Am J Physiol Heart Circ Physiol 301: H1191–H1204, 2011.
First published August 12, 2011; doi:10.1152/ajpheart.00208.2011.
Review
Cardiovascular regulation by skeletal muscle reflexes in health and disease
Megan N. Murphy,1 Masaki Mizuno,1 Jere H. Mitchell,2 and Scott A. Smith1,2
Departments of 1Physical Therapy and 2Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
Submitted 2 March 2011; accepted in final form 2 August 2011
mechanoreflex; metaboreflex; sensory neurons; hypertension; heart failure
THIS ARTICLE is part of a collection on Cardiovascular Response to Exercise. Other articles appearing in this collection,
as well as a full archive of all collections, can be found online
at http://ajpheart.physiology.org/.
Adjustments in autonomic nerve activity to the cardiovascular system during exercise are requisite to meet the metabolic
demands of working skeletal muscle. Dynamic exercise is
characterized by intensity-dependent increases in heart rate
(HR), stroke volume (SV), and cardiac output, whereas total
peripheral resistance is reduced. These changes in circulatory
hemodynamics produce moderate increases in arterial blood
pressure (BP). As a result, skeletal muscle blood flow is rapidly
augmented to provide adequate oxygen and nutrient delivery to
the working muscle (116, 139). In contrast, muscle blood flow
is reduced during static exercise because of the relatively large
increases in intramuscular pressure produced by isometric
contractions. HR-mediated increases in cardiac output are
generated along with little to no change in total peripheral
resistance, resulting in a markedly potentiated BP response.
These changes occur in an attempt to maintain adequate perfusion of muscle during static exercise (116). The autonomic
Address for reprint requests and other correspondence: S. A. Smith, Univ. of
Texas Southwestern Medical Ctr., Southwestern School of Health Professions,
Dept. of Physical Therapy, 5323 Harry Hines Blvd., Dallas, TX, 75390-9174
(e-mail: [email protected]).
http://www.ajpheart.org
nervous system mediates these cardiovascular responses to
both dynamic and static exercise by increasing sympathetic
nerve activity (SNA) and withdrawing parasympathetic nerve
activity via three distinct neural mechanisms: central command, the exercise pressor reflex (EPR), and the arterial baroreflex (152).
Central command is a feed-forward neural mechanism that
transmits excitatory impulses to descending motor neurons for
locomotion and in a parallel fashion activates cardiovascular
control circuits within the medulla oblongata (34). As early as
1895, Johansson (61) postulated that a neural mechanism of
central origin was, in part, responsible for the modulation of
the cardiovascular response to exercise. In 1913, Krogh and
Linhard (83) provided evidence in support of this theory,
quantifying a rapid increase in ventilation and pulse rate within
1 s of the onset of voluntary exercise. In agreement with
Johansson, they concluded that an irradiation of impulses from
the motor cortex was the most likely explanation for such a
rapid response. Since that time, numerous investigations in
both animals and humans have firmly established an important
role for central command in the regulation of the cardiovascular response to exercise. However, this input is only one facet
of the integrated system that finely adjusts the autonomic
response to physical activity.
In 1917, Krogh and Linhard (82) further demonstrated in
humans that pulse rate and ventilation were rapidly increased at
0363-6135/11 Copyright © 2011 the American Physiological Society
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Murphy MN, Mizuno M, Mitchell JH, Smith SA. Cardiovascular regulation by skeletal muscle reflexes in health and disease. Am J Physiol Heart Circ
Physiol 301: H1191–H1204, 2011. First published August 12, 2011;
doi:10.1152/ajpheart.00208.2011.—Heart rate and blood pressure are elevated at
the onset and throughout the duration of dynamic or static exercise. These neurally
mediated cardiovascular adjustments to physical activity are regulated, in part, by
a peripheral reflex originating in contracting skeletal muscle termed the exercise
pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals
of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors
are stimulated by the physical distortion of their receptive fields during muscle
contraction and can be sensitized by the production of metabolites generated by
working skeletal myocytes. The chemical by-products of muscle contraction also
stimulate metaboreceptors. Once activated, group III and IV sensory impulses are
transmitted to cardiovascular control centers within the brain stem where they are
integrated and processed. Activation of the reflex results in an increase in efferent
sympathetic nerve activity and a withdrawal of parasympathetic nerve activity.
These actions result in the precise alterations in cardiovascular hemodynamics
requisite to meet the metabolic demands of working skeletal muscle. Coordinated
activity by this reflex is altered after the development of cardiovascular disease,
generating exaggerated increases in sympathetic nerve activity, blood pressure,
heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex,
and the emerging evidence describing the dysfunction of the reflex with the advent
of cardiovascular disease are highlighted in this review.
Review
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The Exercise Pressor Reflex
Skeletal muscle is innervated by several types of sensory
neurons of which only group III (thinly myelinated, A␦ fibers)
and group IV (unmyelinated, C fibers) afferent fibers participate in the reflex regulation of cardiovascular function during
exercise (69, 102). The majority of group III afferents are
rapidly (2–5 s) excited by mechanical distortion of their receptive field, located on unencapsulated nerve endings and pacinian corpuscles (2, 47, 69, 71, 76, 109). As such, receptors
associated with these afferent fibers are termed “mechanoreceptors,” although a few are responsive to chemical stimuli
(67). Group III nerve endings terminate in the collagenous
connective tissue and the endoneurium of the triceps surae and
calcaneal tendon of the cat (1, 8, 67, 157). Activation of this
group of afferent neurons primarily stimulates the mechaniAJP-Heart Circ Physiol • VOL
cally sensitive component of the EPR termed the “muscle
mechanoreflex.” Group IV afferents are predominately excited
by changes within the chemical milieu of skeletal muscle
interstitium resulting from the accumulation of metabolites
produced by contracting muscle (67, 76). As such, excitatory
impulses are delayed (5–20 s) following muscle contraction
and ischemia potentiates the activity of these neurons (64, 69,
71, 109). Group IV afferent fibers exhibit heterogeneity with
some sensitive to mechanical distortion (69). Anatomically,
sensory receptors associated with group IV afferent neurons
are located on unencapsulated nerve endings that terminate
within the walls of capillaries, venules, and lymphatic vessels
of skeletal muscle (8). These locations are advantageous for
direct sampling of the chemical environment within the vasculature of the skeletal muscle. Stimulation of this group of
afferent neurons primarily activates the chemically sensitive
component of the EPR known as the muscle metaboreflex.
The first site of synapse for most skeletal muscle group III
and IV afferents is the dorsal horn of the spinal cord, specifically Rexed’s laminae I, II, V, and X (65, 93, 108, 186).
Although the specific pathway remains unknown, muscle afferents project from the dorsal horn to the brain stem along a
path that includes the dorsolateral sulcus and the ventral spinal
cord (24, 56, 81). Spinal cord transection at the first cervical
vertebrae eliminates the pressor response to static muscle
contraction, whereas transection of the rostral medulla only
partially attenuates the response (60). Therefore, an intact brain
stem is required to process impulses from group III and IV
afferents. Neuronal cells responsive to EPR stimulation have
been described in the nucleus tractus solitarius (NTS), rostral
ventral medulla, caudal ventrolateral medulla, lateral tegmental
field, nucleus ambiguus, and the ventromedial region of the
rostral periaqueductal grey (15, 57, 58, 88, 92). Of these, the
NTS is likely the primary site of central processing, with
secondary projections to the aforementioned nuclei (65, 127).
Group III and IV afferent impulses evoke graded, intensitydependent increases in efferent SNA and parasympathetic
withdrawal (119, 120). Skeletal muscle contraction reduces the
tonic excitation of vagal motor neurons, serving as one mechanism by which HR is increased (107). In contrast, sympathetic
outflow to the heart and systemic vasculature including the
vasculature of skeletal muscle, kidneys, the splanchnic region,
and skin is increased with the activation of skeletal muscle
reflexes (42, 100, 101, 119, 170, 174). Preganglionic sympathetic neurons originating in the rostral ventral medulla project
to the intermediolateral cell columns of the spinal cord, synapse at the paravertebral sympathetic chain ganglia, and innervate the heart and vasculature. The EPR-mediated adjustments
in parasympathetic and SNA result in increases in cardiac
contractility, SV, HR, and BP (144). It is through these pathways, outlined in Fig. 1, that skeletal muscle reflexes contribute to cardiovascular regulation during physical activity.
Experimental Models to Assess EPR Function
Humans. The cardiovascular response to exercise is tightly
regulated by input from central command, the EPR, and the
baroreflex, making it difficult to isolate the distinct contributions of each component. However, innovative models have
been developed to examine the role of the EPR in humans. For
example, the induction of epidural anesthesia using lidocaine
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the onset of involuntary leg contraction induced by electrical
stimulation of skeletal muscle. As this technique did not
involve voluntary movement and hence eliminated cortical
irradiation, it was concluded that reflex input from the skeletal
muscle itself was likewise involved in mediating the cardiorespiratory response to exercise. In support of this concept, Alam
and Smirk (4, 5) later demonstrated in 1937 to 1938 that
dynamic calf exercise evoked increases in BP and HR that
were maintained by circulatory arrest upon the cessation of
exercise. However, upon the restoration of blood flow, both
mean arterial pressure and HR fell precipitously (4, 5). In a
similar protocol, a spinal cord lesion patient with preserved
motor control and absent sensation below one knee performed
calf exercise in the numb leg, which evoked typical increases
in HR and BP (6). In this patient the sympathoexcitatory
responses were not maintained during postexercise circulatory
occlusion. This elegant series of experiments demonstrated that
a reflex originating in skeletal muscle, the EPR as it is known
today (115), was intimately involved in mediating the precise
cardiovascular adjustments to exercise.
The contribution of the arterial baroreflex to the modulation
of the circulatory response to exercise induced by central
command and the EPR has been more recently recognized.
Arterial baroreceptors located within the carotid sinuses and
the aortic arch function as sensors in a negative feedback
system that modulates beat-to-beat variations in BP by continually adjusting HR, SV, and peripheral resistance (49, 67, 98).
During steady-state exercise, the baroreflex is reset to function
around the higher BPs induced by physical activity in conscious animals and humans (28, 80, 130). In doing so, the
baroreflex maintains the ability to finely tune the cardiovascular response to exercise.
Clearly, each of the described inputs (i.e., central command,
the EPR, and the arterial baroreflex) importantly contributes to
the regulation of the autonomic nervous system during exercise. Not surprisingly, each is known to transmit information
directly to cardiovascular regulatory centers within the medulla
and, therefore, maintain the potential to modify one another
functionally. Adequate discussion of these interactions and the
individual contributions of each of these inputs is a large
endeavor and beyond the scope of the current review. As such,
this review will focus primarily on the EPR since much
attention has been recently given to this reflex in both health
and disease.
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
reduces motor strength and blocks sensory feedback from
contracting skeletal muscle. The pressor response to both static
and dynamic exercise is reduced when performed after epidural
anesthesia compared with control exercise at the same relative
intensity and perceived effort (7, 26, 30, 117, 161). Such
investigations emphasize the important role skeletal muscle
reflexes play in regulating the cardiovascular response to exercise in humans. Likewise, involuntary exercise induced by
electrically stimulating skeletal muscle via electrodes placed
on the limb significantly increases BP and HR while avoiding
excitation of central command (10, 21, 29, 53, 54, 59, 82).
However, electrical stimulation may alter the order of muscle
fiber recruitment from that produced physiologically by direct
activation of motor neurons (52). Passive cycling also removes
the influence of central command while evoking EPR-induced
AJP-Heart Circ Physiol • VOL
increases in HR and BP (23, 84, 124, 125). As an added
advantage, when performed at a low resistance, passive cycling
increases BP and SV without altering lactic acid production,
making it a useful model for examining the contribution of the
muscle mechanoreflex to EPR function (84). Medical antishock trousers, inflated to 60 to 100 mmHg, combined with
suprasystolic inflation of thigh cuffs, to prevent the cephalad
translocation of fluids, evokes a pressor response that is abolished with epidural anesthesia, suggesting it is another technique that can be used to assess EPR activity (184). Additionally, patients with Brown-Séquard syndrome are ideal candidates in which to examine the role of the EPR. These patients
exhibit spinal hemiplegia to the lateral half of the spinal cord
with unilateral damage to group III and group IV muscle
afferents that project to the dorsal horn, rendering sensory
function absent in one leg, while motor function is retained
(95). Experiments in these patients have demonstrated that the
pressor response to postexercise circulatory occlusion in the
leg with reduced sensory function is abolished, establishing a
critical role for the EPR in mediating the cardiovascular response to exercise (187).
In humans, the metabolically sensitive component of the
EPR (i.e., the metaboreflex) has been the subject of many
investigations, most likely because of the relative simplicity
with which it can be examined. As stated previously, Alam and
Smirk (4 – 6) demonstrated that BP and HR remained elevated
after the cessation of calf exercise if the leg circulation was
arrested by the suprasystolic inflation of thigh cuffs. This
attenuates the removal of metabolites produced during muscle
contraction and enhances the stimulation of metaboreceptors
located on afferent sensory neurons. An added advantage of
this technique is that it is performed after exercise is discontinued at a time point when both the muscle mechanoreflex and
central command have been disengaged. This technique has
also been used to demonstrate that the metaboreflex modulates
the sympathetic response to exercise. The sympathetic response to handgrip exercise is sustained during postexercise
circulatory occlusion while increasing forearm blood flow (i.e.,
during the application of suction to the forearm) during circulatory arrest attenuates this response (63). Lower-body positive
pressure can also be used in humans to stimulate the metaboreflex. Reducing blood flow to exercising muscle via lower-body
positive pressure produces a greater elevation in BP and
plasma lactate concentration, suggesting that this technique
reduces the removal of the metabolic by-products of skeletal
muscle work serving to suprastimulate the metaboreflex (123).
Microdialysis studies within exercising skeletal muscle have
demonstrated that interstitial potassium, lactate, and phosphate
concentrations increase concomitantly with elevations in SNA,
BP, and HR and are therefore potential chemical substances
that stimulate metaboreflex activity (97).
Patient populations have also been useful in assessing
metaboreflex function in humans. Patients with McArdle’s
disease have a genetic deficiency in myophosphorylase expression that prevents exercise-induced muscle acidosis. Several
studies have demonstrated that the sympathetic response to
static exercise is attenuated in this patient population although
this finding is not universal (25, 131, 172, 173). In addition,
animal studies have also demonstrated that when acid-sensing
ion channels (ASICs) located on skeletal muscle innervating
sensory afferent neurons are inhibited, there is a significant
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Fig. 1. The exercise pressor reflex arc. Skeletal muscle contraction excites
group III and group IV sensory afferent neurons through several putative
stimuli. Stretch or the application of pressure to skeletal muscle distorts the
receptive field of mechanically sensitive receptors located predominately on
group III afferent neurons. These mechanoreceptors have yet to be identified
but are likely mechanogated cation, potassium, or calcium channels. Metabolites released during muscle contraction such as potassium, lactic acid, bradykinin, analogs of ATP, by-products of arachidonic acid metabolism, and
diprotonated phosphate excite metabolically sensitive receptors located predominately on group IV afferent neurons. Pharmacological agonists for acidsensing ion channels (ASICs), bradykinin receptors, transient potential vanilloid receptor 1 (TRPV1), purinergic receptors, and cannabanoid receptors have
been demonstrated to evoke group IV afferent activity. However, there are
likely other potential metaboreceptors that have yet to be identified. Group III
and group IV afferent sensory neurons transmit impulses, via the spinal cord,
to the cardiovascular control centers located within the medullary region of the
brain stem, specifically the nucleus tractus solitarius, rostral ventrolateral
medulla, and caudal ventrolateral medulla, as well as other secondary nuclei.
Central processing of this input promotes increases in sympathetic nerve
activity and withdrawal of parasympathetic nerve activity. Thus heart rate,
arterial blood pressure, and vascular resistance are reflexively increased upon
the onset of muscle contraction.
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
AJP-Heart Circ Physiol • VOL
Fig. 2. Cumulative histogram of group IV afferent impulses (Imp) before,
during, and after electrically induced static contraction. A: in 8 group IV
sensory neurons, afferent activity was elevated during static contraction (denoted by black bar) compared with the impulses recorded 1 min before and 2
min after contraction. B: administration of indomethacin (5 mg/kg iv) markedly reduced the discharge of the same group IV afferent neurons during static
contraction. Indomethacin did not affect the discharge of afferents before or
following contraction. Data adapted from Rotto et al. (135).
and soleus muscles of the hindlimb is commonly used to
selectively stimulate mechanoreceptors, evoking elevations in
BP, HR, and SNA (119, 151). It should be noted, however, that
Hayes et al. (43) recently determined that stretch excites a
separate population of group III afferent neurons than those
stimulated during muscle contraction, although significant
overlap exists.
Animal models are valuable to researchers, delineating the
mechanisms by which skeletal muscle reflexes modulate cardiovascular function in health and disease. However, there are
limitations to these models. For example, in rats, the activation
of the EPR under inhaled anesthesia evokes a depressor response (151, 165, 174). Therefore, rats must be decerebrated to
generate a cardiovascular response similar to that observed
during exercise in conscious animals. As another example, in
anesthetized or decerebrate animals, intra-arterial injection of
gadolinium, a mechanoreceptor antagonist, significantly attenuates the pressor, chronotropic, and sympathetic response to
mechanoreflex stimulation (41, 45, 119). In contrast, in conscious cats, gadolinium has no effect on the pressor response to
exercise, suggesting that the mechanoreflex may be suppressed
and/or its loss of input compensated for in the conscious state
(99). Despite such limitations, the assessment of EPR function
in animal models allows for a more direct examination of the
reflex in isolation and has played a key role in advancing our
understanding of cardiovascular regulation during exercise in
both health and disease.
The Skeletal Muscle Metaboreflex
Metabolite accumulation in skeletal muscle tissue partially
drives the autonomic response to exercise. Therefore, metab-
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reduction in the pressor response to hindlimb static contraction
(46). Therefore, it is plausible that exercise-induced skeletal
muscle acidosis plays a partial role in the sympathetic response
to exercise. Collectively, the use of these techniques has
established an integral role for the muscle metaboreflex in the
reflex regulation of the cardiovascular system during exercise.
The mechanoreflex has been more difficult to isolate in
humans, largely because the stimulus, muscle contraction, is
accompanied by metabolite production and central command
activation. Low-resistance passive cycling and alternative techniques (e.g., low-intensity involuntary muscle contraction, sustained passive muscle stretch, and leg compression) have been
used in an attempt to preferentially stimulate mechanoreceptors
in the absence of input from the metaboreflex and central
command (27, 33, 113). Batman et al. (9) measured muscle
SNA and metabolite production during prolonged low-intensity rhythmic isotonic handgrip exercise. Despite no alterations
in metabolite production, there was a progressive increase in
muscle SNA that was not observed during postexercise circulatory occlusion, confirming that metaboreceptors were not
stimulated (9). Although central command was intact in this
model, it has little or no affect on the sympathetic response to
forearm handgrip exercise (171). Such experiments demonstrate that the mechanoreflex facilitates the regulation of the
autonomic response to exercise in humans.
Animals. Animal models are commonly used to assess the
activity of the EPR, mechanoreflex, and metaboreflex while
experimentally eliminating the influence of central command
and the arterial baroreflex. Involuntary hindlimb muscle contraction induced via electrical stimulation of spinal nerve
ventral roots is regularly used to examine the respiratory and
cardiovascular response to stimulation of the EPR (16, 66, 70,
102, 151). In many of these investigations, but not all, a
decerebration procedure is performed before EPR stimulation, effectively removing the influence of central command
and the deleterious effects of anesthesia (151). McCloskey
and Mitchell (102) demonstrated that electrical stimulation
of the L7-S1 ventral roots in cats evoked a hindlimb tetanic
muscle contraction that reflexively increased BP, HR, and
respiration. The application of lidocaine to the dorsal roots
attenuated the cardiovascular and respiratory response to
hindlimb contraction, suggesting that it was mediated by
small fiber afferent sensory neurons (102). The dorsal roots
remain intact in this preparation, allowing skeletal muscle
afferent impulses to be transmitted to the brain stem. This
model has also been reduced into a viable preparation in the
rat, allowing for the evaluation of EPR function in a variety
of disease states (106, 150, 151, 155).
Ischemic contraction and postexercise circulatory occlusion
are commonly used to examine the role of the metaboreflex in
animals (3). Additionally, intra-arterial infusions of exogenous
metabolic derivatives or metaboreceptor agonists into the
hindlimb are used to stimulate metaboreflex activity (68). For
example, capsaicin (an exogenous substance demonstrated to
primarily activate group IV afferent fibers), infused and
trapped in the hindlimb circulation, significantly increases BP
and HR in cats and rats (68, 149). As shown in Fig. 2,
metaboreceptor antagonists are also frequently used to assess
the contribution of the metaboreflex to the activation of the
EPR during muscle contraction (149). With regard to the
muscle mechanoreflex, passive stretch of the gastrocnemius
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
AJP-Heart Circ Physiol • VOL
contraction, may sensitize the receptors, making them more
receptive to additional stimuli (35, 164). However, it has yet to
be definitively determined whether these receptors play a
significant role in stimulating afferent sensory neurons as the
data from functional studies have been conflicting (13). Kindig
et al. (75) pharmacologically blocked TRPV1 receptors in cats
with iodoresinaferatoxin (IRTX) during static contraction of
the gastrocnemius and soleus muscles while the hindlimb was
freely perfused or the circulation was occluded. In this study
IRTX did not alter the cardiovascular response to contraction
during either condition (75). On the contrary, in rats, Smith et
al. (149) separately infused three TRPV1 receptor antagonists,
IRTX, capsazepine, and ruthenium red, before static contraction, passive stretch of the hindlimb, or intra-arterial injection
of capsaicin. Each antagonist significantly attenuated the pressor response to EPR and metaboreflex stimulation but had no
affect on the pressor or cardioaccelerator response to mechanoreflex activation (149). Furthermore, capsazepine has been
shown to attenuate the pressor response to hindlimb intraarterial administration of diprotonated phosphate in rats (31).
The discrepancy among studies is not readily apparent. However, the majority of studies do raise the possibility that the
activation of TRPV1 receptors by skeletal muscle metabolites
(e.g., protons) may contribute to the excitation of the skeletal
muscle metaboreflex during exercise. Clearly, further research
is needed in this area.
Purinergic (P) ligand-gated ion channels have been localized
to both group III and IV muscle afferent neurons (175–177).
Skeletal muscle contraction triggers the release of purines such
as adenosine and interstitial ATP, which act as ligands for P1
and P2X receptors, respectively (11, 48, 89, 90). Both adenosine and ATP have been investigated as potential metabolic
stimulators of the EPR. In humans, the infusion of exogenous
adenosine into the forearm arterial circulation has been shown
to increase muscle SNA during postexercise circulatory occlusion, although this finding has been difficult to reproduce
consistently (17, 38, 111). One reason for this difficulty may be
that exogenously administering adenosine leads to its appearance in the systemic circulation, resulting in the direct stimulation of the aortic and carotid chemoreceptors, producing a
chemoreflex-mediated change in muscle SNA (140, 141). As
such, P1 receptors most likely do not play a role in the
metaboreflex-induced cardiovascular response to exercise. In
contrast, an intra-arterial administration of ␣,␤-methylene ATP
(a P2X receptor agonist) into the hindlimb of decerebrated cats
elevates BP and enhances afferent impulses from group IV
fibers by 67% (39, 90, 132). Furthermore, the arterial administration of the P2X receptor antagonist pyridoxal phosphate6-azophenyl-2=,4=-disulfonic acid (PPADS) attenuates the
pressor response to static muscle contraction by 38% in cats
and reduces the pressor response to postcontraction circulatory
occlusion (40). The administration of PPADS also abolishes
the afferent impulses transmitted by group IV fibers during
postcontraction circulatory occlusion (74). In in vitro studies,
in kidney cells, PPADS was shown to also block the release of
arachidonic acid, suggesting that the reduced pressor response
observed in the previous experiments may not be exclusively
due to the inhibition of P2X receptors (146). However, McCord et al. (104) addressed this concern, demonstrating that the
in vivo administration of PPADS to the hindlimb circulation
during contraction in cats did not alter PGE2 production.
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olites that excite metaboreceptors have been the subject of
intense investigation. A candidate metabolite must evoke afferent impulses from metabolically sensitive afferent fibers, be
present in exercising muscle, produce a pressor response when
administered exogenously, and when its production is inhibited, must attenuate the pressor response to exercise. Metabolites that fit these criteria are potassium, lactic acid, bradykinin,
by-products of arachidonic acid metabolism, analogs of adenosine 5=-triphosphate (ATP), and diprotonated phosphate (87,
117, 135, 136, 138, 142, 148, 158, 163, 182) to name a few. An
exogenous administration of these substances individually only
partially recapitulates the cardiovascular response to static
contraction, suggesting that a combination of substances may
excite metaboreceptors during exercise. The intra-arterial administration of a cocktail of metabolites produced during
muscle contraction (e.g., protons, ATP, and lactate) evoked
rapid elevations in calcium in dorsal root ganglion neurons,
innervating skeletal muscle to a greater extent than individual
administration of each substance (94). The inhibition of one or
all of the receptors specific to changes in pH, ATP, and lactate
significantly reduced the number of dorsal root ganglion cells
excited by the combination of substances (94). Although the
exact mechanism by which the metaboreflex is excited remains
undetermined, the aforementioned metabolites likely excite a
variety of receptors that are directly involved. For example,
cannabinoid receptors have been demonstrated to excite skeletal muscle reflexes, whereas ␮-opioid receptors may attenuate
activation of the EPR (166, 183).
Similar to the endogenous chemical substances that stimulate the metaboreflex, several receptors located on sensory
fibers are plausible candidates for mediating EPR function.
ASICs, proton-gated channels localized to group IV fibers,
open when exposed to an extracellular pH of 7.0 or less, such
as occurs when lactic acid accumulates during static muscle
contraction (14, 162, 188). In cats, intra-arterial injection of the
ASIC antagonist A-317567 markedly attenuates the pressor
response to electrically induced static contraction (46). The
infusion of amiloride, a nonspecific ASIC and epithelial sodium channel antagonist, into the hindlimb circulation has no
effect on the immediate (2–5 s) autonomic response to static
contraction or passive stretch (103). However, amiloride blunts
the latent pressor response (⬎ 5 s) to static contraction (103).
Subsequent experiments have demonstrated that amiloride and
A-317567 injection into the popliteal artery attenuates the
change in BP and renal SNA after suprastimulation of the
metaboreflex by circulatory occlusion during and immediately
after muscle contraction (105). Collectively, these data suggest
that metabolites that stimulate ASIC opening partially mediate
the excitation of metabolically sensitive sensory neurons during exercise.
Transient receptor potential vanilloid 1 (TRPV1) receptors
are also predominantly localized to group IV fibers (110).
Intra-arterial injection of capsaicin, a TRPV1 receptor agonist,
markedly increases BP, HR, and SNA, suggesting that this
receptor excites group IV afferent neurons (68, 156). TRPV1
receptors are sensitive to changes in muscle temperature,
increases in extracellular hydrogen ion concentration (pH ⬍
5.7), and inflammatory products such as bradykinin and prostaglandins (35, 62, 134, 164, 181). These potential activators of
the TRPV1 receptor are present during exercise, and decreases
in extracellular pH, characteristic of ischemia during static
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
Therefore, it is likely that arachadonic acid production is not
significantly affected in this model. A recent investigation in
cats has shown that the pressor response to postcontraction
circulatory occlusion is attenuated after the infusion of either a
P2X2/3- or P2X3-selective antagonist into the arterial circulation of the hindlimb (104). Furthermore, Cui et al. (18) demonstrated in humans that the pressor and muscle SNA response
to fatiguing handgrip and postexercise ischemia are attenuated
by infusion of vitamin B6, a P2X receptor antagonist. Collectively, the emergent data suggest ATP produced during exercise binds P2X receptors, thereby exciting skeletal muscle
sensory afferent fibers (91).
Group III sensory afferent neurons are predominately excited by mechanical distortion of their receptive fields; however, the area of the muscle where mechanoreceptors are
optimally exposed to this stimulus has yet to be identified. In
rats, an injection of lidocaine into the myotendinous junction
has been shown to abolish the cardiovascular response to
mechanoreflex stimulation while severing and reattaching the
Achilles tendon has no effect (121, 122). These studies suggest
that mechanoreceptors are located proximally to the Achilles
tendon within the myotendinous junction with the receptive
fields of some group III afferent neurons located near the head
of the muscle. Additionally, the specific receptor type that
excites mechanically sensitive neurons remains unknown.
Gadolinium, a trivalent lanthanide, inhibits mechanoreceptor
excitation to mechanical stimuli such as tendon stretch and
static contraction (41, 45, 119). As shown in Fig. 3, gadolinium
inhibits the opening of mechanogated potassium channels, Land T-type calcium channels and mechanogated cation channels, but these channels have yet to be localized to group III
afferent nerve endings (36).
A small population of group III afferent fibers are polymodal
in nature, exhibiting a secondary excitatory response to muscle
fatigue during static contraction. These neurons appear to be
excited by the accumulation of metabolites such as bradykinin,
potassium, by-products of arachidonic acid metabolism, and
lactic acid (55, 69, 85, 136, 143, 147). Evidence suggests that
mechanoreceptors are sensitized by metabolites, specifically
during conditions of limited perfusion, thereby enhancing the
sympathetic response to mechanoreflex activation (3, 71). For
example, an extension of the wrist (a technique thought to
selectively activate mechanoreceptors) significantly increases
BP and muscle SNA during postexercise ischemia. This finding suggests that metabolites produced during ischemia sensitize mechanoreceptors (19).
A number of investigations have sought to determine which
metabolites are involved in the sensitization of mechanoreceptors. Cyclooxygenases (COXs) and lipoxygenases enzymatically aid in the metabolism of arachidonic acid, producing
prostaglandins (PG), thromboxanes, and leukotrienes. In cats,
intra-arterial infusion of arachidonic acid into the hindlimb
circulation has been demonstrated to stimulate afferent impulses in 50% of group III sensory fibers (136). The administration of arachidonic acid has also been shown to augment the
number of group III impulses fired per second during static
contraction, whereas the infusion of the COX inhibitor indomethacin markedly attenuates contraction-induced group III
AJP-Heart Circ Physiol • VOL
Fig. 3. Cumulative histogram of group III afferent impulses before, during,
and after electrically induced static contraction. A: in 11 group III sensory
neurons, afferent activity was elevated during static contraction (denoted
by black bar, Cx). B: the discharge of group III afferents was markedly
reduced during contraction 60 min after the injection of gadolinium
trichloride (10 mM in 1 ml) into the femoral artery. C: group III afferent
impulses during contraction were partially restored after 120 min. Data
adapted from Hayes and Kaufman (41).
afferent impulses (44, 137). Furthermore, the infusion of exogenous PG partially restores the pressor response to static
contraction after treating the hindlimb with indomethacin
(159). Collectively, these studies suggest that the by-products
of COX-mediated arachidonic acid metabolism sensitize
mechanoreceptors during static exercise. In humans, dynamic
and static exercise increases circulating PG (185). Consistent
with animal data, intrabrachial infusion of indomethacin has
been shown to abolish the muscle SNA response to lowintensity rhythmic exercise in humans (9, 111). However,
indomethacin was not localized to the brachial circulation, and
the results of these studies may have been influenced by a
systemic response. In a separate experiment, ketorolac, a nonselective COX inhibitor, was intravenously infused into the
arm after Bier block, a technique used to reduce the systemic
circulation of exogenously administered substrates (20). The
sympathetic response to wrist extension and postexercise ischemia was abrogated after the inhibition of COX, possibly
because of a reduction in thromboxane production (20).
The purine ATP is produced during exercise, acts as a ligand
for P2X receptors localized on group III and IV fibers, and as
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The Skeletal Muscle Mechanoreflex
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
such may function as a metabolite that sensitizes mechanoreceptors. Hanna and Kaufman (40) demonstrated that an inhibition of P2X receptors in the hindlimb of the cat attenuates the
pressor response to passive stretch by 47%. More recently, this
group measured group III afferent activity during electrically
induced static contraction and passive stretch in decerebrated
cats before and after infusion of the P2X receptor antagonist
PPADS (72). PPADS reduced group III afferent impulses to
static contraction and tendon stretch by 47 and 50%, respectively (72). Additionally, PPADS attenuated the rapid renal
SNA response to static contraction and tendon stretch (73).
Therefore, the evidence supports a role for purinergic receptors in the sensitization of mechanoreceptors during
physical activity.
Cardiovascular diseases, such as hypertension and heart
failure, are characterized by chronic elevations in SNA. In such
diseases, the autonomic response to exercise is altered, generating exaggerated increases in BP, HR, and vascular resistance
during acute physical activity. Therefore, the risk of experiencing myocardial ischemia, myocardial infarction, cardiac
arrest, and/or stroke during or immediately after exercise is
heightened. Recent research has demonstrated that skeletal
muscle reflexes play a significant role in developing this
potentially deleterious cardiovascular response to exercise in
both hypertension and heart failure.
Hypertension. In hypertension, exercise evokes excessive
increases in BP from a chronically elevated baseline (128).
Smith et al. (155) demonstrated that the pressor and tachycardic responses to activation of the EPR are exaggerated in
spontaneously hypertensive rats (SHRs) compared with their
normotensive counterparts (Fig. 4). This heightened cardiovascular responsiveness has been shown to manifest at both
maximal and submaximal exercise intensities. Additionally,
ganglionic and ␣-adrenergic blockade with hexamethonium
and phentolamine, respectively, abolishes the exaggerated
pressor response to EPR activation in SHRs, suggesting that
the heightened cardiovascular response to exercise is likely
mediated by potentiated increases in efferent SNA (155).
Direct measurement of renal SNA in SHRs demonstrated that
renal SNA is indeed abnormally elevated in response to the
activation of the EPR in these animals (119). Collectively,
these studies support the contention that the exaggerated cardiovascular response to exercise in hypertension is mediated,
in part, by abnormally large EPR-induced elevations in SNA.
In an animal model of essential hypertension, investigations
have demonstrated that both the mechanically and metabolically sensitive components of the EPR contribute significantly
to its overactivity as shown in Fig. 5 (86, 119). Selective
activation of mechanically sensitive afferent fibers via passive
muscle stretch produces enhanced elevations in BP, HR, and
renal SNA in hypertensive rats (86, 119). In addition, gadolinium infusion into the hindlimb while stimulating the EPR
abrogates the abnormally large pressor, tachycardic, and sympathetic responses produced in hypertensive animals (119).
Moreover, preliminary studies performed in our laboratory
have demonstrated that static contraction in an ischemic
Fig. 4. A representative tracing of the cardiovascular response to electrically induced
static contraction in normotensive and hypertensive rats. The pressor and sympathetic
response to a given amount of tension generated during electrically induced static contraction is greater in spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats. ABP,
arterial blood pressure; RSNA, renal sympathetic nerve activity. Tracing adapted from
Mizuno et al. (119).
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EPR Dysfunction in Disease
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EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
hindlimb (an experimental strategy designed to suprastimulate
the metaboreflex) likewise evokes excessive increases in mean
arterial pressure, HR, and renal SNA in hypertensive rats
(118). With respect to the latter, the findings reported in
animals have recently been corroborated in a series of investigations in patients with hypertension of various etiologies
(22, 145). In hypertensive humans, post-handgrip exercise
circulatory occlusion (a predominantly metabolic stimulus) has
been shown to produce significantly greater increases in BP
compared with age-matched normotensive subjects (145). Extending these findings, Delaney et al. (22) recently demonstrated that the muscle SNA response to the activation of the
metaboreflex is abnormally large in older patients with hypertension, although conflicting results have been reported in
younger patients (133).
Collectively, the animal and human data support the hypothesis that skeletal muscle reflexes are exaggerated in hypertension. The etiology of this dysfunction is currently unclear but
may result from a shift in the expression and/or sensitivity of
metaboreceptors and mechanoreceptors. For example, TRPV1
receptor protein expression is augmented in the dorsal root
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Fig. 5. Stimulation of the metaboreflex and the mechanoreflex evokes an
exaggerated pressor response in hypertension. A: injection of graded doses of
capsaicin into the femoral artery of hypertensive rats produced an exaggerated
increase in mean arterial pressure (MAP) compared with normotensive rats.
Sal, saline; Veh, vehicle. B: passive stretch of the hindlimb evoked a significantly greater pressor response in SHRs compared with WKY rats, specifically
from 34 to 100% maximal tension development. *SHRs significantly different
from WKY. †Significantly different from the preceding stimulus. Significance
was set at P ⬍ 0.05. Data adapted from Leal et al. (86).
ganglion of SHRs compared with normotensive rats (118).
Whether such changes in receptor protein expression lead to
abnormal group III and/or group IV afferent activity remains
unknown. As another possibility, central processing of sensory
input within the brain stem may be altered in hypertension.
Within the cardiovascular control circuits, nitric oxide (NO)
synthase catalyzes the oxidation of L-arginine, producing NO
and L-citrulline. In cats, increasing endogenous NO production
within the NTS has been shown to buffer EPR activity such
that the sympathetic response to contraction is not as large as
it otherwise would be (153). Therefore, NO may either directly
or indirectly function as a neuromodulator of the cardiovascular response to EPR activation by attenuating increases in
sympathetic outflow. Several mechanisms could facilitate the
dysfunction of this potential NO buffering system in hypertension. For example, in hypertensive rats, circulating angiotensin
II (ANG II) is elevated as are the substrates and enzymes
necessary for ANG-II production and activity within brain
stem nuclei important to cardiovascular control. In addition,
ANG-II binding receptor protein expression is greater within
brain stem cardiovascular regulatory centers (169). Binding of
ANG II to its receptor activates redox-sensitive pathways,
resulting in a greater production of reactive oxygen species
(ROS), such as superoxide, which have been shown to be
increased in the brain stem of hypertensive rats (51, 126, 169).
Moreover, superoxide is a well-known scavenger of NO (51,
126). As such, increased superoxide production within the
brain stem in hypertension could potentially reduce NO bioavailability. As another example, a reduction in NO synthase
expression or an uncoupling of this enzymatic protein could
likewise lead to a decrease in NO production, reducing the
sympathetic buffering capacity of NO. Although highly speculative at this point, such alterations in the neurochemistry of
the brain could significantly contribute to EPR-induced exaggerations in SNA during exercise in hypertension.
Heart failure. Chronic hypertension may lead to deleterious
structural changes in the myocardium, as a result of pumping
blood against a heightened arterial resistance (i.e., afterload).
Patients with heart failure exhibit a dilated left ventricle,
decreased cardiac output, chronically elevated SNA, and peripheral endothelial dysfunction (50, 168). Additionally, in
patients with heart failure, exercise evokes excessive increases
in BP, HR, and SNA similar to that observed in hypertension
(37, 114). Research suggests that skeletal muscle reflexes are
likewise dysfunctional in heart failure; however, the etiology
appears to be different than that observed in hypertension
(150). A review of mechanoreflex and metaboreflex dysfunction in heart failure has been previously published (152) but
will be briefly discussed. As seen in Fig. 6, an activation of the
EPR via static contraction in rats with dilated cardiomyopathy
(induced by ligation of the left anterior descending coronary
artery) elicits a greater pressor, cardioaccelerator, and renal
sympathetic response compared with control and sham-operated animals with similar baseline BP (79, 150). Animal and
human data have suggested that the exaggerated EPR observed
in heart failure is mediated by mechanoreflex overactivity,
whereas metaboreflex function appears to be blunted (12, 154,
156, 160, 178).
Speculatively, the blunting of the metaboreflex in patients
with heart failure may result from a chronic reduction in
skeletal muscle perfusion, preventing sufficient removal of
Review
EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
H1199
metabolites produced during exercise. As such, the potential
chronic exposure to excess metabolites could result in a downregulation of metaboreceptors or a decrease in their sensitivity.
In support of this concept, two separate groups have demonstrated that TRPV1 mRNA and protein expression are significantly reduced in the dorsal root ganglion, subserving
hindlimb skeletal muscle of rats with dilated cardiomyopathy
compared with controls (156, 178). Furthermore, TRPV1
mRNA expression has also been shown to be reduced in the
soleus muscle of the hindlimb (156). Collectively, these data
suggest that metabolically sensitive group IV afferent impulses
may be significantly reduced in an animal model of ischemiainduced heart failure, possibly because of a downregulation of
metaboreceptors.
In heart failure, evidence suggests that an overactive mechanoreflex mediates the exaggerated EPR evoked cardiovascular
response to physical activity. Isolated stimulation of mechanoreceptors produces a significantly greater increase in muscle
and renal SNA in rats with dilated cardiomyopathy compared
with normal rats (112, 113, 178). The exaggerated cardiovascular response may be due to a heightened sensitization of
mechanoreceptors to metabolites because of a reduced ability
to remove metabolites produced during contraction. For example, intra-arterial injection of a bradykinin receptor blocker
reduced the renal SNA response to hindlimb static contraction
in rats with dilated cardiomyopathy while having no affect on
the renal SNA response in normal rats (78). Middlekauff and
Chiu (111) sought to determine whether the by-products of
arachidonic acid metabolism sensitize mechanoreceptors in
humans with heart failure. Low-intensity rhythmic handgrip
exercise evoked heightened increases in BP, HR, and muscle
SNA, which were markedly reduced after the infusion of
indomethacin into the forearm arterial circulation (111). This is
consistent with the tenet that an excessive accumulation of
arachidonic acid by-products sensitizes muscle mechanorecepAJP-Heart Circ Physiol • VOL
tors during physical activity in patients with heart failure.
However, direct measurements of these metabolites in patients
with heart failure during exercise have yet to be obtained. As
another example, intra-arterial administration of an antagonist
of the P2X receptor, also thought to sensitize mechanoreceptors, significantly attenuated the discharge of group III afferents during passive stretch and static contraction (178). Additionally, the administration of a P2X receptor agonist increased
the pressor response to muscle stretch by 72% in heart failure
rats, compared with only 42% in control rats (32). Furthermore, P2X receptor protein expression has been demonstrated
to be significantly increased in the dorsal root ganglion, subserving skeletal muscle afferent fibers in heart failure rats
compared with healthy controls (32, 178).
Other mechanisms may have a role in generating abnormal
EPR function in heart failure as well. For example, chronic
peripheral ischemia due to an insufficient cardiac output in
heart failure potentiates the generation of ROS (e.g., superoxide) within skeletal muscle (167). Augmented ROS production
is strongly associated with endothelial dysfunction and may
contribute to the exaggerated sympathoexcitatory response to
exercise in heart failure (96). In normal rats, hindlimb infusion
of a superoxide dismutase inhibitor increased ROS production
within the skeletal muscle and augmented the pressor response
to static muscle contraction (180). This sympathoexcitatory
response was significantly attenuated by intra-arterial infusion
of a superoxide dismutase mimetic Tempol (180). However, it
should be noted that in this investigation Tempol was not
trapped in the hindlimb circulation; therefore, it is possible that
the attenuated pressor response to EPR stimulation was mediated by a systemic effect of Tempol, not an attenuation of
muscle afferent activity. In support of this concern, a separate
experiment in which Tempol was injected and trapped in the
hindlimb circulation of normal rats was unable to verify that
Tempol attenuated the pressor response to static contraction in
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Fig. 6. Electrically induced static contraction evokes an
exaggerated sympathetic response in rats with dilated cardiomyopathy. Static contraction of the hindlimb for 30 s (A)
evoked a significantly (*P ⬍ 0.05) greater change in RSNA
and lumbar SNA (LSNA) in rats with ischemia-induced
dilated cardiomyopathy (black bars) compared with normal
control rats (white bars) (B). Change in RSNA (C) and
LSNA (D) was significantly greater for a given amount of
tension generated over the 30-s contraction [tension time
index (TTI)]. Int, integrated; AU, arbitrary units. Data
adapted from Koba et al. (79).
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H1200
EXERCISE PRESSOR REFLEX-MEDIATED CONTROL OF THE CIRCULATION
normal rats (77). However, in rats with heart failure induced by
myocardial infarction, the entrapment of Tempol within the
hindlimb circulation did produce a marked reduction in BP,
HR, and renal SNA in response to the activation of the EPR
(77). Collectively, these data suggest that increases in ROS
generation in the hindlimb skeletal muscle contributes to the
exaggerated cardiovascular response to stimulation of the EPR
in heart failure.
Future Directions/Perspectives
GRANTS
This work was supported by National Heart, Lung, and Blood Institute
Grant HL-088422 (to S. A. Smith) and the Lawson & Rogers Lacy Research
Fund in Cardiovascular Disease (to J. H. Mitchell).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
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