Megan N. Murphy

Cardiovascular regulation by skeletal muscle reflexes in health and disease

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.

Skeletal muscle reflex-mediated changes in sympathetic nerve activity are abnormal in spontaneously hypertensive rats

In hypertension, the blood pressure response to exercise is exaggerated. We demonstrated previously that this heightened pressor response to physical activity is mediated by an overactive skeletal muscle exercise pressor reflex (EPR), with important contributions from its metaboreflex and mechanoreflex components. However, the mechanisms driving the abnormal blood pressure response to EPR activation are largely unknown. Recent evidence in humans suggests that the muscle metaboreflex partially mediates the enhanced EPR-induced pressor response via abnormally large changes in sympathetic nerve activity (SNA). Whether the muscle mechanoreflex induces similarly exaggerated alterations in SNA in hypertension remains unknown, as does the role of the mechanoreceptors mediating muscle reflex activity. To address these issues, the EPR was selectively activated by electrically inducing hindlimb muscle contraction in decerebrate normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Stimulation of the EPR evoked significantly larger increases in mean arterial pressure (MAP) and renal SNA (RSNA) in SHR compared with WKY (ΔRSNA from baseline: 140 ± 11 vs. 48 ± 8%). The mechanoreflex was stimulated by stretching hindlimb muscle which likewise elicited significantly greater elevations in MAP and RSNA in SHR than WKY (ΔRSNA from baseline: 105 ± 11 vs. 35 ± 7%). Blockade of mechanoreceptors in muscle with gadolinium significantly attenuated the MAP and RSNA responses to contraction and stretch in SHR. These data suggest that 1) the exaggerated pressor response to activation of the EPR and muscle mechanoreflex in hypertension is mediated by abnormally large reflex-induced augmentations in SNA and 2) this accentuated sympathetic responsiveness is evoked, in part, by stimulation of muscle mechanoreceptors.

Antagonism of the TRPv1 receptor partially corrects muscle metaboreflex overactivity in spontaneously hypertensive rats

Non‐technical summary  The cardiovascular response to exercise is exaggerated in hypertension. This heightened circulatory responsiveness increases the risk of occurrence of an adverse cardiovascular event during and immediately following a bout of exercise. Accumulating evidence suggests the muscle metaboreflex, a chemically sensitive peripheral reflex originating in skeletal muscle, contributes significantly to this abnormal cardiovascular response to exercise. However, its role remains controversial. In addition, the receptor mechanisms underlying metaboreflex dysfunction in hypertension remain undetermined. To this end, the current investigation demonstrates that the metaboreflex is overactive in hypertensive rats eliciting exaggerated increases in sympathetic nerve activity and blood pressure. Importantly, the study shows, for the first time, that the metaboreflex dysfunction manifest in hypertension is mediated, in part, by activation of the skeletal muscle TRPv1 receptor. As such, the investigation identifies the muscle metaboreflex, specifically the TRPv1 receptor, as a potential target for the treatment of cardiovascular hyperexcitability during exercise in hypertension.

The TRPv1 receptor is a mediator of the exercise pressor reflex in rats

The skeletal muscle exercise pressor reflex (EPR) induces increases in heart rate (HR) and mean arterial pressure (MAP) during physical activity. This reflex is activated during contraction by stimulation of afferent fibres responsive to mechanical distortion and/or the metabolic by‐products of skeletal muscle work. The molecular mechanisms responsible for activating these afferent neurons have yet to be identified. It has been reported that activation of the transient receptor potential vanilloid 1 (TRPv1) receptor within skeletal muscle (localized to unmyelinated afferent fibres) elicits increases in MAP and HR similar to those generated by the EPR. Thus, we hypothesized that stimulation of the TRPv1 receptor during muscle contraction contributes to the activation of the EPR. The EPR was activated by electrically induced static muscle contraction of the hindlimb in decerebrate Sprague–Dawley rats (n= 61) before and after the administration of the TRPv1 receptor antagonists, capsazepine (Capz; 100 μg/100 μl), iodoresinaferatoxin (IRTX; 1 μg/100 μl), or Ruthenium Red (RR; 100 μg/100 μl). Static muscle contraction alone induced increases in both HR (8 ± 2 bpm) and MAP (21 ± 3 mmHg). The HR and MAP responses to contraction were significantly lower (P < 0.05) after the administration of Capz (2 ± 1 bpm; 7 ± 1 mmHg, respectively), IRTX (3 ± 2 bpm; 5 ± 3 mmHg, respectively) and RR (0 ± 1, bpm; 5 ± 2 mmHg, respectively). These data suggest that the TRPv1 receptor contributes importantly to activation of the EPR during skeletal muscle contraction in the rat.

Neuronal nitric oxide synthase expression is lower in areas of the nucleus tractus solitarius excited by skeletal muscle reflexes in hypertensive rats.

The functions of the skeletal muscle exercise pressor reflex (EPR) and its mechanically sensitive component are augmented in hypertension producing exaggerated increases in blood pressure during exercise. Afferent information from the EPR is processed in the nucleus tractus solitarius (NTS). Within the NT, nitric oxide (NO), produced via L-arginine oxidation by neuronal nitric oxide synthase (nNOS), buffers the pressor response to EPR activation. Therefore, EPR overactivity may manifest as a decrease in NO production due to reductions in nNOS. We hypothesized that nNOS protein expression is lower in the NTS of spontaneously hypertensive (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. Further, we examined whether nNOS is expressed with FOS, a marker of neuronal excitation induced by EPR activation. The EPR and mechanoreflex were intermittently activated for 1 h via hindlimb static contraction or stretch, respectively. These maneuvers produced significantly greater pressor responses in SHR during the first 25 min of stimulation. Within the NTS, nNOS expression was lower from -14.9 to -13.4 bregma in SHR compared with WKY. For example, at -14.5 bregma the number of NTS nNOS-positive cells in SHR (13 ± 1) was significantly less than WKY (23 ± 2). However, the number of FOS-positive cells after muscle contraction in this area was not different (WKY = 82 ± 18; SHR = 75 ± 8). In both groups, FOS-expressing neurons were located within the same areas of the NTS as neurons containing nNOS. These findings demonstrate that nNOS protein expression is lower within NTS areas excited by skeletal muscle reflexes in hypertensive rats.

A role for nitric oxide within the nucleus tractus solitarii in the development of muscle mechanoreflex dysfunction in hypertension

Evidence suggests that the muscle mechanoreflex, a circulatory reflex that raises blood pressure and heart rate (HR) upon activation of mechanically sensitive afferent fibres in skeletal muscle, is overactive in hypertension. However, the mechanisms underlying this abnormal reflex function have yet to be identified. Sensory input from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) in the medulla oblongata. Within the NTS, the enzymatic activity of nitric oxide synthase produces nitric oxide (NO). This centrally derived NO has been shown to modulate muscle reflex activity and serves as a viable candidate for mediating the mechanoreflex dysfunction that develops in hypertension. We hypothesized that mechanoreflex dysfunction in hypertension is mediated by abnormal alterations in NO production in the NTS. Mechanically sensitive afferent fibres were stimulated by passively stretching hindlimb muscle before and after blocking the endogenous production of NO within the NTS via microdialysis of the NO synthase inhibitor l‐NAME (1 and 5 mm) in normotensive Wistar–Kyoto rats and spontaneously hypertensive rats (SHRs). Changes in HR and mean arterial pressure in response to stretch were significantly larger in SHRs compared with Wistar–Kyoto rats prior to l‐NAME dialysis. Attenuating NO production via l‐NAME in normotensive rats recapitulated the exaggerated cardiovascular response to stretch observed in SHRs. Dialysing l‐NAME in SHRs further accentuated the increases in HR and mean arterial pressure elicited by stretch. These findings support the contention that reductions in NO production within the NTS contribute to the generation of abnormal cardiovascular control by the skeletal muscle mechanoreflex in hypertension.

Muscle mechanoreflex overactivity in hypertension: A role for centrally-derived nitric oxide

The cardiovascular response to exercise is abnormally large in hypertension. Over the past decade, it has become clear that the exercise pressor reflex (a peripheral feed-back mechanism originating in skeletal muscle) contributes significantly to the generation of this hyper-responsiveness. Further, it has been determined that overactivity of the mechanically (muscle mechanoreflex) and chemically (muscle metaboreflex) sensitive components of the exercise pressor reflex underpin its dysfunction. Given the recent attention in the literature, this review focuses upon the aberrant function of the muscle mechanoreflex in this disease. Evidence supporting a role for the mechanoreflex in the pathogenesis of the exaggerated cardiovascular response to physical activity is highlighted. The peripheral and central mechanisms that may be responsible for mechanoreflex overactivity in hypertension are likewise discussed. Particular attention is given to emerging evidence implicating a role for centrally-derived nitric oxide in this process.

Exercise pressor reflex function following acute hemi-section of the spinal cord in cats

Cardiovascular disease is a leading cause of morbidity and mortality in patients post spinal cord injury (SCI). The prescription of exercise as a therapeutic modality for disease prevention in this population is promising. It is logical to suggest that the sooner an exercise program can begin the more benefit the patient will receive from the therapy. However, the time point after injury at which the requisite circulatory responses needed to support exercise are viable remains largely unknown. The skeletal muscle exercise pressor reflex (EPR) significantly contributes to cardiovascular control during exercise in healthy individuals. Experiments in patients with a chronic lateral hemi-section of the spinal cord (Brown-Séquard syndrome) suggest that the EPR, although blunted, is operational when examined months to years post injury. However, whether this critically important reflex remains functional immediately after lateral SCI or, in contrast, experiences a period of reduced capacity due to spinal shock has not been established. This study was designed to assess EPR function after acute lateral transection of the spinal cord. The EPR was selectively activated in seven decerebrate cats via electrically stimulated static contraction of the triceps surae muscles of each hindlimb before and after lateral hemi-section of the T13–L2 region of the spinal cord. Compared to responses prior to injury, increases in mean arterial pressure (MAP) were significantly decreased when contracting the hindlimb either ipsilateral to the lesion (MAP = 17 ± 3 mmHg before and 9 ± 2 mmHg after) or contralateral to the lesion (MAP = 22 ± 5 mmHg before and 12 ± 4 mmHg after). The heart rate (HR) response to stimulation of the EPR was largely unaffected by induction of acute SCI. The findings suggest that the EPR maintains the ability to importantly contribute to cardiovascular regulation during exercise immediately following a Brown-Séquard-like injury.