autonomic adjustments to exercise in humans · the autonomic nervous system plays a critical role...

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Autonomic Adjustments to Exercise in HumansJames P. Fisher,1 Colin N. Young,2 and Paul J. Fadel3,4*

ABSTRACTAutonomic nervous system adjustments to the heart and blood vessels are necessary for mediatingthe cardiovascular responses required to meet the metabolic demands of working skeletal muscleduring exercise. These demands are met by precise exercise intensity-dependent alterations insympathetic and parasympathetic nerve activity. The purpose of this review is to examine thecontributions of the sympathetic and parasympathetic nervous systems in mediating specificcardiovascular and hemodynamic responses to exercise. These changes in autonomic outfloware 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 negativefeed-back mechanism originating from the carotid sinus and aortic arch), and cardiopulmonarybaroreceptors (a feed-back mechanism from stretch receptors located in the heart and lungs). Inaddition, arterial chemoreceptors and phrenic afferents from respiratory muscles (i.e., respiratorymetaboreflex) are also capable of modulating the autonomic responses to exercise. Our goalis to provide a detailed review of the parasympathetic and sympathetic changes that occurwith exercise distinguishing between the onset of exercise and steady-state conditions, whenappropriate. In addition, studies demonstrating the contributions of each of the aforementionedneural mechanisms to the autonomic changes and ensuing cardiac and/or vascular responseswill be covered. C© 2015 American Physiological Society. Compr Physiol 5:475-512, 2015.

IntroductionThe autonomic nervous system plays a critical role in medi-ating the cardiovascular adjustments necessary to meet themetabolic demands of the exercising muscle, and as suchis paramount for the performance and sustainment of phys-ical activity. A reduction in the tonic suppressive influ-ence of parasympathetic (vagus) nerve activity contributes toexercise-induced increases in heart rate (HR), ventricular con-tractility, stroke volume, and thus, cardiac output. Increases inHR and ventricular contractility are also evoked by activationof cardiac sympathetic nerve activity (SNA) and sympatheticstimulation of epinephrine release from the adrenal medulla.In addition, a sympathetically mediated vasoconstriction innonexercising muscles and visceral organs (e.g., splanchniccirculation) facilitates the redistribution of cardiac output tothe active skeletal muscles. At the same time, the normalability of SNA to cause vasoconstriction is attenuated in theactive muscles, in part due to an effect of muscle metabo-lites to diminish the vasoconstrictor response to α-adrenergicreceptor activation (123,268). Such modulation, termed func-tional sympatholysis, may constitute a protective mechanismthat optimizes muscle blood flow in the face of the increasedsympathetic vasoconstrictor drive that occurs during exercise.However, sympatholysis is not complete and the increasedSNA to active muscles does have a restrictive effect on bloodflow, which is important for the maintenance of arterial bloodpressure (BP) during exercise (337). Overall, the importanceof the autonomic adjustments to exercise can be readily appre-ciated from the finding that patients with autonomic failure

cannot maintain the lightest loads of dynamic exercise evenif performed in the supine position to enhance central bloodvolume and venous return (199).

The autonomic responses to exercise are dependent uponthe type of exercise that is being performed. In general, exer-cise can be divided into two categories: dynamic and isometric(or static) (185, 221). Dynamic exercise involves rhythmicalcontractions that alter both muscle length and joint angleand involves intermittent changes in intramuscular force thatoccur in conjunction with the contraction and relaxation of theworking muscles. This intermittent pumping action of skeletalmuscle (i.e., muscle pump) contributes to increases in muscleblood flow. Isometric exercise on the other hand involves asustained contraction with minimal change in muscle lengthor joint angle and includes a substantial development of intra-muscular force. The large increases in intramuscular pressureare 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 Kingdom2Biomedical Sciences, College of Veterinary Medicine, CornellUniversity, Ithaca, NY, USA3Department of Medical Pharmacology & Physiology, University ofMissouri, Columbia, MO, USA4Dalton Cardiovascular Research Center, University of Missouri,Columbia, MO, USAPublished online, April 2015 (comprehensivephysiology.com)DOI: 10.1002/cphy.c140022Copyright C© American Physiological Society.

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skeletal muscle blood flow. These contrasting contractilecharacteristics and the subsequent hemodynamic alterationscontribute importantly to the differences in the cardiovas-cular responses evoked. While HR and BP increase withboth dynamic and isometric exercise, there are distinct dif-ferences. At a constant work load, during dynamic exer-cise HR increases to a steady-state value, whereas duringisometric exercise HR continually rises at a given workload until fatigue. However, perhaps the most notable dif-ference between dynamic and isometric exercise is the pres-sor response, which occurs to a much greater extent duringisometric exercise owing to the more immediate and largeincreases in SNA with this form of exercise, as discussed indetail later in this review.

Studies designed to examine the autonomic responses toexercise have incorporated both dynamic and isometric exer-cise protocols. Handgrip and knee extensions performed as apercent of maximal voluntary contraction (% MVC) are theprimary forms of isometric exercise used. The classic modeof dynamic exercise for investigation is cycling; however,laboratory studies investigating neural cardiovascular controlduring dynamic exercise more often use a rhythmical form ofisometric exercise which incorporates intermittent isometriccontractions separated by timed relaxation periods. A majoradvantage of this form of exercise is that it more readilyallows for movement sensitive measurements such as muscleSNA (microneurography) or beat-to-beat blood flow (Doppler

ultrasound) to be obtained without the motion artifacts inher-ent to whole body dynamic exercise. Likewise, the use ofdynamic and isometric exercise in human research protocolshas been instrumental in teasing apart the contributions ofthe underlying neural mechanisms involved in evoking theautonomic and ensuing cardiovascular responses to exercise.

Several neural mechanisms working in concert are respon-sible for the autonomic adjustments to exercise and throughcomplex interactions precisely control the cardiovascularand hemodynamic changes in an intensity-dependent manner(Fig. 1). It is well accepted that central signals from the higherbrain associated with the volitional component of exercise(i.e., central command) (264,362,378), peripheral signals aris-ing from mechanically and metabolically sensitive afferentsin contracting skeletal muscle (i.e., exercise pressor reflex)(162,164,219,220,315), and feedback from stretch receptorsoriginating in the carotid and aortic arteries (i.e., arterialbaroreflex) (75, 76, 78, 263, 265) are all involved. Less appre-ciated, but also important, are low-pressure mechanicallysensitive stretch receptors located in the heart, great veins andblood vessels of the lungs that sense changes in central bloodvolume and pressure (i.e., the cardiopulmonary baroreflex)(41, 76, 78, 88, 163, 209). In addition, arterial chemoreceptorshoused in the carotid and aortic bodies and phrenic afferentsfrom respiratory muscles (i.e., respiratory metaboreflex)are also capable of modulating the autonomic responses toexercise. This review will focus on the contributions of the

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Figure 1 Schematic summarizing the mechanisms involved in mediating the autonomicadjustments to exercise. Neural signals originating from higher brain centers (i.e., centralcommand), chemically sensitive receptors in the carotid and aortic bodies (i.e., arterialchemoreflex), stretch receptors in the carotid and aortic arteries (i.e., arterial baroreflex),mechanically and metabolically sensitive afferents from skeletal muscle (i.e., exercise pressorreflex), mechanically sensitive stretch receptors in the cardiopulmonary region (i.e., cardiopul-monary baroreflex) and metabolically sensitive afferents from respiratory muscles (i.e., res-piratory metaboreflex) are processed within brain cardiovascular control areas that influenceefferent sympathetic and parasympathetic nerve activity. The alterations in autonomic outflowelicited by these inputs during exercise evoke changes in cardiac and vascular function, aswell as release of catecholamines from the adrenal medulla.

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sympathetic and parasympathetic nervous systems in medi-ating specific cardiovascular and hemodynamic responsesto exercise. Studies demonstrating the contributions of theaforementioned neural mechanisms to the autonomic changesand ensuing cardiac and/or vascular responses will be cov-ered. In addition, distinctions between the onset of exerciseand steady-state conditions will be made, when appropri-ate. Of note, nonadrenergic hormonal contributions (e.g.,Angiotensin II, Vasopressin) to the cardiovascular responsesto exercise will not be covered nor will autonomic effects onmetabolic and respiratory responses. Overall, the literatureexamining the autonomic nervous system and the mechanismsof neural cardiovascular control during exercise is vast. Assuch, it is not feasible to include all of the research within thesefields in a single article and therefore, additional review arti-cles are cited throughout to direct the reader to further work inthese important areas. It should also be noted that this reviewwas designed to focus primarily on studies in healthy humansand more recently published work with only brief mention toanimal studies and historical data.

Autonomic Responses to ExerciseCardiac autonomic regulationFollowing a brief description of the organization of the auto-nomic neural control of the heart and the methods commonlyused for its assessment in humans, the influence of exer-cise phase (e.g., onset, steady-state, and recovery), duration,intensity, and modality on cardiac autonomic control will bediscussed.

Cardiac autonomic organization

Parasympathetic and sympathetic efferent activity can mod-ulate the chronotropic, inotropic, and lusitropic functioningof the heart. The cell bodies of the parasympathetic pregan-glionic neurons are situated in the nucleus ambiguus anddorsal motor nucleus of the medulla oblongata (154). Theaxons travel within the tenth cranial nerve (vagus nerve) andsynapse at a postganglionic neuron located at the cardiacplexus. Sympathetic preganglionic cell bodies are located inthe intermediolateral cell column of the spinal cord and thepreganglionic fibers directed to the heart synapse at the stel-late ganglion and upper thoracic ganglia (T1-T5). Postgan-glionic parasympathetic and sympathetic fibers synapse atthe sinoatrial node, atrioventricular node, atria, and ventri-cles. The classical view of cardiac autonomic neurotransmis-sion whereby parasympathetic efferents release acetylcholineonto muscarinic receptors and sympathetic efferents releasenorepinephrine onto β1-receptors is well established (154).However, the importance of the complex pre- and postsy-naptic interactions between parasympathetic and sympatheticfibers (e.g., excitatory facilitation and accentuated antago-nism) (189) and the role of intrinsic and locally released neu-romodulators (e.g., neuronal nitric oxide and neuropeptide

Y) (18, 136) should not be overlooked. Although the richsympathetic innervation of ventricles is widely recognized,as recently reviewed by Coote (39), there is accumulat-ing evidence for dense parasympathetic innervation of thisregion and its functional significance in the control of ven-tricular rhythm, rate and contractility. In addition, a positivechronotropic response to α1-adrenergic stimulation has beenreported in young individuals (287). However, the importanceof parasympathetic regulation of ventricular function and α1-adrenoreceptor chronotropism during exercise in health anddisease remains to be elucidated.

Assessment of cardiac autonomic regulation

The limited accessibility of cardiac autonomic efferentsmeans that obtaining direct intraneural recordings fromhumans is not plausible, thus indirect assessments of cardiacautonomic control must be relied upon. The relative meritsand faults of these experimental approaches have been dis-cussed extensively elsewhere (32) and will only be brieflymentioned here. The use of pharmacological blocking agentsprovides a valuable means of dissecting the contributions ofparasympathetic and sympathetic activity to cardiac regula-tion. Cardiac parasympathetic activity may be assessed bythe administration of muscarinic receptor antagonists such asatropine sulfate or glycopyrronium bromide (also known asglycopyrrolate), with the latter being preferred in more recentinvestigations as its penetration of the blood-brain barrier ismuch lower, which decreases the likelihood of any poten-tial confounding central effects (259). The pharmacologicalassessment of cardiac sympathetic activity may be achievedby the administration of β-adrenergic blockade. Although β-blockade has been usually administered prior to exercise, asmall number of studies in animals have initiated administra-tion during exercise (22, 239), thus circumventing any con-founding effects of a change in baseline HR. The potentiallyconfounding effects of drug non-specificity (e.g., combinedβ1- and β2-adrenergic receptor blockers) and blockade com-pleteness should be considered when interpreting pharma-cological investigations of cardiac autonomic control duringexercise. Also, while very useful in the assessment of HRregulation during exercise, the associated changes in dias-tolic filling time and thus preload, means that pharmacologi-cal examination of the inotropic effects of cardiac autonomicactivity in vivo can be difficult.

On the basis that cardiac SNA is proportional to theappearance of norepinephrine in the coronary venouseffluent (coronary sinus); cardiac norepinephrine spilloverrate can provide an accurate assessment of cardiac sym-pathetic firing (169). Norepinephrine spillover from theheart may be studied with the infusion of radio-labelednorepinephrine and appropriate catheterization and regionalblood sampling (74). To the best of the authors’ knowledge,a comparable approach has not been used to assess cardiacacetylcholine spillover from the human heart, which wouldrequire appropriate control for the high catalytic activity




of acetylcholinesterase (309). While the directness of thisapproach is a key strength, its invasiveness and the associatedtechnical challenges limits it widespread use. Albeit muchmore indirect, time and frequency domain analysis of HRvariability provides a noninvasive means of assessing cardiacautonomic activity (69). As power spectral analysis offluctuations in R-R interval occurring around a respiratoryfrequency (i.e., high frequency, 0.15-0.40 Hz) and short-termtime domain measures (e.g., root mean square of successivedifferences) of HR variability are virtually abolished bycholinergic-muscarinic blockade (69, 262) they are widelyutilized to estimate cardiac parasympathetic activity. Incontrast, low frequency (i.e., 0.04-0.15 Hz) R-R intervalpower is attenuated by both cholinergic and β-adrenergicblockade suggesting that the activities of the parasympatheticand sympathetic nerves contribute, and thus the interpretationof changes in low frequency power is complex (69,169). Thespecific limitations associated with the use of HR variabilityto interrogate cardiac autonomic control during exercisehave been discussed at length elsewhere (32). Patients whopossess a functionally denervated heart as a consequence ofspinal cord transection or heart transplantation also providea valuable means of interrogating cardiac autonomic controlin humans. Cardiac adrenergic innervation and activationcan also be assessed with radio-scanning methods (74). Thisapproach has been used to document heightened cardiacsympathetic activity in chronic heart failure patients and isalso associated with elevated SNA directed to the skeletalmuscle vasculature, reduced exercise capacity and futurecardiac events in this population (387,388). Although provid-ing a powerful research tool, limited studies have used thisapproach 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 ofexercise. The involvement of a reduction in cardiac parasym-pathetic activity (or “inhibition of the normal restrainingaction of the inhibitory centre”) in humans was suggested atthe turn of the last century (26) although experimental supportfor this proposition is much more recent (343). Administrationof atropine has been shown to significantly attenuate the ini-tial increase in HR to a variety of exercise modalities, includ-ing isometric handgrip (98,194), isometric arm flexion (143),and leg cycling (80,271). Furthermore, HR variability derivedindices of cardiac parasympathetic activity are decreased inearly exercise (11, 22). In contrast, the magnitude of the car-diac acceleration at the onset of leg cycling is not diminishedby prior β-adrenergic blockade, implying a minimal influ-ence of sympathetic activity at this time (80, 271). Takentogether these findings suggest that the early HR response toexercise is principally mediated by the withdrawal of cardiacparasympathetic activity, with the sympathetic contributionbeing manifest at a longer latency. This concept is supportedby investigations showing a rapid reduction in HR resulting

from stimulation of cardiac parasympathetic efferents anda more sluggish response to sympathetic nerve stimulation(∼3-6 s) (133).

Contrary to the traditional view, Matsukawa and col-leagues have advanced the hypothesis that it is an increasein cardiac SNA at the onset of exercise that principally causesthe initial rise in HR. This view is supported by studies inconscious cats in which directly recorded cardiac SNA wasshown to rapidly increase at the onset of treadmill exercise (by168%-297% within ∼7 s) (346). However, reconciling theseobservations in cats with the human studies described aboveis challenging in the absence of direct cardiac sympatheticrecordings in humans. Furthermore, alternative techniques fordirectly assessing cardiac SNA in humans do not offer suffi-cient temporal resolution to capture the kinetics of the onsetresponse (e.g., cardiac plasma norepinephrine spillover). Ithas also been shown that tetraplegic subjects, in whom acomplete cervical spinal cord lesion (C6-C7) has caused car-diac sympathetic denervation while cardiac parasympatheticinnervation remains intact, display an attenuated increase inHR at the start of isometric arm exercise (329). Furthermore,the normal reduction in R-R interval high frequency spec-tral power is more sluggish in these patients during isomet-ric exercise, compared to control participants (328). Theseobservations have been taken as further evidence for the rel-ative importance of SNA to the initial cardiac accelerationthat accompanies exercise. However, an alteration in cardiacparasympathetic regulation as a consequence of a chronicadaptation to spinal lesion cannot be excluded.

Cardiac autonomic regulation during steady-stateexercise

There is an approximately linear relationship between HRand oxygen uptake during incremental dynamic exercise of alarge muscle mass (180). It is generally considered that therelative contribution of cardiac parasympathetic withdrawalto this HR response is greatest at lower exercise workloadsand becomes less significant as exercise intensity increases,particularly once HR exceeds ∼100 b·min−1. Conversely, therelative contribution of cardiac sympathetic stimulation to theexercise-induced elevation in HR increases along with exer-cise workload. Indeed, administration of atropine diminishesthe magnitude of the HR rise during low-to-moderate intensityexercise, whereas HR is unaffected by propranolol administra-tion (80,194,271). In contrast, at higher exercise intensities β-adrenergic blockade significantly attenuates the size of the HRresponse, thus suggesting a key role for heightened SNA andcirculating catecholamines at such workloads (80, 194, 271).An exercise intensity-dependent reduction in high frequencypower spectral density has also been described, indicative ofprogressive cardiac parasympathetic withdrawal (11). This ismuch more marked in the transition from rest to low-intensityexercise, than between moderate to high exercise intensity inhealthy individuals (11). Such changes in autonomic mod-ulation of the heart were absent in heart transplant patients




possessing a denervated heart (11). Nevertheless, the relativecontributions of cardiac parasympathetic activity and SNAto the HR response at differing dynamic exercise intensitiescontinues to be debated (374). HR variability derived indicesof cardiac parasympathetic activity have also been demon-strated to decrease during isometric exercise (149), althoughthe magnitude of this reduction is less marked than observedduring dynamic exercise and typically accompanied by a moremodest increase in HR (128). As mentioned above, HR vari-ability analyses do not permit a robust assessment of cardiacSNA, and to the authors’ knowledge, the influence of dynamicexercise intensity on cardiac norepinephrine spillover has notbeen comprehensively evaluated in healthy humans. However,Hasking et al. (129) has reported that cardiac norepinephrinespillover was markedly increased during moderate intensityleg cycling exercise (from 5 ± 2 to 73 ± 23 ng·min−1).

During prolonged submaximal dynamic exercise at asteady-state workload, there is a progressive increase in HR,mirrored by a fall in stroke volume, such that cardiac outputis maintained relatively stable (43, 66). This “cardiovascu-lar drift” phenomenon is exacerbated when exercise is com-bined with heat stress and dehydration (111). Intriguingly,β1-adrengeric blockade prevented the normal increase in HRobserved after 15 min of leg cycling exercise (∼57% peakoxygen uptake, thermo-neutral conditions) and consequentlystroke volume did not fall, likely as a consequence of therelatively longer diastolic filling time (100). Whether cardiacnorepinephrine spillover increases over the time course ofsuch exercise is unclear, however in dogs performing pro-longed steady-state submaximal treadmill exercise the pro-gressive increase in HR was accompanied by a progressivereduction in HR variability determinants of cardiac parasym-pathetic activity (182). An increase in core temperature mayexplain the autonomic contribution to the drift in HR notedduring prolonged submaximal exercise (100, 157), althoughincreased central command and skeletal muscle afferent feed-back likely also contribute (178).

The heart appears to retain at least some parasympatheticcontrol at high exercise intensities. Indeed, atropine admin-istration elicits a robust increase in HR in dogs performingheavy-intensity treadmill exercise (239) and respiratory medi-ated fluctuations in HR are still evident (22). However, thelack of an increase in HR with atropine administration duringexhaustive dynamic exercise and the absence of appreciableHR variability in humans, suggests that cardiac parasympa-thetic withdrawal is complete at these workloads (272). Anearly study by Robinson et al. (272) reported that cardiacparasympathetic blockade reduced maximal oxygen uptake,although this observation was not substantiated by later inves-tigations (65). As recently reviewed, an extensive body ofwork has evaluated the contribution of cardiac SNA to maxi-mal exercise performance using a variety of human and animalmodels (343). The most relevant studies with respect to thefocus of the present review are those employing β-adrenergicblockade in humans. Several of these studies have reporteda reduction in maximal oxygen consumption and exercise

capacity (9, 72, 336); however, this has not been a universalfinding with no effect of β-adrenergic blockade often reported(65, 196, 269). Part of the reason for these equivocal findingsmay relate to the training status of the participants studied.Joyner et al. (159) demonstrated that β-adrenergic blockadewith propranolol had little effect on maximal oxygen uptakein untrained subjects (≈45 mL·min−1.kg−1) whereas in aer-obically trained individuals (≈63 mL·min−1.kg−1) a notablereduction in maximal oxygen uptake was observed. While, theimportance of a direct cardiac effect is clear from the reportedreduction in maximal cardiac output, indirect mechanismsmay also contribute (e.g., metabolic and hormonal alterations)particularly when nonspecific β-adrenergic antagonists havebeen utilized.

Along with a reduction in intrinsic HR, a reduction inβ-adrenergic sensitivity contributes to the well-establishedreduction in maximal HR with age (33) that makes a sig-nificant contribution to the age-related lowering of maximaloxygen consumption (134). Maximal HR is often estimated as220—age (93), but may underestimate maximal HR in olderindividuals and on the basis of extensive meta-analyses andlaboratory-based investigations alternative regression equa-tions have been derived (e.g., Tanaka equation; 208 × 0.7—age) (270, 333). An inability of HR to increase appropriatelyin proportion to the metabolic demands of exercise has beentermed “chronotropic incompetence” and has been linkedwith an impairment in β-adrenergic sensitivity (37, 71). Itmay be defined in a number of ways, but the failure to attain≥80% of HR reserve during an incremental maximal exercisetest is most commonly used (28). Importantly, chronotropicincompetence is associated with exercise intolerance and is anindependent predictor of mortality in clinical (e.g., heart fail-ure) and healthy populations (28, 71). It should be noted thatwhile alterations in cardiac autonomic control may be impli-cated in chronotropic incompetence the underlying mecha-nisms remain incompletely understood.

At the immediate cessation of exercise the initial recov-ery of HR is quite abrupt, but this is generally followed bya more gradual decline occurring over minutes, the specifickinetics of which are dependent on the intensity and dura-tion of the prior exercise (130, 150). HR recovery is delayedin heart transplant patients (292) indicative of a contributionof cardiac autonomic efferent activity in this process. Therapid recovery of HR following exercise has been attributedto the rapid restoration of cardiac parasympathetic activity,since it is virtually abolished by atropine administration, butunaffected by β-adrenergic blockade (87, 150). Furthermore,endurance trained athletes in whom cardiac parasympatheticactivity is elevated demonstrate a more rapid recovery of HR(150). The secondary more gradual decline in HR followingexercise may be attributable to a slower restoration of theremaining cardiac parasympathetic activity and reduction incardiac sympathoexcitation (11), which sustains a modest ele-vation in cardiac output, thus preserving perfusion pressurein the face of peripheral vasodilatation. HR recovery kinet-ics have been shown to have prognostic value, with a poor




recovery (e.g., a fall in peak exercise HR by <12 b.min−1 in1 min of supine recovery) being a predictor of an increasein all-cause mortality (34, 360). The reason for this perhapsrelates to the association with the cardioprotective effects ofcardiac parasympathetic activity (347).

In summary, the available evidence generally supports theview that increases in HR during low intensity steady-statedynamic exercise are principally driven by a reduction in car-diac parasympathetic activity, whereas the relative contribu-tion of a sympathetic mechanism is greater as exercise inten-sity increases. However, this viewpoint should not be consid-ered absolute as some parasympathetic control of HR has beenreported during higher intensity exercise. During prolongeddynamic exercise at a steady-state submaximal workload asympathetically mediated HR rise is evoked (cardiac drift),which is exacerbated by dehydration and high ambient tem-perature. Furthermore, a reduction in β-adrenergic receptorsensitivity has been associated with a failure to normallyincrease HR and a reduction in aerobic exercise capacity.Thus, a normally functioning autonomic nervous system isrequisite for an appropriate cardiac response during exerciseand has important implications for exercise performance.

Sympathetic regulation of the peripheryAlthough both parasympathetic and sympathetic activity con-tribute to the cardiac responses to exercise, it is the sym-pathetic nervous system that is essential for the peripheral

vascular adjustments to exercise. Here, we will provide abrief description of the organization of the sympathetic inner-vation of the peripheral vasculature and methods used for itsassessment in humans. This will be followed by discussion ofthe current understanding of the sympathetic adjustments toexercise onset and steady-state conditions of varying intensityand duration.

Peripheral sympathetic organization

The tonic rhythmic discharge of sympathetic nerves is a majorcontributor to resting vasomotor tone in the peripheral circu-lation, and via modulation of the arterial baroreflex plays anessential role in BP homeostasis (42). However, the sympa-thetic nervous system is not only important for vascular toneand BP control under resting conditions, but is also intimatelyinvolved in the regulation of these processes during exercise.The central regulation of sympathetic outflow occurs mainlywithin cardiovascular areas of the brainstem (i.e., medullaoblongata) (50) (Fig. 2). Sympathetic preganglionic neuronsare located in the intermediolateral cell column (IML) of thethoracic and upper two lumbar segments of the spinal cord(T1 - L2; i.e., thoracolumbar). These preganglionic neuronsare cholinergic, fast conducting (∼15 m/s), thinly myelinatedfibers that project via the ventral roots and the white ramito then synapse on postganglionic neurons in the paraver-tebral and prevertebral ganglia. The postganglionic neuronsare noradrenergic, slower conducting (∼1 m/s), unmyelinated

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Figure 2 Simplified schematic illustrating putative neural areas involved in the controlof parasympathetic and sympathetic outflow. The activity of efferent autonomic outflow isdetermined by complex interactions within and between central neural circuits, peripheralafferent inputs to the nucleus tractus solitarii (NTS) and other neural areas (not shown) aswell as circulating factors. The integrated response of all of these ascending and descendingneural signals ultimately determines parasympathetic and sympathetic outflow. See text foradditional details. CVLM, caudal ventrolateral medulla; CVO, circumventricular organs; IML,intermediolateral cell column; NA, nucleus ambiguus; RVLM, rostral ventrolateral medulla.




fibers that project through gray rami, and peripheral nervesto innervate target organs such as the heart and peripheralblood vessels. The sympathetic preganglionic neurons in theIML receive strong excitatory drive from neurons of the rostralventrolateral medulla (RVLM) (50,324). Sympathetic pregan-glionic neurons at the IML also receive direct excitatory inputsfrom other regions of the central nervous system including theventromedial medulla, caudal raphe nuclei, A5 noradrenergiccell group of the caudal ventrolateral pons, and the paraven-tricular hypothalamic nucleus (50,324). The regulation of thisexcitatory drive to the IML is multifaceted and can be intrinsi-cally generated, hormonally mediated (e.g., Angiotensin II),or attributable to integration of excitatory inputs from otherregions of the central nervous system (50). The circumventric-ular organs, which lack a blood brain barrier, provide an addi-tional means by which circulating factors can influence keycentral regions involved in the regulation of SNA (310). Whileactivation of sympathetic preganglionic neurons would leadto greater sympathetic outflow and norepinephrine releasein the periphery, another important consequence of activat-ing the sympathetic nervous system, particularly with exer-cise, is the stimulation of the release of epinephrine from theadrenal medulla and its impact on the cardiac and peripheraladjustments to exercise. However, our focus in this reviewwill be on postganglionic sympathetic fibers to target organsand norepinephrine release with adrenal medulla stimulationand epinephrine effects only being discussed in brevity. Sev-eral excellent original articles and reviews are available foradditional detail and description of this research literature(27, 103, 170, 171, 207, 389).

In any description of the control of the sympatheticnervous system, the arterial baroreflex warrants discussionbecause of its profound beat-to-beat influence on SNA(138, 158, 197, 340). Arterial baroreceptor afferents emanat-ing from mechanoreceptors at the carotid sinus bifurcationand the aortic arch terminate at the nucleus tractus solitarii(NTS) in the medulla oblongata, a major center for autonomicintegration in the brainstem that receives both ascending anddescending projections. The NTS exerts a tonic sympatho-inhibitory influence on RVLM neurons by its projections tothe caudal ventrolateral medulla (50). It is also important toconsider that afferent inputs from other peripheral reflexessuch as the arterial chemoreflex can impinge on the NTS tomodulate sympathetic outflow (295) (Fig. 2). An alteration inthe activity of any of these neural areas, and/or the recipro-cal interactions amongst them, has the potential to modulatecentral sympathetic outflow at rest as well as during exer-cise. Indeed, the complex neuroanatomical interactions thatcontribute to the central regulation of SNA continue to be anintense area of investigation.

Peripheral sympathetic assessment

There are a multitude of methodologies for quantification ofthe activity of the sympathetic nervous system (74, 114, 115)(Fig. 3). A global measure of SNA can be assessed from

analysis of plasma or urine catecholamine concentrations.Norepinephrine is the primary neurotransmitter released frompostganglionic sympathetic nerves in response to neural firingand has been mainly used to estimate sympathetic activationto stressors, particularly exercise; however, epinephrine con-centrations have also been utilized. Although useful, a caveatto using plasma concentrations is that they cannot account forthe complexities of sympathetic neuronal discharge includ-ing reuptake of norepinephrine back into nerve terminals,extraneuronal metabolism of norepinephrine, and/or clear-ance of norepinephrine. These measures also do not accountfor potential regional differences. To minimize such concerns,the work of Murray Esler and associates (74, 114, 115) haspioneered the use of radiotracer techniques in humans forthe determination of global or specific organ spillover ratesof norepinephrine. The general use of these techniques islimited by the required catheterizations, invasiveness, andmedical oversight required; however, when utilized impor-tant information regarding the control of sympathetic out-flow has been garnered, particularly during dynamic exercise(73, 129, 169, 208, 368, 369). Studies have also used spectralanalysis of BP variability to estimate peripheral sympatheticdrive (248); however, the validity of these indices is question-able (335) and studies relying solely on such measures shouldbe interpreted with caution. In humans, a direct assessment ofcentral sympathetic activity can be made using microneurog-raphy to selectively record from postganglionic muscle or skinsympathetic nerves (349). These recordings are analogous todirect recordings of SNA (i.e., lumbar) commonly obtained inanimals by the surgical implantation of recording electrodesonto sympathetic fibers however, for obvious reasons, directsympathetic recordings to internal organs cannot be made inhumans. Nevertheless, direct muscle SNA recordings stronglycorrelate with renal, cardiac and whole-body noradrenalinespillover (368, 369). In addition, the temporal resolution thatcan be achieved with direct measurements from sympatheticnerves is superior to all other sympathetic measurement tech-niques. Overall, much of the information regarding the sym-pathetic nervous system and its regulation in humans has beendetermined using microneurographic recordings and many ofthe exercise studies will be highlighted in this review.

Peripheral sympathetic activity at exercise onset

During large muscle mass dynamic exercise direct microneu-rographic recordings of SNA in humans are challenging dueto contamination from action potentials generated by skeletalmuscle cells, as well as movement and the associated riskof recording electrode displacement from the nerve. Thus,much of the information regarding SNA onset dynamics inhumans has been obtained from inactive limbs using smallermuscle masses (e.g., handgrip) as well as from animal stud-ies where the electrode can be firmly implanted around thenerve. Allyn Mark and Gunnar Wallin obtained some of thefirst direct recordings of muscle SNA in exercising humansfrom the peroneal nerve of the inactive leg during isometric




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Figure 3 Summary of methods used for measuring regional SNA in humans. Sympathetic nerve firingcan be measured directly in postganglionic sympathetic nerve fibers of skin and skeletal muscle using thetechnique of microneurography. Isotope dilution methods can be used to measure the spillover rates ofnorepinephrine to plasma from individual organs, which provides an assessment of regional SNA in thelimbs as well as specific organs. Cardiac sympathetic nerve scans can be used to study the anatomy ofthe sympathetic innervation of the heart. Reprinted, with permission, from (74).

handgrip (198). This study set forth the concept that muscleSNA does not increase at the onset of exercise, but ratherthere is a delay of about 1 min during an isometric hand-grip contraction performed at 30% MVC (Fig. 4). In contrast,skin SNA increases at the immediate onset of isometric hand-grip and leg extension exercise (267, 344, 358, 359, 384). Theincrease in skin SNA at exercise onset appears proportional tothe exercise intensity and remains elevated throughout exer-cise (267,283,344,358,359). Likewise, animal investigationsdemonstrated immediate increases in renal and cardiac SNA atthe onset of dynamic exercise (54,237,346). Overall, the onsetof dynamic exercise does not appear to produce mass, uni-form sympathetic discharge to all tissues, rather the majorityof studies suggest selective sympathetic activation at exerciseonset.

To further explore such differential control and betterunderstand the latency of muscle sympathetic activation dur-ing dynamic exercise, Seals and Victor undertook a series ofstudies using rhythmic handgrip and one or two-arm cycling.

In general, these studies further supported the idea that dur-ing dynamic exercise sympathetic outflow to skeletal mus-cle did not immediately increase above resting values andthere was a latency of approximately 30 to 60 s before a sig-nificant change occurred, which was most notable at higherworkloads or when the circulation to the exercising musclewas occluded (299, 300, 353, 354). Around the same time,Saito and colleagues also performed several studies examin-ing SNA responses and latencies to different modes of exer-cise (279-282, 284, 286) and in general, observed a temporalresponse pattern similar to that reported by Seals and Victor.Aside from identifying the temporal pattern of muscle sympa-thetic activation during exercise, these studies also indicatedthat the buildup of metabolites and stimulation of metabol-ically sensitive skeletal muscle afferents contribute impor-tantly to the muscle SNA response to exercise. The specificcontributions of the different neural mechanisms to exercisemediated sympatho-excitation will be discussed in detail inthe following sections.




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Figure 4 Muscle SNA, mean arterial pressure (MAP), and HR responses to isometric handgrip (35% MVC)followed by a period of post exercise ischemia (PEI) to isolate the muscle metaboreflex. As originally reportedby Mark et al. (198) HR increases from the onset of exercise, MAP rises more gradually and a delay is presentfor muscle SNA consistent with muscle metaboreflex mediation. This is supported by the maintenance of muscleSNA and MAP during PEI, a period in which muscle metaboreflex mediated responses are isolated from centralcommand and muscle mechanoreceptors. In contrast, HR returns to baseline values during PEI.

These concepts were further substantiated by studiesexamining muscle SNA in the arm (e.g., radial nerve) duringdynamic leg exercise (30, 266, 286). A reduction in muscleSNA was reported during the preparation for (30) and at theonset of low intensity leg cycling exercise (30,286); however,this sympathetic inhibition was overcome at higher exerciseintensities (>60% peak workload) where increases in mus-cle SNA were observed. Ray et al. (266) reported that duringone legged kicking muscle SNA was reduced below base-line when exercise was performed in the upright position, andunchanged during supine exercise. As discussed in more detailbelow, these findings point to the important modulatory roleplayed by venous return, central blood volume, and thus car-diopulmonary baroreceptor loading status to the muscle SNAresponses at the onset of low-intensity dynamic exercise, butat higher exercise intensities this sympatho-inhibitory effectis obscured by other sympatho-excitatory mechanisms (e.g.,exercise pressor reflex and central command).

Collectively, studies examining SNA responses at theonset of exercise support a nonuniform sympatho-excitationthat likely assists in initiating the appropriate cardiovascularadjustments to exercise. In this regard, the reported immediateincreases in SNA to the kidney and skin would be importantfor redistribution of blood flow to active muscles upon the

initiation of exercise. At the same time, lack of an increase oran inhibition of muscle SNA would facilitate vasodilation andincreased blood flow within active skeletal muscles. Lastly,the increase in cardiac SNA would elevate HR (along withreduced parasympathetic nerve activity) and cardiac contrac-tility contributing to increases in cardiac output, which wouldbe preferentially distributed to active skeletal muscle due tothe aforementioned peripheral SNA responses. While this dif-ferential sympathetic activation pattern at the onset of exer-cise seems reasonable and appropriate, it is important to notethat some studies have indicated an immediate and sustainedexercise-induced increase in lumbar SNA to skeletal mus-cle in conscious rats (56) and unanesthetized decorticate cats(121).

Peripheral sympathetic activity during steady-stateexercise

In contrast to the onset of exercise, there is substantial evi-dence that SNA increases in an intensity dependent man-ner during sustained levels of dynamic exercise in humans.Indeed, for the most part, studies using direct muscle SNArecordings, plasma norepinephrine as well as norepinephrinespillover have all suggested that sympathetic activation




becomes progressively greater as exercise intensity and dura-tion is increased (24,103,146,186). Galbo et al. (103) reporteda progressive increase in venous norepinephrine concentra-tion during graded treadmill exercise at workloads above50% maximal oxygen uptake (VO2max). Likewise, arte-rial and venous norepinephrine concentrations were foundto progressively increase during incremental leg cycling(24, 186, 334, 341). An exercise intensity dependent andmarked elevation in whole body norepinephrine spillover wasalso observed, to which a large contribution was attributableto the kidney (188,341). However, Seals et al. (300) reported astrong relationship between plasma norepinephrine and mus-cle SNA during graded intensity two-arm cycling, but notably,at low workloads neither norepinephrine nor muscle SNAwere increased. In addition, more recent work by Ichinoseet al. (146) demonstrated that during 6-min stages of gradedleg cycling from very mild to exhaustive exercise an initialdecrease in directly recorded muscle SNA at low workloadswas followed by progressive increases reaching an approxi-mate 265% elevation from baseline during exhaustive exer-cise (Fig. 5). These data clearly demonstrate that profoundincreases in muscle SNA can occur with dynamic exercise.

Aside from exercise intensity, the duration of exercisehas a major impact on the temporal pattern and degree ofsympatho-excitation. In this regard, Davy and colleagues (52)reported an increase in plasma venous norepinephrine after10 min of treadmill walking at approximately 65% peak oxy-gen uptake (VO2peak) that increased further as exercise con-tinued. Furthermore, progressive increases in norepinephrinehave been reported during 3 h of treadmill running at 60% ofVO2peak (103). It is important to note that both the inten-sity and duration of exercise will combine to dictate theoverall sympathetic response. For example, during 30 minof sustained leg cycling performed at 25% of maximumworkload, plasma norepinephrine concentration and whole-body norepinephrine spillover were increased by 15 min ofexercise 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 inplasma norepinephrine concentration and whole-body nore-pinephrine spillover that progressively increased throughoutthe exercise period. A similar progressive increase in sym-pathetic activation was observed using direct muscle SNArecordings obtained during 30 min of upright cycling at 40%VO2max (285). Thus, in describing the sympathetic responseto dynamic exercise the duration and intensity need to beconsidered as both contribute importantly to the degree ofsympathetic activation.

An important distinction that requires consideration iswhether sympathetic responses are being measured in activeor inactive skeletal muscle beds. Indeed, many of the studiesexamining sympathetic responses to exercise in humans,particularly those using direct recording of muscle SNA,have assessed the inactive limb. Furthermore, whole bodynorepinephrine measures represent a marker combiningactive and inactive beds. This becomes quite important

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Figure 5 Muscle SNA responses to a bout of incremental leg cyclingranging in intensity from very mild to exhausting. Raw recordings ofarterial BP and muscle SNA (MSNA) during rest, very mild, mild, mod-erate, heavy, and exhausting exercise and recovery in a representativesubject from Ichinose et al. (146). After an initial decrease in MSNAfrom rest during very mild exercise, MSNA was increased progressivelyas exercise intensity increased. Reprinted, with permission, from (146).




because the limited data available suggests that the activelimbs may be the major targets of the increase in sympatheticactivation. For example, it has been reported that 60% ofnorepinephrine release during submaximal dynamic exercisecomes from the skeletal muscle circulation (73). In addition,the classic work of Savard and colleagues (291) demonstratedthat norepinephrine spillover was greater from the active legcompared to the inactive during one legged knee extensionexercise undertaken at 50% and 100% of maximum work-load. Although the concept that there is greater SNA to activeskeletal muscle is intriguing and seems reasonable as this maybe needed to offset local metabolically mediated vasodilation,not all studies have reported a difference between active andinactive SNA during exercise. In this regard, Hansen et al.(124) reported similar increases in directly measured muscleSNA in the active and inactive limb during ischemic unilateralstatic toe extension at 20% MVC. The reason for the lackof a difference in muscle SNA between the exercising andnonexercising limbs in this study is not clear but may relateto the exercise modality employed, the low exercise intensity,and/or the small muscle mass engaged. Indeed, althoughischemic, a mild intensity was used in this study, and whenmatched for relative exercise intensity, sympathetic activationwill be greater when a larger compared to smaller musclemass is engaged (23). However, even though the size of thecontracting muscle mass reportedly increases the magnitudeof the resultant SNA and BP response, this association is com-plex and likely affected by a multitude of factors includingbut 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 clearevidence for intensity and duration-dependent increases inmuscle SNA to both the active and inactive limbs duringisometric and dynamic exercise in humans. This is accompa-nied by increased norepinephrine spillover from the cardiac(129,368), renal (129,341), and splanchnic (208) vasculature.Nevertheless, regional differences in the temporal pattern ofthe sympathetic activation and the impact that both intensityand duration have on the sympathetic response have to becarefully considered when examining studies reporting SNAduring exercise. In the following sections of this review,we will discuss the neural mechanisms underpinning theparasympathetic and sympathetic adjustments to exercise.

Neural Cardiovascular ControlMechanismsCentral commandIn 1886, Zuntz and Geppert proposed the existence of a corti-cal control mechanism that simultaneously activated respira-tory centers and voluntary locomotor pathways. This feed for-ward parallel activation of locomotor and respiratory neuralcircuits was further advanced to incorporate the cardiovascu-lar responses to exercise (156, 180, 181). Originally termed“cortical irradiation” (181) and later “central command”

(113), this concept refers to descending neural signals thatelicit skeletal muscle contraction and concomitantly activatecentral nervous system centers involved in the control of auto-nomic neural outflow to the cardiorespiratory system. It isnow clear that an individual’s perception of effort contributesto the magnitude of central command during exercise, inde-pendent of the actual force produced (Fig. 6). However, it isimportant to note that effort sense is a complex variable thatcan be influenced by numerous stimuli (e.g., pain), which pro-vide afferent feedback to cardioregulatory centers of the brain(377, 378). Thus, in addition to the traditional feed-forwardconcept (180,181,390), it is likely that central command alsoinvolves feedback mechanisms (377, 378), and in this regardmultiple brain sites (116).

Due to the complexity of central command, the identi-fication of specific brain region(s) responsible for evokingautonomic adjustments has remained elusive. However,putative locations for central command have been identifiedin animals using direct electrical or chemical stimulation ofneural structures including the Fields of Forel, motor cortex,insular cortex, mesencephalic, and hypothalamic areas(1, 15, 68, 314, 332, 362). The advancement of neuroimagingtechniques has provided an opportunity for translationof these findings to humans and the insular and anteriorcingulate cortices have been suggested as human brainregions that are activated by central command during exer-cise (45, 168, 234, 235, 339, 379, 380). More recently, directelectrical stimulation of midbrain areas during neurosurgery(e.g., deep brain stimulation) in awake humans has been usedto enhance our understanding of potential central commandareas (16, 117, 118, 338) (Fig. 7). While constrained byelectrode placement and a patient population (e.g., chronicpain), these novel studies have indicated that the thalamus,subthalamic nucleus, substantia nigra, periaqueductal gray,and periventricular gray may all be involved in determin-ing the cardiovascular response to exercise. Collectively,although these studies identify specific regions of interest, thedevelopment of an integrated neurocircuitry model of centralcommand remains an open area of investigation. The influ-ence of the exercise phase, duration, intensity, and modalityon this complex neural mechanism is discussed below.

Central command at exercise onset

The idea of a central neural signal driving cardiovascularresponses during exercise arose from early observations thatHR increased in anticipation of and immediately at the onsetof exercise—a response that was suggested to be too rapid tobe explained by reflex mechanisms in the contracting skeletalmuscle (29, 108, 156, 180, 181). These initial observations,intuitively, albeit indirectly, suggested a fast feed-forwardneural mechanism, and were supported by subsequent studiesdemonstrating an increase in HR within the first beat dur-ing static arm contraction (143) and large muscle dynamicexercise (153, 231, 382). A more definitive role for centralcommand 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 bloodpressure, and rating of perceived exertion during actual (left) and imagined (right) handgrip exercise. Subjects were categorizedinto low (n = 4) and high (n = 5) hypnotizability groups. Muscle electromyographic recordings demonstrated no measurableincreases in force during imagined handgrip, not shown. The data are presented as mean ± SD. ∗P < 0.05 low versus highhypnotizability. Reprinted, with permission, from (379).




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Figure 7 Electrophysiology recordings from the periaqueductal gray suggest that this neural region isinvolved in mediating the cardiovascular adjustments to exercise. Three patients had stimulation electrodesplaced 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 at15 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 powerspectral density from all three subjects. (D) Normalized spectral changes (rest = 1.0) divided into frequencybands. ∗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 ofcentral command influence. According to the latter approach,partial neuromuscular blockade decreases the contractile abil-ity of the paralyzed muscles and thus, a greater neurally gen-erated signal is required to maintain the same level of absoluteforce (i.e., exaggerated central command input). In this regard,the initial rise in HR in response to voluntary contractionsis unaffected by partial neuromuscular blockade (i.e., sameHR response with less absolute muscular force developed),suggesting that the rapid tachycardic response is related tovoluntary effort, rather than feedback from the contractingskeletal muscle (153, 301). These findings are in line withclassic work in cats in which stimulation of locomotor brainregions elicited stimulation-dependent increases in cardiovas-cular variables, despite lack of muscle contraction due to deepanesthesia or paralysis (57, 67, 363).

Thus, it is well accepted that the initial rapid increasein HR at the onset of exercise is due to descending centralnervous system input, although as discussed later, reflex inputscontribute quickly. Due to the latency of parasympathetic and

sympathetic influences on HR, the general assumption hasbeen that central command-induced cardiac vagal withdrawalmediates the increase in HR at the onset of exercise. Indeed,vagal blockade with atropine blunts the rapid rise in heart inresponse to static contractions (98,108,143). However, recentevidence suggests a potential role for early increases in cardiacsympathetic outflow during spontaneous motor activity in afeline model (346), although the translational applicability ofthese findings to humans remains yet to be determined.

In contrast to cardiac autonomic control, relatively fewinvestigations have examined a direct role for central com-mand mediated peripheral vascular regulation at the onset ofexercise. However, BP increases in anticipation of exercise,relative to the perceived level of effort necessary, which isconsistent with a centrally mediated mechanism (116). Usingbrief (3 s) maximal isometric contractions, Iwamoto et al.(153) demonstrated that the exercise induced increase in BPwas attenuated, but not eliminated, following partial neuro-muscular blockade. That is, central command, in the absenceof reflex skeletal muscle feedback, contributed in part to therise in BP. These findings are consistent with work in cats in




which pharmacological blockade of skeletal muscle stretchactivated ion channels did not influence early increases in BPduring spontaneous muscle contractions (i.e., central com-mand induced pressor response) (201). However, the auto-nomic contribution to potential central command inducedearly increases in BP has yet to be fully determined, althoughin support of a sympathetic contribution, BP and renal SNAhave been shown to increase prior to and at the onset ofstatic exercise (206), locomotion (277), grooming (203) andtreadmill exercise (237) in animals. Although not specificallydesigned to examine the onset of exercise, work from Victorand colleagues using brief rhythmic handgrip exercise andpartial neuromuscular blockade lends some additional insight(355). Short 3-s handgrip contractions below 50% MVC wereshown to have no influence on muscle SNA. However, underintense conditions (75% MVC) every muscular contractionwas accompanied by a synchronized burst of muscle SNAand this synchronization persisted following partial curiza-tion, although muscular force development was minimized.These observations highlight the potential for central com-mand to increase muscle SNA at the onset of exercise, albeitlikely only at high intensities. In contrast, central commandappears crucial for controlling skin SNA, due to the rapidincreases observed prior to and at the immediate onset ofexercise (267, 344, 358, 359, 384).

At the onset of dynamic muscular contractions a rapidincrease in active skeletal muscle vasodilatation occurs,concomitant with a decrease, increase or no change in BPdepending on the exercise modality and intensity (174). Whilethe cause of this rapid vasodilation remains unresolved andhas been attributed to a number of factors including the musclepump and vascular compression, vasodilatory or metabolicfactors, myogenic responsiveness, and sympathetic vasocon-strictor withdrawal, the concept of a sympathetically mediatedvasodilatory mechanism (e.g., cholinergic) has remainedcontentious in humans. Cholinergic (muscarinic) blockadehas been shown not to influence the hyperemic response atthe onset of rhythmic handgrip exercise (308); findings thatare consistent with the observation that there are no obvioussympathetic cholinergic vasodilator fibers in human skeletalmuscle (25,348). Furthermore, the increase in forearm bloodflow in response to an attempted maximal contraction isminimal following limb paralysis with pipecuronium, anagent that blocks postsynaptic nicotinic receptors with noeffect on acetylcholine release, suggesting that acetylcholinespillover from other areas (e.g., motor nerves) is not involvedin skeletal muscle vasodilation in humans (63, 372). In con-trast, Secher and colleagues (303) demonstrated that BP wasstable at the onset (first 6 s) of a control bout of low-intensitydynamic exercise, but with partial curarization BP decreased,suggesting that the augmentation of central commandstimulates a peripheral neurogenic vasodilatory mechanism.More recent examinations using a novel technique of motorimagery of exercise to stimulate central command havesuggested that a neural signal induces vasodilation in skeletalmuscle (152). However, the transient increase in lower limb

vascular conductance evoked by an isometric contraction ofthe contralateral calf muscle is no different when performedeither volitionally or electrically evoked, suggesting thatcentral command is not requisite for this rapid vasodilatoryresponse (89). Despite conflicting findings in humans, anumber of observations in animal models demonstrate thatstimulation of certain neural regions can produce skeletalmuscle vasodilation (1, 15, 70, 142, 202, 204) and that theincreases in blood flow and vascular conductance at the onsetof muscular contractions are blocked to a similar extent witheither ganglionic blockade or atropine (177). Overall, while arole for central command in mediating the peripheral vascularresponses at the onset of exercise has been demonstratedin humans, further investigations are warranted, includingconsiderations for the specific autonomic contributionsrelative to the exercise modality, muscle mass, and intensity.

Central command during steady-state exercise

As highlighted above, a primary strategy used to study thepotential role of central command during exercise in humanshas been neuromuscular blockade. Freychuss (97) reportedthat an unsuccessful attempt to isometrically contract theforearm muscles, following complete neuromuscular block-ade, was still accompanied by an increase in HR and BP,albeit approximately 50% of the normal response. In line withthis, partial neuromuscular blockade to augment the level ofcentral command has generally resulted in an exaggeratedcardiovascular response during static and dynamic exercise(13, 106, 187, 224, 250, 261, 351) (Fig. 8). Although such arelationship is not as clear during high intensity isometriccontractions (107,184) and maximal dynamic exercise (104).Studies employing additional strategies to modulate centralcommand input such as electrical stimulation of resting skele-tal muscle (180), hypnosis (49, 339, 370, 379, 380), muscletendon vibration (113, 155, 246), and patients with unilaterallimb weakness (151, 385) or sensory neuropathies (61) havealso demonstrated a role for central command in mediating thecardiac acceleration and increases in BP in response to exer-cise. For example, Williamson et al. (379) showed that the HRand BP responses to actual and imagined (i.e., hypnosis withno force produced) handgrip exercise were identical, support-ing the concept that central command mediated responses aredictated by the perception of effort (Fig. 6). Although lessextensively investigated, the increase in cardiac output dur-ing exercise appears to be mediated in part by central com-mand, 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 centralcommand-induced increase in HR during exercise is dueto parasympathetic withdrawal. Indeed, muscarinic, but notnonselective β-adrenergic, blockade, reduces the centralcommand-induced tachycardia during exercise with partialcurization (224, 354). However, this area may warrant fur-ther investigation in humans given recent findings that cen-tral command has been shown to primarily influence cardiac




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sympathetic nerve activation (345, 346) versus parasympa-thetic nerve activity (160) in cats. In regards to BP, Mitchellet al. (224) demonstrated that α- or β-adrenergic blockersalone or in combination with muscarinic blockade do notblock the central command induced elevation in exercisingBP during partial neuromuscular blockade. These findingsillustrate a redundancy in the autonomic control of BP viacentral command signals, although additional investigationsare needed. Exaggerated elevations in plasma catecholamineconcentrations have been found when central command isincreased during static (250) and dynamic (104) exercisewith partial neuromuscular blockade, implying a role forcentral command mediated sympathetic activation. Indeed,elevations in skin SNA during handgrip exercise with neuro-muscular blockade were shown to be similar to the responsesduring a control contraction despite the decrease in forcedevelopment and feedback from skeletal muscle afferents(358). These findings highlight the importance of central

command in mediating skin SNA responses to exercise. Incontrast, as mentioned above, using direct recordings of mus-cle SNA in experiments designed to isolate the reflex effectsof skeletal muscle metaboreceptor afferents, Mark and col-leagues suggested that central command has a minimal influ-ence on sympathetic outflow to the skeletal muscle vascu-lature during low- to moderate-intensity static and dynamicexercise (198,354). Furthermore, the magnitude of the rise inmuscle SNA during contractions following partial neuromus-cular blockade is minimal (351). Collectively, these findingssuggest that central command is crucial for increasing efferentskin SNA during exercise, but has a modest effect on skeletalmuscle sympathetic outflow at low to moderate exercise lev-els, although a more prominent role may be apparent duringhigh intensities of exercise (355).

Exercise pressor reflexThe contribution of a reflex originating in skeletal muscleto the cardiorespiratory response to exercise was recognizedtoward the end of the 19th century (156, 390); however, itwas the work of Alam and Smirk (5, 59) that unequivocallyestablished the importance of afferent feedback from skeletalmuscle in evoking the pressor response to exercise in humans(Fig. 9). Since this seminal work, an abundance of research hasbeen devoted to understanding this neural reflex mechanismemanating from skeletal muscle, including the identificationof its afferent and efferent components, which have collec-tively been termed the “exercise pressor reflex” (209). Duringexercise both mechanically and metabolically sensitive sen-sory fibers provide feedback via the dorsal horn of the spinalcord to brainstem cardiovascular areas in response to mechan-ical and metabolic stimuli, respectively (41, 163, 165, 209).The muscle mechanoreflex is mainly comprised of thinly-myelinated group III afferent neurons whose receptors areprimarily activated by mechanical deformation as inducedby changes in pressure or stretch (318, 381). Thus, the mus-cle mechanoreflex is primarily activated at the immediateonset of muscle contraction coincident with a distortion of themechanoreceptors’ receptive field. Indeed, group III afferentshave been shown to fire with an abrupt and profound burstof impulses at the onset of muscle contraction (162, 219). Incontrast, the afferent fibers of the muscle metaboreflex aremostly unmyelinated group IV neurons whose receptors areprimarily chemically sensitive and stimulated by metabolitesproduced by contracting skeletal muscle (163, 222). There-fore, the muscle metaboreflex is thought to require a suf-ficient period of time before it responds due to the delayin production of metabolites by contracting skeletal muscle(198). However, this separation in activation of these exercisepressor reflex afferent neurons is not absolute as group III andIV fibers exhibit polymodal qualities such that some groupIII fibers respond to metabolic changes while some groupIV fibers respond to mechanical distortion (219). In addi-tion, both fiber types can be sensitized (191, 275) or desensi-tized (275) by changes in the metabolic milieu of the muscle




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Figure 9 Original report identifying a BP-raising reflex originatingin skeletal muscle in humans. (A) Schematic showing preparation forthe experimental protocol used in which a cuff was placed around theexercising forearm to perform ischemic exercise, while a cuff on theopposite arm was used to measure arterial BP. (B) Shows part ofthe seminal results from this study documenting the mild increase in BPduring freely perfused rhythmic exercise (top panel) in comparison tothe massive increase in systolic BP during and after exercise when theforearm was made ischemic by cuff inflation to supra-systolic pressure.Reprinted, with permission, from (220).

interstitium. Overall, there is substantial research demonstrat-ing that during muscle contraction, activation of both mechan-ically and metabolically sensitive afferent fibers contributeimportantly to the autonomic responses to exercise and assuch, play a major role in mediating the neural cardiovascularadjustments to exercise.

Skeletal muscle mechanoreflex at exercise onset

As noted in the previous section, there is substantial work inhumans attributing the immediate HR increase at the onsetof exercise (e.g., the shortening of the first R-R interval) toa central command mediated reduction in cardiac parasym-pathetic activity (153, 181, 301, 382). However, pronouncedincreases in HR at the onset of muscular contraction can beinduced in the absence of central command. Krogh and Lind-hard (180) demonstrated in 1917 that percutaneous electricalstimulation can evoke a muscular contraction accompaniedby an increase in HR, but only after the first R-R interval. Ascentral command is bypassed during an electrically stimulatedcontraction the resultant HR response is attributable to mus-cle afferent feedback. Although, a “muscle-heart” reflex wasproposed by Hollander and Bouman (143) with a latency of550 ms during either voluntary or electrically stimulated exer-cise, these investigators may have inadvertently stimulated theskeletal muscle afferents directly (153). Isometric contrac-tions evoked by ventral root stimulation in anesthetized ratshas also been shown to produce a rapid decrease in cardiacparasympathetic activity (213) and increase in sympatheticactivity (205, 345, 346). al-Ani et al. (6) reported that whencardiac parasympathetic activity is increased during expira-tion the magnitude of the HR response to electrically evokedupper arm flexion is greater than when contractions are per-formed during inspiration, thus indicating that feedback fromskeletal muscle afferents can inhibit cardiac parasympathetictone. Mechanically sensitive group III skeletal muscle affer-ents are known to be robustly activated at the onset of an elec-trically evoked muscular contraction (163), and as such therapidity of the cardiac autonomic responses described abovesuggests a predominant role for these afferents. However, theuse of electrically evoked contractions does not permit the rel-ative contribution of mechanically and metabolically sensitivemuscle afferents to be dissected.

Passive limb movement and external compression havebeen employed to experimentally activate mechanically sen-sitive muscle afferents, without engaging those that aremetabolically activated. The relative strengths and weak-nesses of the approaches used to investigate the influenceof human muscle mechanoreceptors on cardiac autonomiccontrol have been reviewed in detail elsewhere (163). Passivehindlimb stretch in cats evokes an increase in HR associatedwith transient cardiac sympathetic nerve activation and a moresustained reduction in parasympathetic activity (205, 226).Studies in humans utilizing medical anti-shock trousers tocompress the limbs (381) and passive muscle stretch (17) havereported no effect on HR. However, HR was shown to increase




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during 4 s of passive leg cycling movements (231), whileWilliamson et al. (382) demonstrated that when passive legcycling movements were combined with percutaneous elec-trical stimulation and triggered early enough in the cardiaccycle (first one-third) an instantaneous increase in HR waselicited. Subsequent to this Coote and colleagues (109, 110)demonstrated that passive calf muscle stretch evoked a tran-sient HR increase that was accompanied by a reduction in HRvariability and abolished with prior administration of glycopy-rrolate (Fig. 10). Thus, despite some evidence to the contrary,it appears that activation of mechanically sensitive muscleafferents in humans can increase HR via inhibition of cardiacparasympathetic activity. However, it is pertinent to note thatof the mechanically sensitive group III muscle afferents thatrespond to tendon stretch, only ∼50% have been shown torespond during an isometric muscle contraction (132).

The influence of the muscle mechanoreflex on periph-eral SNA is arguably less well understood than its influenceon cardiac autonomic control. Animal studies have identifiedthat the muscle mechanoreflex increases renal (175, 352) andmuscle (140) SNA. In humans, Herr et al. (135) reported thatmuscle SNA increases at the onset of isometric quadricepscontractions at 25% maximum voluntary contraction with alatency of 4-6 seconds. While the short latency of this responseis indicative of a muscle mechanoreflex effect, a contributionfrom central command and/or the muscle metaboreflex can-not be excluded. Isolated muscle mechanoreflex activationin humans, induced by passive dynamic forearm stretch, hasbeen reported to evoke a slight transient increase in muscleSNA with a latency of 1 to 3 s (46). Thus, it appears thatthe muscle mechanoreflex evokes rapid, albeit modest, auto-nomic alterations at the level of both the heart and skele-tal muscle vasculature, and thus contributes to the initialcardiac and hemodynamic responses to exercise in healthyhumans.

Skeletal muscle mechanoreflex during steady-stateexercise

Following an initial burst of activity at the onset of a tetaniccontraction the discharge rate of mechanically sensitive groupIII skeletal muscle afferents typically decreases if the contrac-tion is nonfatiguing (163, 217). However, the discharge rateof these afferents rises or falls with a respective increaseor decrease in isometric tension, and their discharge canbecome synchronized to electrically evoked intermittent iso-metric tetanic contractions (163, 217). Furthermore, duringlow-intensity dynamic exercise induced by mesencephaliclocomotor region stimulation in cats muscle mechanorecep-tor activity becomes synchronized with step cycle (2). Suchobservations highlight the potential importance of musclemechanoreceptors to autonomic control not only at the onsetof exercise, but also during steady-state dynamic exercise at alow intensity. However, studies in humans using lower bodypositive pressure have suggested that intense mechanorecep-tor stimulation is needed to evoke a mechanoreflex medi-ated increase in muscle SNA (101, 102). Overall, additionalresearch is needed to delineate the contribution of mechanore-flex to muscle SNA, particularly during dynamic exercise.

During a fatiguing isometric contraction at a constanttension the activity of muscle mechanoreceptors typicallyincreases, possibly due to the accumulation of metabolic by-products within the muscle (165). This sensitization effectis also evident from studies showing that mechanoreceptordischarge is potentiated by ischemia or substances such asbradykinin, arachidonic acid, ATP, or cyclooxygenase prod-ucts (3, 165, 228). Work examining the potential importanceof muscle mechanoreceptor sensitivity on autonomic controlin humans is limited. Fisher and colleagues (84) investigatedwhether the HR and BP responses to passive calf stretch werepotentiated when performed during postexercise ischemia,a period in which the concentration of metabolites withinthe muscle is elevated. The magnitude of both the HR andBP response to passive stretch was the same irrespective ofwhether muscle metabolites were elevated or not. In con-trast, Cui et al. (47) reported that when static passive wristextension stretch was applied during postexercise ischemiafollowing fatiguing handgrip exercise significant increases inmuscle SNA and BP were evoked, whereas no change in mus-cle SNA or BP were observed when wrist extension was con-ducted under free-flow conditions. Although, no HR responseto static passive wrist extension was observed under eithercondition, the sensitization effect on muscle SNA and BP wassubsequently shown to be diminished following cyclooxyge-nase inhibition (48). The reason for the conflicting findings ofFisher et al. (84) and Cui et al. (47) may relate to differencesin muscle group (calf, forearm), exercise mode (nonfatiguing,fatiguing) or method used to induce passive stretch.

Collectively, these observations imply that the accumula-tion of metabolites within the skeletal muscle during steady-state exercise can sensitize the mechanically sensitize skeletalmuscle afferents, most likely leading to an increase in muscle




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Figure 11 Activation of group III and IV skeletal muscle afferents during dynamic exer-cise induced by stimulation of the mesencephalic locomotor region in cats. Cumulativehistograms for 24 group III afferents (A) and 10 group IV afferents (B) before, during, andafter dynamic exercise. The exercise period is denoted by horizontal bars. These findingsdemonstrate that low-intensity dynamic exercise stimulated both Group III and IV skeletalmuscle afferents. Imp, impulses. Reprinted, with permission, from (2).

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

Skeletal muscle metaboreflex at exercise onset

While the thin fiber skeletal muscle afferents respond tomechanical distortion and therefore, typically respond imme-diately at the onset of muscular contraction, those respon-sive to metabolic perturbation respond with a longer latency(163). These observations, along with the time delay for theaccumulation of most metabolites during exercise, means thecontribution of muscle metaboreceptors to autonomic reg-ulation is generally believed to be minimal at the onset ofexercise. However, the studies of Kaufman and colleagueshave illustrated that both group III and group IV skeletalmuscle afferents are engaged during short duration (60 sec-onds) low-intensity dynamic exercise and that their dischargeis coupled to the rhythmical contraction of the working mus-cles (2, 3) (Fig. 11). These direct afferent recordings suggestthat the Group IV afferents have the potential to contribute tothe autonomic responses in early exercise, prior to the gener-ation of a substantial metabolic “error signal.” Nevertheless,central command is traditionally viewed as setting the initialautonomic response to exercise, and if the exercise pressorreflex is involved at exercise onset it would likely be throughmechanically sensitive group III afferents. A caveat to thisviewpoint is that studies in humans isolating the contribution

of muscle metaboreceptors to the initial autonomic responsesto exercise are lacking. This likely has to do with the com-plexity of onset kinetics in regards to neural interactions andthe robust nature of the cardiovascular responses with theinitiation of exercise.

Skeletal muscle metaboreflex during steady-stateexercise

The first attempt to experimentally isolate the contributionof the skeletal muscle metaboreflex to the cardiovascularresponse to exercise was made by Alam and Smirk (5). Ina landmark study, subjects performed rhythmic forearm andcalf contractions, first under free-flow conditions and secondwith circulation to the limb occluded such that they wereischemic both during and following exercise (see Fig. 9). Thepostexercise ischemia maneuver trapped the exercise-inducedmetabolites within the previously active muscle, thus preserv-ing their stimulatory effect on metabolically sensitive skeletalmuscle afferents in the absence of the muscle mechanore-flex or central command. This maneuver, first performedwith direct muscle SNA measures by Allyn Mark, GunnarWallin, and colleagues, has been used in numerous stud-ies to investigate the muscle metaboreflex in humans. Con-sistently, during postexercise ischemia, the exercise-inducedincrease in BP and muscle SNA remain robustly elevated (seeFig. 4) (198), whereas the HR response appears to depend




significantly on the muscle mass and/or exercise modalitystudied (4, 96). Indeed, HR returns toward baseline levelsduring postexercise ischemia following rhythmic or isomet-ric handgrip (87, 198, 230), static leg extension (149), andisometric calf plantar flexion (89). In contrast, HR is ele-vated above baseline during postexercise ischemia followingrhythmic calf plantar flexion (4) and cycling (96, 128) withboth legs. Such findings imply that the autonomic control ofthe heart is differentially modified during these maneuvers.In addition, the intensity of the preceding exercise and thus,magnitude of metaboreceptor activation during postexerciseischemia can also play a role in the degree to which HR isaffected by the muscle metaboreflex. This is likely due to theintensity dependence of cardiac sympathetic activation via themetabolically sensitive afferents (87).

As the muscle metaboreflex activation is a potent stimulusof the sympathetic nervous system it is seemingly incongruousthat in many circumstances HR remains at baseline values dur-ing postexercise ischemia (87,149,198,230). Part of the expla-nation for this seems to be the loss of the powerful inhibitoryinput from central command (224) and muscle mechanoreflex(110) to cardiac parasympathetic preganglionic nuclei uponthe cessation of exercise. In addition, the excitatory input tothese nuclei is likely increased as a consequence of arterialbaroreceptor stimulation resulting from the robust elevation

in BP during postexercise ischemia. As originally demon-strated in dogs (238), and more recently in humans (87),the activation of cardiac parasympathetic activity at this timecan overpower a potential sympathetically mediated elevationin HR. Indeed, O’Leary (238) reported that during postex-ercise ischemia following treadmill exercise in canines HRreturned toward baseline levels under control (no drug) con-ditions, whereas with the administration of atropine to blockcardiac parasympathetic activity HR remained at the levelobserved during exercise. Thus with the cardiac parasympa-thetic activity removed a sympathetically mediated elevationin HR elicited by the muscle metaboreflex was seeminglyrevealed. In humans, cholinergic muscarinic blockade withglycopyrrolate unmasked an elevation in HR during postex-ercise ischemia following low intensity handgrip (87). Thisdirect pharmacological evidence (Fig. 12) supported earlierwork showing increases in HR variability derived indices ofboth cardiac parasympathetic (230) and sympathetic (149)nerve activity during postexercise ischemia in humans.

As mentioned above, an elevation in HR with postexerciseischemia is observed following some modes of exercise.We have reported a modest HR elevation during postex-ercise ischemia subsequent to moderate intensity handgrip(40% maximum voluntary contraction for 2 min) thatwas eliminated with β-adrenergic blockade (87) (Fig. 12).

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Figure 12 HR responses to isometric handgrip (IHG) and postexercise ischemia (PEI) under control conditions(black symbols), and following β-adrenergic blockade (light gray symbols) and parasympathetic blockade (darkgray symbols). HR during all experimental phases (A) and change (�) in HR from rest (B) are shown. PEI-M, PEIfollowing 25% IHG; PEI-H, PEI following 40% IHG. ∗P < 0.05 versus exercise, †P < 0.05 versus control, ‡P < 0.05versus β blockade, #P < 0.05 versus 25% MVC. Reprinted, with permission, from (87).




Thus, it appears that strong activation of the muscle meta-boreflex may increase cardiac SNA to an extent that canovercome a reactivation of cardiac parasympathetic activity.Intriguingly, HR variability analysis indicates that elevationsin HR during postexercise ischemia following leg cyclingare associated with reductions in cardiac parasympatheticactivity (128). However, pharmacological investigations haveshown that this HR elevation persists with either muscarinicor β-adrenergic blockade, implying a redundancy in the sym-pathetic and parasympathetic control of the heart under theseconditions (83).

The role of the muscle metaboreflex in cardiac auto-nomic control has also been evaluated by the occlusion orpartial occlusion of perfusion to the exercising skeletal mus-cles. Unlike postexercise ischemia, however, this maneuverengages the muscle metaboreflex whilst central commandand muscle mechanoreceptors are also activated. Experimen-tal hypoperfusion in exercising dogs (238) and humans (83)can evoke a robust increase in HR that is attenuated by β-adrenergic blockade and not affected by cardiac parasym-pathetic blockade. However, as β-adrenergic blockade doesnot entirely block this response (83, 238) and as HR vari-ability derived estimates of cardiac parasympathetic activityare reduced during leg cycling with restricted flow (128), theability of the muscle metaboreflex to inhibit cardiac parasym-pathetic activity cannot be entirely ruled out. Intriguingly,increases in HR during electrically evoked cycling exercise inindividuals with spinal cord injury (no afferent feedback) areattenuated by the inflation of thigh cuffs to restrict blood flowto and from the active limbs (173). This perhaps indicatesa role for blood borne factors released from active skeletalmuscle on the HR responses to exercise.

Rather than the augmentation of skeletal muscle afferentactivation during exercise an alternative approach is to phar-macologically block or inhibit their activity. Administrationof an epidural anesthetic to partially block skeletal muscleafferent feedback has been used in a number of investiga-tions (82, 95, 99, 223, 302, 316). While a diminished HR andBP response to exercise can result (223), indicative of theimportance of skeletal muscle afferents to the normal cardio-vascular response to exercise, this has not been a consistentfinding, possibly due to variations in the depth of analgesia andconfounding effects on efferent neuromuscular control (302).Likewise, this may have to do with the mode of exercise.Although epidural anesthesia caused clear reductions in HRand BP responses to static handgrip (223), a blunting of theBP but not the HR response has been shown during dynamicexercise (172, 326). An important caveat to epidural anesthe-sia usage is the muscle “weakness” induced likely means thatcentral motor drive and thus central command are enhancedto produce a fixed workload. However, this limitation maybe circumvented by the pharmacological agonism of spinalopioid receptors, thus modulating the ascending activity ofskeletal muscle afferent feedback without affecting centralmotor drive (386). In exercising dogs, intrathecal adminis-tration of the opiate agonist morphine virtually abolishes the

HR and BP responses to unilateral iliac arterial occlusion(253), while agonism of spinal opioid receptors also attenu-ates the exercise reflex pressor in cats (141). In humans it hasbeen reported that HR and BP is reduced during leg cyclingat moderate-to-high workloads following lumbar intrathecaladministration of fentanyl, a morphine analogue and selectiveμ-opioid receptor agonist, to partially block lower limb mus-cle afferents (7, 247). Similar results were recently reportedduring single leg knee extensor exercise following fentanyladministration (8). However, the autonomic basis for suchchanges remains to be determined. Nevertheless, the avail-able evidence indicates that the major effect of metabolicallyskeletal muscle afferents on HR occurs via an increase incardiac SNA whereas the effect on cardiac parasympatheticactivity is more minor (83, 87, 149, 230, 238).

Unlike the more subtle influence the metaboreflex hason cardiac SNA, there is unequivocal data to support therobust effect metaboreceptors have in increasing muscle SNA.Numerous studies using postexercise ischemia to isolate themuscle metaboreflex or experimental restriction of activemuscle perfusion to augment muscle metaboreflex activa-tion, have demonstrated large intensity-dependent increasesin muscle SNA and BP. However, the specific chemical prod-uct(s) that activate metabolically sensitive muscle afferentsremains controversial (162, 164, 219, 220, 315). This litera-ture has been reviewed in detail by others, but some dis-cussion is warranted due to the robust nature in which themetaboreflex stimulates muscle SNA. Several of the metabo-lites produced by muscular work that have been targetedas candidates for the activation of the muscle metabore-flex during exercise in humans include, but are not lim-ited to lactic acid, potassium, adenosine, arachidonic acid,diprotonated phosphate, prostaglandins, and hydrogen ion(81, 91, 122, 274, 311, 331, 350, 375). However, equivocalresults have been reported for most of these candidates withstudies supporting and refuting the involvement of each sub-stance to some degree. For example, studies using individ-uals who produce minimal amounts of lactic acid due to amyophosphorylase enzyme deficiency (i.e., McArdle’s dis-ease) have indicated that the BP and muscle SNA responsesto static handgrip are markedly attenuated compared to nor-mal healthy subjects (79, 260) suggesting that the produc-tion of lactic acid is requisite for the full expression ofthe muscle metaboreflex (Fig. 13). However, even withinthis unique patient population disparate results have beenreported (356, 357), although it should be noted that Kauf-man and colleagues have demonstrated a major role for lacticacid in stimulating skeletal muscle afferents through acid-sensing ion channel receptors (ASIC) (131, 210). In regardsto the latter, there is an accumulating body of research exam-ining the receptors responsible for activating metabolicallysensitive skeletal muscle afferents with a role for transientreceptor potential vanilloid 1 receptors, purinergic receptorsand the CB1 cannabinoid receptor along with ASIC recep-tors (120, 190, 376). There is also now research focusing onthe central integration of this afferent information. However,




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Figure 13 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 timeto fatigue. (B) Summary data showing MSNA, mean arterial pressure (MAP) and HR responses during fatiguing handgripfollowed by postexercise forearm ischemia and recovery. The MSNA response to exercise was severely blunted in theMcArdle’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 theinterested reader is directed to some excellent recent reviews(162, 164, 219, 220, 315).

In an intriguing recent study, Pollak et al. (252) infusedmetabolites known to be produced during exercise into theabductor pollicis brevis muscle of the hand of healthy humans.Although the sensations of skeletal muscle fatigue and painwere the main outcome variables of this study, rather thancardiovascular or autonomic responses, this approach holdsgreat promise to further probe the metabolite(s) responsiblefor stimulating skeletal muscle afferents and evoking the exer-cise pressor reflex mediated cardiovascular response. Inter-estingly, the infusion of individual metabolites at maximalamounts evoked no fatigue or pain and it was only when acombination of metabolites was infused did the subjects reportsensations of fatigue or pain. These findings suggest that it isa combination of substances that excite metabolically sensi-tive skeletal muscle afferents. Indeed, as the research in thisarea continues, this is the most probable scenario to evolve inregards to the cardiovascular responses evoked by the musclemetaboreflex, and there is likely also, redundancy that existsamong the metabolites capable of stimulating skeletal muscleafferent fibers.

Emerging evidence also indicates that metabolically sen-sitive afferent fibers emanating from respiratory muscles mayplay a role in increasing sympathetic outflow during exercise.Indeed, unmyelinated nerve fibers are present in the phrenicnerve (62) and prolonged heavy intensity exercise in rats hasbeen shown to elevate diaphragm lactic acid concentrations

(and likely other metabolites) several fold above basal levels(94). In anesthetized animals, type IV phrenic afferents areactivated during fatiguing diaphragm contractions (139),whereas chemical stimulation of phrenic afferents elicitsincreases in HR, BP, and reduces blood flow in renal andmesenteric arterial vascular beds (145). Thus, a respiratorymetaboreflex could be activated during prolonged high-intensity exercise in which a fatiguing diaphragm and otherrespiratory muscles lead to an accumulation of metabolicbyproducts (53, 119). However, isolating the effect of a res-piratory metaboreflex, particularly during exercise, is techni-cally challenging in humans. A series of studies pioneered byDempsey and colleagues utilized a novel approach in which amechanical ventilator was used to reduce the amount of respi-ratory muscle work during exercise, and thus, the stimulationof the respiratory metaboreflex. Interestingly, an increase inactive skeletal muscle blood flow was found when diaphragmfatigue was prevented during maximal exercise (125, 126),whereas no changes in leg blood flow and vascular resistancewas seen during respiratory muscle unloading at submaximalexercise intensities (373). While the autonomic mechanismsinvolved in these changes remains unclear, vasoconstrictionin active skeletal muscle of dogs due to stimulation ofphrenic afferents with lactic acid was prevented by combinedα- and β-adrenergic blockade (273). Moreover, underresting conditions, fatiguing the respiratory muscles leads toincreases in muscle SNA (317) and decreases leg blood flowand vascular conductance (305,306). Thus, although more in-depth investigations are needed, the respiratory metaboreflex




Figure 14 Schematic illustration depicting the afferent and efferent neural responses ofthe arterial baroreceptors. Reductions in BP in the carotid sinus and aortic arch are sensed bythe baroreceptors eliciting decreases in afferent nerve firing. This reduction in neural input tothe 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 sensedby the baroreceptors and bring BP back to its original value. The converse occurs when thebaroreceptors are exposed to an increase in BP. Adapted, with permission, from (76).

appears to mediate increases in sympathetic vasoconstrictoroutflow at high-intensities of exercise, likely as a means toredirect exercising muscle blood flow to fatiguing respiratorymuscles.

Arterial baroreflexThe arterial baroreflex plays a major role in the autonomicand ultimately BP adjustments that accompany acute cardio-vascular stressors, including exercise. A number of animaland human investigations have been performed in an effortto identify the components of the baroreflex arc, establishingthe basis for our current understanding of arterial barorecep-tor anatomy, neural processing and function (197, 278, 304).Briefly, the carotid and aortic baroreceptors are comprisedof unencapsulated free nerve endings located at the medial-adventitial border of arteries in the carotid sinus bifurcationand aortic arch (278, 304) that function as the sensors in anegative feedback control system (138). Alterations in BPcause a conformational change in the baroreceptors leadingto changes in afferent neuronal firing. A branch of the glos-sopharyngeal nerve, the Hering nerve, carries impulses fromthe carotid baroreceptors, while small vagal branches carryimpulses from the aortic baroreceptors. These afferent sig-nals converge centrally within the NTS of the medulla oblon-gata. When BP is elevated, the baroreceptors are stretched andthis deformation causes an increase in afferent neuronal firing,which results in a reflex-mediated increase in parasympathetic

nerve activity and decrease in SNA. Conversely, when BP islowered, afferent firing is reduced, resulting in a decrease inparasympathetic nerve activity and an increase in SNA. Inboth cases, the autonomic adjustments will affect both theheart and the blood vessels altering cardiac output and vascu-lar conductance, respectively (76,158,263), and returning BPto its original set point value (138) (Fig. 14).

Although initially debated, the fundamental role of thearterial baroreflex to the autonomic adjustments to exercise isnow well established. It has been demonstrated in both ani-mals (40,364,365) and healthy subjects (19,76,249,258,263)that during exercise the arterial baroreflex continues to reg-ulate BP by resetting to operate around the exercise-inducedelevation in BP. Moreover, there is convincing evidencethat a properly functioning arterial baroreflex is requisitefor an appropriate neural cardiovascular response to exer-cise (54, 293, 312, 342, 365). In this regard, previous studieshave reported that acute baroreceptor denervation leads to anexaggerated increase in BP in exercising dogs (51, 365, 366).Similarly, in humans who have surgically denervated carotidbaroreceptors, 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 BPresponse to exercise by buffering increases in SNA producedby activation of central command and the exercise pressorreflex (14, 35, 158, 307). This concept is substantiated by thegreater increase in muscle SNA and HR observed during




handgrip in young healthy subjects when arterial baroreflexactivation is prevented by pharmacologically clamping BPat resting values and negating the exercise-induced rise inBP (293). Thus, impaired arterial baroreflex function (i.e.,decreased sensitivity or gain) can lead to altered neural car-diovascular responses during exercise indicating that an oper-ational baroreflex is necessary for the appropriate autonomicand cardiovascular response to exercise. Overall, there is con-siderable research demonstrating that the arterial baroreflexcontributes importantly to the autonomic responses to exer-cise and as such, plays a major role in mediating the neuralcardiovascular adjustments to exercise.

Arterial baroreflex at exercise onset

While, much more is known about arterial baroreflex regula-tion under steady-state exercise conditions, a functional arte-rial baroreflex appears necessary for evoking the appropriatecentral cardiovascular and peripheral circulatory adjustmentsin the transition from rest to exercise (54). The magnitude ofR-R interval lengthening in response to carotid baroreceptorstimulation in the decerebrate cat is attenuated by electricallyevoked hindlimb contraction (213) or selective activation ofgroup III and IV skeletal muscle afferents (214). In contrast,the magnitude of the fall in HR in response to aortic depressornerve stimulation in decerebrate cats was similar at rest andthe onset of both electrically evoked muscle contraction andmuscle stretch (227). However, the bradycardic response toaortic depressor nerve stimulation was transiently attenuatedat the onset of volitional isometric exercise in conscious cats,but restored later in exercise (177, 200, 227). Taken togetherthese findings suggest that the activation of central commandand/or skeletal muscle afferents can inhibit baroreflex regu-lation of HR via the parasympathetic nerves at the onset ofexercise.

Limited work has examined whether arterial baroreflexfunction is modified in humans during the transition from restto exercise. We noted a transient attenuation of the magnitudeof the fall in HR in response to carotid baroreceptor loading(neck suction, −60 mmHg) at the immediate onset (∼1 s) ofhigh intensity handgrip (45%-60% MVC), but not during low-moderate intensity handgrip (15%-30% MVC). Attributionof the blunted baroreflex responsiveness observed to eitherthe activation of central command or the muscle mechanore-flex is not presently possible, as the activation of both wouldbe expected to be graduated with exercise intensity. How-ever, in an attempt to understand the mechanism involved weperformed carotid baroreceptor loading (neck suction, −60mmHg) during the anticipation of isometric handgrip exer-cise. Intriguingly, we noted a blunting of the magnitude ofthe reduction in HR evoked by neck suction when deliveredimmediately prior to handgrip (Fig. 15). Given the lack ofmuscle mechanoreflex or metaboreflex activation at this timeone presumes a central mechanism is responsible, althoughinterestingly this effect was only observed in the first twoof 4 trials, indicative of a habituation response. Although, it

Figure 15 Anticipation of exercise blunts carotid baroreflex medi-ated HR responses. Summary data showing the HR responses to necksuction (NS) at −60 Torr performed at rest and in anticipation of iso-metric handgrip exercise during four repeat trials. This anticipatoryperiod was used to isolate feedforward central command input in theabsence of any feedback from skeletal muscle. To create an anticipa-tory period, subjects were instructed that immediately after the cessationof NS they must take hold of the handgrip dynamometer and start exer-cising as rapidly as possible at 45% MVC and sustain the contractionfor 1 min. Although a clear blunting of carotid-cardiac responses wasobserved in the first two trails, a habituation in the response was found.∗ represents P < 0.05 versus rest. Unpublished observations made bythe authors.

is interesting to note that passive calf stretch to selectivelyactivate the muscle mechanoreflex has also been shown toattenuate the HR response to carotid baroreceptor loading inhumans (−30 mmHg, neck suction) (110). Finally, it remainsto be determined whether such modulation of arterial barore-flex responses at the onset of exercise in humans is attributableto 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) inconscious rabbits identified the importance of an immediatebaroreflex resetting in mediating the increases in renal sym-pathetic outflow, BP, and HR at the onset of exercise. Thus, arapid baroreflex resetting appears requisite to the initiation ofthe autonomic response to exercise and subsequent hemody-namic and cardiovascular adjustments.

Arterial baroreflex during steady-state exercise

During steady-state dynamic exercise the arterial barore-flex stimulus-response relationship is reset to function aboutthe established BP and in general, the baroreflex main-tains its ability to regulate BP as effectively as during rest(19,40,216,249,258). It was Bevegard and Shepherd (19) whoinitially reported that carotid baroreflex regulation was main-tained during exercise in humans. These investigators demon-strated that HR, BP, and vascular conductance responses tosimulated carotid sinus hypertension with the applicationof neck suction were similar during exercise compared tothose observed at rest. Subsequently, Melcher and Donald




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Figure 16 A schematic summary of carotid baroreflex resetting thatoccurs from rest to heavy exercise. In general, the carotid baroreflexfunction curve for HR, muscle SNA, and MAP is progressively reset fromrest to heavy exercise. However, the functional characteristics of thestimulus-response curve differ depending on the dependent variablestudied. See text for details.

(216) constructed full stimulus-response curves of the iso-lated carotid baroreceptors in chronically instrumented exer-cising dogs and were the first to demonstrate that the barore-flex function curve was reset by exercise to operate around theprevailing BP without a change in reflex sensitivity. Potts et al.(258) confirmed these findings in humans using the variablepressure neck chamber to simulate carotid hypotension (neckpressure) and hypertension (neck suction). These investiga-tors demonstrated that the carotid baroreflex was reset duringupright dynamic leg cycling to functionally operate aroundthe exercising BP without a change in sensitivity. Numerousstudies followed that have confirmed and extended these ini-tial findings, demonstrating that baroreflex resetting occurs indirect relation to the intensity of exercise from rest to maxi-mum (Fig. 16) (77,105,106,232,233,242,249). Although thevariable pressure neck chamber, which selectively describescarotid baroreflex function, has been the primary method usedto examine exercise resetting in humans, the assumption ismade that the aortic baroreflex operates in parallel with thecarotid baroreflex and therefore will similarly respond andreset with exercise (76, 263).

Arterial baroreflex resetting during exercise has beendemonstrated to occur due to the interactive effects of centralcommand (106, 148, 212, 246) and sensory feedback frommetabolically and mechanically sensitive skeletal muscleafferents [i.e., exercise pressor reflex; (90,105,148,212,316)].Raven and colleagues undertook an important series of exper-imental studies in humans that discerned the roles for centralcommand and the exercise pressor reflex in the exercise reset-ting of the baroreflex. This work, which was performed to testa hypothesis originally put forth by Rowell and O’Leary, hasbeen comprehensively outlined in several reviews (76,78,263)and so will only be briefly covered here. Importantly, althoughit is clear that both the carotid-cardiac and carotid-BP (i.e.,vasomotor) curves are reset with exercise to operate at theprevailing BP there are some differences in baroreflex control

of HR and BP that deserve discussion. Indeed, studies havedemonstrated that both central command and the exercisepressor reflex are capable of inducing a bi-directional right-ward and upward shift of the carotid-BP curve through afacilitative interaction (76, 78, 263). Moreover, this exerciseresetting occurs without a change in maximal gain or operat-ing point gain such that the control of BP is well maintained.In contrast, while central command is capable of relocatingthe carotid-cardiac baroreflex stimulus-response curve bothrightward and upward, it appears that input from the exercisepressor reflex contributes to a rightward shift only. In addition,although resetting of the carotid-cardiac baroreflex functioncurve during exercise is accompanied by a preservation ofmaximal gain (i.e., sensitivity), the gain at the operating point(i.e., point about which HR is regulated) is reduced. This isassociated with movement of the operating point away fromthe centering point (i.e., region of maximal gain) and towardthe reflex threshold (243). “Spontaneous” cardiac baroreflexsensitivity (cBRS), calculated from the dynamic fluctuationsin BP and HR (e.g., sequence technique), is associated withthe operating point gain and also decreases during dynamicexercise (86, 243, 288, 289).

Ogoh et al. (243), using separate cholinergic (muscarinic)and β1-adrenergic blockade, demonstrated that the reduc-tion in spontaneous cBRS and operating point gain of thecarotid cardiac baroreflex function curve during steady-statedynamic exercise were attributable to a reduction in car-diac parasympathetic activity. Since central command and themuscle mechanoreflex have been implicated in the withdrawalof cardiac parasympathetic activity during exercise (110,224),they may reasonably be considered as prime candidates formediating exercise-induced changes in baroreflex sensitivity.Indeed, Iellamo et al. (148) reported that spontaneous cBRSwas reduced during low intensity electrically evoked exerciseunder free-flow conditions, and given that central commandwas bypassed and muscle metaboreflex activation minimal, arole of the muscle mechanoreflex was postulated. On the otherhand, Gallagher and colleagues (106) noted that partial neuro-muscular blockade to enhance central command during exer-cise evoked a reduction in operating point gain of the carotidcardiac baroreflex function curve. Thus, it appears likely thatinput from both central command and muscle mechanorecep-tors can contribute to the relocation of the operating pointgain on the carotid cardiac baroreflex function curve duringdynamic exercise and the resultant reduction in cBRS that hasalso been observed with spontaneous cBRS measures.

In contrast, neither spontaneous cBRS (149) nor thegain at the operating point of the carotid cardiac baroreflexfunction curve are altered during isolated muscle metabore-flex activation with postexercise ischemia following handgrip(90). However, when the muscle metaboreflex is activated byhypoperfusing a large mass of dynamically exercising skele-tal muscle in either canines (288, 289) or humans (127, 128),a reduction in spontaneous cBRS is observed. The reasonfor these apparently discrepant findings likely relates to dif-ferences among these protocols in the prevailing levels of




cardiac autonomic activity and degree of input from neuralcontrol mechanisms. Indeed, during postexercise ischemiathe loss of inhibitory input from central command and musclemechanoreflex and/or baroreflex activation once exercise hasceased would lead to a relative increase in cardiac parasym-pathetic activity (230, 238) that could mask a muscle meta-boreflex mediated reduction in cBRS as noted earlier in thisreview for metaboreflex-mediated HR responses. In addition,it remains a matter of debate whether the partial restrictionof blood flow to the exercising muscle; (i) increases centralcommand along with the muscle metaboreflex (179,253), (ii)causes an attenuation of cBRS by directly reducing cardiacparasympathetic activity or via an indirect mechanism (225),and (iii) reduces the operating point gain or maximal gain ofthe full stimulus-response function curve. It is also possiblethat during exercise the accumulation of metabolites withinthe exercising skeletal muscles sensitizes mechanically sen-sitive muscle afferents that are known to modulate cardiacparasympathetic activity. However, Drew et al. (60) observedthat the magnitude of the passive calf stretch mediated reduc-tion in cBRS was no different when performed during postexercise ischemia following calf exercise at 0%, 30%, 50%,and 70% MVC to grade the concentration of metaboliteswithin the muscle. Nevertheless, the presently available evi-dence implicates central command, the muscle mechanoreflexand the muscle metaboreflex in the exercise induced reset-ting of the carotid-cardiac baroreflex function curve and theaccompanying reduction in operating point gain and sponta-neous cBRS, although the relative contribution of each likelyvaries as a function of the exercise modality studied.

In contrast to the extensive body of work examining thearterial baroreflex in terms of its sensitivity (i.e., gain), its tem-poral response pattern (i.e., latency) has received less atten-tion. A delay in the latency of the peak cardiac baroreflexresponse has previously been reported during dynamic exer-cise in young individuals (193, 325), although this has notbeen a universal finding (256). Sundblad and Linnarsson (327)proposed that this delay resulted from an exercise-inducedincrease in sympathetic activation. More recently, pharma-cological antagonism of cardiac parasympathetic control hasbeen reported to prolong the latency of the peak carotid-HRresponse (85,167), thus raising the possibility that withdrawalof cardiac parasympathetic tone may account for the moresluggish cardiac-baroreflex responses during exercise.

Studies in both animals and humans have also investi-gated the means by which the arterial baroreflex mediateschanges in BP both at rest and during exercise. In otherwords, given that BP is the product of cardiac output and totalperipheral resistance, how much does the arterial baroreflexrely on changes in HR and stroke volume (i.e., cardiac out-put) compared to total vascular resistance or conductance tomodulate BP. Several studies that have examined the relativecontribution of changes in cardiac output and total vascu-lar conductance to carotid baroreflex-mediated changes inBP demonstrated that the capacity of the carotid baroreflexto regulate BP depends almost exclusively on its ability to

alter total vascular conductance both at rest and during exer-cise (35, 241, 242). In fact, although at rest approximately25% of the carotid baroreflex-mediated BP response couldbe attributed to changes in cardiac output, during exercise theability of the carotid baroreflex to control BP was solely relianton reflex-mediated changes in peripheral conductance (242).This critical reliance of the baroreflex on vascular changeswas not significantly altered by subject posture (241). Similarfindings indicating the dominance of alterations in vascu-lar conductance contributing to carotid baroreflex-mediatedchanges in BP have been identified in the dog using bilateralcarotid occlusion at rest and during treadmill exercise (35).Thus, the ability of the arterial baroreflex to regulate BP iscritically dependent on alterations in vascular tone both at restand during exercise.

Considering that the neural stimulus from the arterialbaroreflex to the vasculature is the sympathetic nervoussystem, an understanding of baroreflex control of sympa-thetic outflow is critical. Although technically challenging todirectly assess sympathetic outflow in humans during physi-cal activity due to the associated movement, the application ofthe microneurography technique to measure baroreflex con-trol of muscle SNA during exercise has provided some veryinsightful and important information. In this regard, the func-tional characteristics of the baroreflex control of SNA havebeen shown to dynamically change throughout a given bout ofexercise to allow for the effective modulation of BP (Fig. 17)(147,161). Ichinose et al. (147) reported that along with a pro-gressive resetting of the muscle SNA-diastolic BP relation-ship during 3 min of handgrip, a time-dependent increase inmuscle SNA baroreflex sensitivity occurred. These findings ofdynamic temporal changes in the baroreflex control of muscleSNA have been extended to dynamic exercise as well how-ever; the intensity of exercise may be of greater importance forinducing changes in muscle SNA baroreflex sensitivity (245).Indeed, in humans the carotid baroreflex control of muscleSNA appears preserved during moderate-intensity one-leggedkicking and arm cycling exercise (77,166,245), whereas dur-ing moderate to high intensity leg cycling an increase in arte-rial baroreflex-muscle SNA gain has been observed (146).In general agreement, the sensitivity of the arterial barore-flex control of renal SNA has been shown to be increasedduring high-intensity (90% maximal HR) treadmill exercisein conscious rats (218). Collectively, these studies indicatea progressive resetting of the baroreflex control of SNA tooperate around the exercise-induced elevations in BP with amaintained or increased sensitivity depending on the inten-sity of the exercise performed. Thus, the arterial baroreflexcontrol of sympathetic outflow is well maintained throughouta bout of exercise.

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




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Figure 17 Progressive resetting of the arterial baroreflex control ofmuscle SNA (MSNA) in the transition from rest to steady-state two armcycling exercise. (A) Summary data showing the average operatingpoints (•) with the corresponding mean linear regression lines relatingMSNA burst incidence and diastolic BP at rest, unloaded exercise (EX),initial 50% EX, and later 50% EX. (B) Group summary data for the slopesof the linear regression lines between MSNA burst incidence and dias-tolic BP (i.e., arterial baroreflex sensitivity). These findings indicate thatbaroreflex control of MSNA is well maintained throughout dynamicexercise in humans, progressively being reset to operate around theexercise-induced elevations in BP without any changes in reflex sen-sitivity. See text for further details. Reprinted, with permission, from(245).

(C-fibers) in response to changes in central venous pressureand volume (197). The loading of these cardiopulmonaryreceptors exerts a reflex inhibition of sympathetic adrener-gic activity to several vascular beds and conversely theirunloading evokes a marked increase in SNA. The experimen-tal approaches utilized to evaluate cardiopulmonary barore-ceptor function have been reviewed in detail elsewhere (197)and will be discussed sparingly here.

Cardiopulmonary baroreflex at exercise onset

Callister et al. (30) specifically evaluated the muscle SNA(radial nerve at elbow) responses to 1 min of upright legcycling at submaximal workloads ranging from approxi-mately 10% to 80% of peak aerobic power (Fig. 18). Irre-spective of workload, a marked reduction in muscle SNA wasobserved during the preparation for and at the onset of exer-cise, while muscle SNA did not increase until 40 to 60 s ofexercise at the highest workload. While the suppression ofmuscle SNA in anticipation of exercise may be related to themild cognitive effort or arousal associated with the task (31),as described in detail below, the inhibition of muscle SNA atthe onset of dynamic exercise is likely linked to a loading ofthe cardiopulmonary baroreceptors.

Cardiopulmonary baroreflex during steady-stateexercise

The observation that HR is typically lower during dynamicexercise performed in a supine position compared to anupright position provided an early indication that changesin central blood volume and cardiopulmonary loading mayinfluence the cardiovascular response to steady-state exercisein humans (320). The earliest studies specifically examiningthe functional significance of the cardiopulmonary baroreflexon the autonomic adjustments to exercise during exercise inhumans typically employed handgrip exercise. Walker et al.(1980) reported that low intensity isometric handgrip evoked avasoconstriction in the nonexercising forearm that was three-fold greater when handgrip was combined with mild lowerbody negative pressure (LBNP, −5 mmHg) to unload the car-diopulmonary baroreceptors (367). Further, the increase inforearm vascular resistance was significantly greater duringcombined LBNP and handgrip, than the algebraic additionof the response to LBNP alone plus handgrip alone. Thus itwas contended that the cardiopulmonary baroreceptors ton-ically inhibit sympathetic vasoconstriction during isometrichandgrip. However, these findings and this conclusion weredisputed by subsequent investigations (290, 294, 296) thatobserved no interaction between either the forearm vascu-lature or sympathetic responses to LBNP and isometric hand-grip. The reasons for these discrepant findings are unclear,but are suggested to relate in part to the level of LBNP, andthus cardiopulmonary unloading, utilized (12).

While isometric handgrip has a limited effect on eitherpreload (central venous pressure) or left-ventricular end-diastolic volume in young healthy individuals (319), dynamicexercise with a relatively large muscle mass evokes a muchgreater increase in left ventricle preload, stroke volume, andcontractility (367). Thus, it would be reasonable to expect car-diopulmonary vagal afferents to provide a marked inhibitionof SNA during dynamic exercise. Despite reports that acuteor chronic cardiopulmonary denervation has no effect on thecardiovascular 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 thepreparation and initiation of leg cycling exercise at 33 W (panel A) and 166 W (panel B). A notable reduction in MSNAis 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 ofthe peripheral circulation during exercise. In humans, Saitoet al. (286) observed that muscle SNA, obtained using themicroneurography technique at the median nerve (elbow),was reduced below baseline during low intensity leg cycling(20% VO2max), but increased at higher intensities (60% and75% VO2max). A muscle pump-mediated enhancement ofvenous return, cardiac filling pressure, and thus cardiopul-monary baroreceptor loading, in the absence of a powerfulconcomitant sympatho-excitatory drive from central com-mand or the exercise pressor reflex, may account for the fallin muscle SNA at the lower workload compared to higherintensities. In agreement, Ray et al. (266) reported that bothcentral venous pressure increased and muscle SNA fell dur-ing dynamic knee-extension exercise when subjects were in anupright-seated position, but remained unchanged from base-line when subjects were supine, once again indicative of theimportance of cardiac filling pressure and central blood vol-ume on the sympathetic adjustments to dynamic exercise inhumans.

Following pioneering studies in animals examining therole of the cardiopulmonary baroreceptors during exercise(51, 364), Mack et al. (195) reported that the forearm vas-cular responses to LBNP were similar at rest and duringleg cycling exercise in humans. Subsequently, Ogoh et al.(240) manipulated cardiac filling volumes with both LBNPand infusion of 25% human serum albumin and observedno differences between the forearm and systemic vascular

responses evoked at rest and exercise. One presumes that theability of the cardiopulmonary baroreflex to modulate mus-cle SNA is also unchanged from rest to exercise, but thisremains to be determined. Nevertheless, the available evi-dence indicates that the cardiopulmonary baoreflex remainsfunctional in exercising humans but is reset to operate aroundan increased central venous pressure or central blood vol-ume (195, 240). Moreover, cardiopulmonary loading dur-ing exercise results in a diminished upward and rightwardresetting of the carotid-vasomotor baroreflex function curve(244, 361). Several studies have also indicated that unload-ing of the cardiopulmonary baroreceptors heightens the gainof the carotid baroreflex both at rest and during exercise(20, 21, 176, 251, 257), although this has not been a univer-sal finding (64, 330). The interaction between the cardiopul-monary baroreflex and the arterial baroreflex during exercisehas recently been reviewed (78). Finally, the functional sig-nificance of the cardiopulmonary baroreceptors may becomeparticularly important when whole-body exercise is accom-panied by heat stress and/or dehydration (44,112). Secondaryto the notable increase in cutaneous perfusion and reductionin plasma volume through sweating under these conditions,central blood volume, stroke volume and cardiac output arereduced, while HR and plasma norepinephrine concentrationare markedly increased (44,112,276). A resultant reduction inperfusion and oxygen delivery to the exercising skeletal mus-cle is likely a major factor in the development of fatigue dur-ing maximal aerobic exercise (44,112). The complex effect ofthermal stress on the integrative control of the cardiovascular




system during exercise has been the subject of several excel-lent recent reviews (44, 112).

In summary, while the involvement of the cardiopul-monary baroreflex in autonomic and hemodynamic regulationis perhaps not as well understood or as widely appreciated ascentral command, the exercise pressor reflex and the arterialbaroreflex, there is ample evidence to indicate that it playsan important functional role. Indeed, the initial inhibition ofmuscle SNA at the onset of dynamic leg exercise may beattributed to the increase in venous return and subsequentelevations in central venous pressure and cardiopulmonarybaroreceptor load. As exercise continues, this effect would beovercome by stimulation of skeletal muscle afferents and thegreater central command input during higher intensity exer-cise contributing to increases in muscle SNA to active andinactive skeletal muscle.

Arterial chemoreflexChemically sensitive receptors located primarily in the carotidbodies, and to a lesser extent in the aortic bodies, sensechanges in the chemical composition of the bloodstream andrelay afferent information to medullary regions via the carotidsinus and vagus nerve, respectively. This afferent informationsubsequently modulates the respiratory and autonomic sys-tems in a homeostatic effort. The carotid body is highly vas-cularized and the sensing of PO2, PCO2, and pH is thoughtto primarily occur via type I (i.e., glomus) cells, which formchemical synapses with the carotid sinus nerve (137, 211).

However, the neurotransmission that determines the affer-ent signal to the medulla is complex and includes inhibitoryand excitatory inputs from numerous type I cells, chemicaland electrical intercellular communication among type I andbetween other cell types (e.g., type II cells), pre- and post-synaptic neuromodulation, as well as efferent sympatheticand parasympathetic innervation of the carotid body (183). Inaddition to the classical modulators, the carotid chemoreflexalso 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 efferentrespiratory and autonomic pathways by responding to changesin the chemical milieu of the extracellular and cerebrospinalfluid, and the sensitivity of the central and peripheral chemore-ceptors is likely interdependent upon each other (313).

It is well accepted that the chemoreflex is intimatelyinvolved in resting autonomic, cardiovascular and ventilatoryregulation (211). However, during exercise, the influence ofthe chemoreflex has primarily focused on respiratory adjust-ments, which are reviewed in detail elsewhere (92, 211), andinvestigations on chemoreflex-mediated cardiovascular con-trol are sparse. Recently, Stickland, Dempsey, and colleaguesconducted a series of experiments to examine the role ofthe chemoreflex in modulating SNA and blood flow duringexercise. Pharmacological (intravenous dopamine) or physio-logical (acute hyperoxia) methods to inhibit the chemoreflexincreased femoral blood flow and vascular conductance dur-ing rhythmic leg exercise, but had no influence under restingconditions in healthy humans (321) (Fig. 19). In addition, a

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reduction in muscle SNA was reported in response to tran-sient hyperoxia during moderate intensity isometric hand-grip exercise (323). These findings are in line with work inexercising dogs in which inhibition of the carotid chemore-flex, with intracarotid infusion of dopamine or hyperoxicRinger’s solution, caused hindlimb vasodilation; a responsethat was most evident in the exercising skeletal muscle, ver-sus the mesenteric vasculature, and attributable to chemore-flex induced sympathetic vasoconstrictor withdrawal as theresponses were abolished following α-adrenergic blockade orcarotid body denervation (322). Taken together, these findingssuggest that the chemoreflex restrains exercising blood flowvia vasoconstrictor sympathetic outflow to skeletal muscle.However, others have shown that sustained hyperoxia (3-15min) did not influence (298) or increased (144) the muscleSNA response to exercise and reduced exercising skeletalmuscle blood flow (371). Therefore, while examination of therole of the chemoreflex during exercise is in its infancy, fur-ther investigations are warranted with consideration for thecontribution of the central/peripheral chemoreflex, influenceof the chemoreflex on cardiac autonomic regulation, exercisemodality and temporal patterns.

Overall SummaryWe have provided a detailed review of the current under-standing of the parasympathetic and sympathetic adjustmentsthat occur with exercise along with a discussion of the con-tributions of several neural reflex mechanisms in mediatingthese autonomic changes and the ensuing cardiac and/or vas-cular responses in healthy humans. A short synthesis follows,including the identification of key gaps in our understandingand suggestions for further research.

The onset of exercise is accompanied by an immedi-ate increase in HR secondary to a withdrawal of cardiac

parasympathetic activity principally due to the combinedactions of central command and the muscle mechanoreflex.Presently, the evidence for the contribution of cardiac SNA tothe initial increase in HR at exercise onset is lacking in humansand requires (re)investigation in light of recent studies in ani-mals. An initial reduction in cardiac baroreflex control hasbeen noted in humans as a consequence of central commandand/or muscle mechanoreflex activation. However, whetherthis is attributable to a decrease in arterial baroreflex sensitiv-ity or a rapid resetting of the baroreflex function curve remainsunclear. Vasoconstrictor SNA to the skeletal muscle vascula-ture typically decreases at the initiation of dynamic exercisewith a substantial muscle mass as a consequence of the mus-cle pump-mediated enhancement of venous return, cardiacfilling pressure and loading of the cardiopulmonary barore-ceptors. However, a slight muscle mechanoreceptor mediatedincrease in muscle SNA may be evoked at the onset of exer-cise modes where increases in cardiopulmonary loading areminimal (e.g., isometric contractions of a small muscle mass).The potential contribution of the arterial chemoreflex to theinitial autonomic adjustments to exercise is unclear.

HR increases approximately linearly with oxygen uptakeduring incremental dynamic exercise. Reductions in car-diac parasympathetic activity primarily mediate the increasesin HR during low intensity steady-state dynamic exercise;whereas cardiac SNA contributes more as exercise intensityincreases (Fig. 20). How exercise intensity influences the pre-cise “sympatho-vagal balance” is still debated. Recent workhas highlighted the underappreciated contribution of cardiacparasympathetic nerve activity to ventricular control, but theimplications of this for cardiac control during exercise inhumans remains to be determined. During intense exercise thehigh level of cardiac SNA likely leads to the release of neu-romodulatory cotransmitters (e.g., neuropeptide Y) that mayfurther diminish cardiac parasympathetic control (i.e., accen-tuated antagonism); however, our understanding of these

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




processes in exercising humans is limited and requires furtherstudy. During prolonged dynamic exercise at a steady-statesubmaximal workload a sympathetically mediated increase inHR is evoked (cardiac drift), which is exacerbated by dehy-dration and high ambient temperature. Although not as welldocumented, a reduction in β-adrenergic receptor sensitivityhas been associated with an attenuated HR increase and areduction in aerobic exercise capacity (e.g., in normal aging),but the exploitation of this as a therapeutic target for improv-ing exercise capacity has to date been unfruitful. Nevertheless,a normally functioning autonomic nervous system is requisitefor an appropriate cardiac response during exercise, which hasimportant implications for exercise performance.

The intensity-dependent changes in cardiac autonomicactivity described above facilitate an increase in HR, car-diac contractility, stroke volume, and ultimately cardiac out-put. Collectively the sympathetic responses to exercise, alongwith the metabolic modulation of sympathetic vasoconstrictoractivity in the active muscle (i.e., functional sympatholysis),enhance the redistribution of cardiac output to the exercisingskeletal muscles. There is compelling evidence for intensityand duration-dependent increases in muscle SNA to both theactive and inactive limbs during exercise that are accompa-nied by increased norepinephrine spillover from the cardiac,renal, and splanchnic vasculature. However, it is importantto appreciate regional differences in the temporal pattern ofexercise-induced sympathetic activation and the impact thatboth intensity and duration have on the sympathetic response.

The neural reflex mechanisms underpinning the parasym-pathetic and sympathetic adjustments to exercise are com-plex with clear evidence for the involvement of central com-mand, the exercise pressor reflex, the arterial baroreflex, andcardiopulmonary baroreceptors, along with further potentialmodulation via arterial chemoreceptors and phrenic afferentsfrom respiratory muscles (i.e., respiratory metaboreflex). Asdiscussed in this review, these neural mechanisms are all capa-ble of modulating the autonomic adjustments to exercise andappear to work interactively to orchestrate an appropriateneural cardiovascular response to exercise in an intensity-dependent manner.

Increases in sympathetic outflow to skeletal muscle vas-culature are manifest with a latency of 30 to 60 s duringexercise, arguably due to the time taken for the accumula-tion of metabolites and the activation of metabolically sen-sitive skeletal muscle afferents. A plethora of candidate sub-stances have been implicated in the stimulation of skeletalmuscle afferents during exercise, but the definitive resolutionof the specific “cocktail” of substances needed for a “nor-mal” response has remained elusive. A small effect of themuscle mechanoreceptors on muscle SNA has been reported,that is more substantial when the presence of metabolites isincreased. At high exercise intensities a contribution fromcentral command to the increase in sympathetic vasoconstric-tor drive during exercise has also been observed. Togethercentral command and the exercise pressor reflex elevate mus-cle SNA during high-intensity exercise and overcome any

potential sympatho-inhibitory effects of cardiopulmonaryreceptor loading. A role for central command in evoking acholinergic vasodilatation has been muted, but remains con-troversial and further human investigations are warranted,including considerations for exercise modality, intensity andthe magnitude of the muscle mass engaged. Due to the com-plexity of central command, the identification of specific brainregion(s) responsible for evoking autonomic adjustments hasremained elusive and additional work is required to betterdevelop an integrated neurocircuitry model.

An intensity-dependent resetting of the arterial barore-flex stimulus-response relationship around the established BPoccurs during steady-state exercise, meaning that the barore-flex maintains its ability to regulate BP as effectively as dur-ing rest. It is clear that both central command and the exercisepressor reflex are actively involved in the resetting of thearterial baroreflex during exercise with the cardiopulmonarybaroreceptors playing a modulatory role. Anatomically, theNTS of the medullary brainstem has emerged as the primarycandidate for the convergence and integration of input fromeach of these neural reflex mechanisms and, as such, likelyplays an essential role in governing the autonomic outputmediating the cardiovascular responses to exercise.

Investigation of the autonomic adjustments to exercise isan ongoing area of research with more recent work attemptingto understand potential dysregulation in the neural mecha-nisms and the ensuing autonomic adjustments to exercise thatappear to accompany several cardiovascular disease states(e.g., hypertension). These studies are founded on the funda-mentals of the normal regulation of the autonomic and car-diovascular responses to exercise in health outlined in detailin this review.

AcknowledgementsThe authors express gratitude and appreciation to Dr. PeterRaven, Dr. Jere Mitchell, and Prof. John Coote for their con-tinued support and guidance, which has been instrumentalto each of our careers. The authors gratefully acknowledgethe research support received from United States of Amer-ica National Institutes of Health Grant #HL-093167 (P.J.F.),Grant #K99HL166776 (C.N.Y.), British Heart FoundationPG/11/41/28893 (J.P.F.), and Arthritis Research UK #196633(J.P.F.).

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