity isometric handgrip exercise (323). These findings are in line with work in exercising dogs in which inhibition of the carotid chemoreflex, with intracarotid infusion of dopamine or hyperoxic Ringer’s solution, caused hindlimb vasodilation; a response that was most evident in the exercising skeletal muscle, versus the mesenteric vasculature, and attributable to chemoreflex induced sympathetic vasoconstrictor withdrawal as the responses were abolished following α-adrenergic blockade or carotid body denervation (322). Taken together, these findings suggest that the chemoreflex restrains exercising blood flow via vasoconstrictor sympathetic outflow to skeletal muscle. However, others have shown that sustained hyperoxia (3-15 min) did not influence (298) or increased (144) the muscle SNA response to exercise and reduced exercising skeletal muscle blood flow (371). Therefore, while examination of the role of the chemoreflex during exercise is in its infancy, further investigations are warranted with consideration for the contribution of the central/peripheral chemoreflex, influence of the chemoreflex on cardiac autonomic regulation, exercise modality and temporal patterns.

Overall Summary We have provided a detailed review of the current understanding of the parasympathetic and sympathetic adjustments that occur with exercise along with a discussion of the contributions of several neural reflex mechanisms in mediating these autonomic changes and the ensuing cardiac and/or vascular responses in healthy humans. A short synthesis follows, including the identification of key gaps in our understanding and suggestions for further research. The onset of exercise is accompanied by an immediate increase in HR secondary to a withdrawal of cardiac


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parasympathetic activity principally due to the combined actions of central command and the muscle mechanoreflex. Presently, the evidence for the contribution of cardiac SNA to the initial increase in HR at exercise onset is lacking in humans and requires (re)investigation in light of recent studies in animals. An initial reduction in cardiac baroreflex control has been noted in humans as a consequence of central command and/or muscle mechanoreflex activation. However, whether this is attributable to a decrease in arterial baroreflex sensitivity or a rapid resetting of the baroreflex function curve remains unclear. Vasoconstrictor SNA to the skeletal muscle vasculature typically decreases at the initiation of dynamic exercise with a substantial muscle mass as a consequence of the muscle pump-mediated enhancement of venous return, cardiac filling pressure and loading of the cardiopulmonary baroreceptors. However, a slight muscle mechanoreceptor mediated increase in muscle SNA may be evoked at the onset of exercise modes where increases in cardiopulmonary loading are minimal (e.g., isometric contractions of a small muscle mass). The potential contribution of the arterial chemoreflex to the initial autonomic adjustments to exercise is unclear. HR increases approximately linearly with oxygen uptake during incremental dynamic exercise. Reductions in cardiac parasympathetic activity primarily mediate the increases in HR during low intensity steady-state dynamic exercise; whereas cardiac SNA contributes more as exercise intensity increases (Fig. 20). How exercise intensity influences the precise “sympatho-vagal balance” is still debated. Recent work has highlighted the underappreciated contribution of cardiac parasympathetic nerve activity to ventricular control, but the implications of this for cardiac control during exercise in humans remains to be determined. During intense exercise the high level of cardiac SNA likely leads to the release of neuromodulatory cotransmitters (e.g., neuropeptide Y) that may further diminish cardiac parasympathetic control (i.e., accentuated antagonism); however, our understanding of these

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Figure 20 Summary of the neural control mechanisms underlying the HR response to the onset of exercise, steady-state exercise, and recovery from exercise. The contribution of changes in cardiac parasympathetic and sympathetic activity and the influence of central command and feedback from metabolically (muscle metaboreceptors) and mechanically (muscle tetanoreceptors) sensitive skeletal muscle afferents are indicated. Reprinted, with permission, from (38).


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processes in exercising humans is limited and requires further study. During prolonged dynamic exercise at a steady-state submaximal workload a sympathetically mediated increase in HR is evoked (cardiac drift), which is exacerbated by dehydration and high ambient temperature. Although not as well documented, a reduction in β-adrenergic receptor sensitivity has been associated with an attenuated HR increase and a reduction in aerobic exercise capacity (e.g., in normal aging), but the exploitation of this as a therapeutic target for improving exercise capacity has to date been unfruitful. Nevertheless, a normally functioning autonomic nervous system is requisite for an appropriate cardiac response during exercise, which has important implications for exercise performance. The intensity-dependent changes in cardiac autonomic activity described above facilitate an increase in HR, cardiac contractility, stroke volume, and ultimately cardiac output. Collectively the sympathetic responses to exercise, along with the metabolic modulation of sympathetic vasoconstrictor activity in the active muscle (i.e., functional sympatholysis), enhance the redistribution of cardiac output to the exercising skeletal muscles. There is compelling evidence for intensity and duration-dependent increases in muscle SNA to both the active and inactive limbs during exercise that are accompanied by increased norepinephrine spillover from the cardiac, renal, and splanchnic vasculature. However, it is important to appreciate regional differences in the temporal pattern of exercise-induced sympathetic activation and the impact that both intensity and duration have on the sympathetic response. The neural reflex mechanisms underpinning the parasympathetic and sympathetic adjustments to exercise are complex with clear evidence for the involvement of central command, the exercise pressor reflex, the arterial baroreflex, and cardiopulmonary baroreceptors, along with further potential modulation via arterial chemoreceptors and phrenic afferents from respiratory muscles (i.e., respiratory metaboreflex). As discussed in this review, these neural mechanisms are all capable of modulating the autonomic adjustments to exercise and appear to work interactively to orchestrate an appropriate neural cardiovascular response to exercise in an intensitydependent manner. Increases in sympathetic outflow to skeletal muscle vasculature are manifest with a latency of 30 to 60 s during exercise, arguably due to the time taken for the accumulation of metabolites and the activation of metabolically sensitive skeletal muscle afferents. A plethora of candidate substances have been implicated in the stimulation of skeletal muscle afferents during exercise, but the definitive resolution of the specific “cocktail” of substances needed for a “normal” response has remained elusive. A small effect of the muscle mechanoreceptors on muscle SNA has been reported, that is more substantial when the presence of metabolites is increased. At high exercise intensities a contribution from central command to the increase in sympathetic vasoconstrictor drive during exercise has also been observed. Together central command and the exercise pressor reflex elevate muscle SNA during high-intensity exercise and overcome any

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potential sympatho-inhibitory effects of cardiopulmonary receptor loading. A role for central command in evoking a cholinergic vasodilatation has been muted, but remains controversial and further human investigations are warranted, including considerations for exercise modality, intensity and the magnitude of the muscle mass engaged. Due to the complexity of central command, the identification of specific brain region(s) responsible for evoking autonomic adjustments has remained elusive and additional work is required to better develop an integrated neurocircuitry model. An intensity-dependent resetting of the arterial baroreflex stimulus-response relationship around the established BP occurs during steady-state exercise, meaning that the baroreflex maintains its ability to regulate BP as effectively as during rest. It is clear that both central command and the exercise pressor reflex are actively involved in the resetting of the arterial baroreflex during exercise with the cardiopulmonary baroreceptors playing a modulatory role. Anatomically, the NTS of the medullary brainstem has emerged as the primary candidate for the convergence and integration of input from each of these neural reflex mechanisms and, as such, likely plays an essential role in governing the autonomic output mediating the cardiovascular responses to exercise. Investigation of the autonomic adjustments to exercise is an ongoing area of research with more recent work attempting to understand potential dysregulation in the neural mechanisms and the ensuing autonomic adjustments to exercise that appear to accompany several cardiovascular disease states (e.g., hypertension). These studies are founded on the fundamentals of the normal regulation of the autonomic and cardiovascular responses to exercise in health outlined in detail in this review.

Acknowledgements The authors express gratitude and appreciation to Dr. Peter Raven, Dr. Jere Mitchell, and Prof. John Coote for their continued support and guidance, which has been instrumental to each of our careers. The authors gratefully acknowledge the research support received from United States of America National Institutes of Health Grant #HL-093167 (P.J.F.), Grant #K99HL166776 (C.N.Y.), British Heart Foundation PG/11/41/28893 (J.P.F.), and Arthritis Research UK #196633 (J.P.F.).

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Cardiovascular, respiratory, and metabolic adjustments to exercise in dogs.

Circulatory and thermal adjustments to prolonged exercise in paraplegic women.

inactivity.

A comparison of cardiovascular and autonomic adjustments to three types of cold stimulation tasks.

Sympathetic neural adjustments to stress in physically trained and untrained humans.

Regular physical exercise improves cardiac autonomic and muscle vasodilatory responses to isometric exercise in healthy elderly.

Autonomic responses to exercise: where is central command?

Ventilatory response to steady-state exercise in hypoxia in humans.

Stroke volume and systolic time interval adjustments during bicycle exercise.

Effect of physical training on cardiovascular adjustments to exercise in man.

Cardiovascular responses to voluntary and nonvoluntary static exercise in humans.

Renal neurohormonal and vascular responses to dynamic exercise in humans.

Cardiovascular adjustments to high- and low-intensity exercise do not regulate temporary threshold shifts.

Autonomic responses to exercise: cortical and subcortical responses during post-exercise ischaemia and muscle pain.

Preclinical and clinical evaluation of autonomic function in humans.

Autonomic activity during sleep predicts memory consolidation in humans.

Caffeine delays autonomic recovery following acute exercise.

Cardiac autonomic regulation during hypoxic exercise.

Exercise upregulates salivary amylase in humans (Review).

Exercise training and DNA methylation in humans.

Muscle chemoreflexes and exercise in humans.

Breathing during prolonged exercise in humans.

Plasma glucose metabolism during exercise in humans.

Exercise hemodynamics in Parkinson's disease and autonomic dysfunction.