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

Abstract

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. AbstractThe circulatory response to exercise is exaggerated in hypertension potentially increasing the risk for adverse cardiovascular events. Evidence suggests the skeletal muscle metaboreflex contributes to this abnormal circulatory response. However, as the sensitivity of this reflex has been reported to be both reduced and potentiated in hypertension, its role remains controversial. In addition, the receptor mechanisms underlying muscle metaboreflex dysfunction in this disease remain undetermined. To address these issues, metaboreflex activity was assessed during 'supra-stimulation' of the reflex via ischaemic hindlimb muscle contraction. This manoeuvre evoked significantly larger increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. The skeletal muscle TRPv1 receptor was evaluated as a potential mediator of this metaboreflex response as it has been shown to contribute significantly to muscle reflex activation in healthy animals. Stimulation of the TRPv1 receptor by injection of capsaicin into the arterial supply of the hindlimb evoked significantly larger elevations in MAP and RSNA in SHR compared to WKY. The pressor and sympathetic responses to ischaemic muscle contraction in WKY and SHR were attenuated by the administration of the TRPv1 receptor antagonist capsazepine with the magnitude of the capsazepine-induced reductions being greater in SHR than WKY. TRPv1 protein expression in dorsal root ganglia, but not skeletal muscle, was significantly greater in SHR than WKY. The results suggest the muscle metaboreflex is overactive in hypertension. Further, this reflex overactivity can be partially normalized by antagonizing TRPv1 receptors in skeletal muscle.

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

“…One was 30-s continuous static contraction, commonly used to study the physiological roles of the exercise pressor reflex (19,20,37,38,43). Another was 1-min intermittent (1-4 s of stimulation to relaxation) static contraction.…”

“…This muscle-based reflex is termed the exercise pressor reflex (35). A series of studies by Smith and colleagues (24,37,38,43) using a decerebrate rat preparation has suggested that in spontaneous hypertensive rats (SHRs), both mechanically and chemically sensitive muscle afferents engaged during skeletal muscle contraction are stimulated excessively compared with those in normotensive rats, thereby evoking exaggerated sympathoexcitatory and pressor responses to contraction. In humans with hypertension, the elevation in muscle sympathetic nerve activity seen during postexercise ischemia, a maneuver that selectively excites chemically sensitive muscle afferents, was higher than that in normotensive subjects (10).…”

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

“…4,18,19). Of these, recent evidence in both the animal and human literature suggests that the EPR contributes significantly to the abnormally accentuated circulatory response to exercise in hypertension (2,22,23,38). Activation of the EPR, a reflex originating in skeletal muscle, is mediated by stimulation of mechanically sensitive receptors located primarily on group III afferent fibers and metabolically sensitive receptors located primarily on group IV afferent fibers (10, 11).…”

“…Activation of the EPR, a reflex originating in skeletal muscle, is mediated by stimulation of mechanically sensitive receptors located primarily on group III afferent fibers and metabolically sensitive receptors located primarily on group IV afferent fibers (10,11). In hypertension, combined or individual activation of either the mechanical (i.e., mechanoreflex) or metabolic component (i.e., metaboreflex) of the EPR results in a heightened sympathetically mediated cardiovascular response (2,13,22,23,34,38). To date, however, the mechanisms underlying EPR overactivity in hypertension remain largely unknown.…”

Exercise pressor reflex in health and diseases: Animal studies

“…Mizuno et al 86) supported the concept of the enhanced muscle mechanoreflex in hypertension by showing that the blockade of muscle mechanoreceptors with gadolinium attenuated the RSNA and pressor responses to continuous contraction in SHR. Mizuno et al 87) also supported the notion that the muscle metaboreflex is enhanced in hypertension by demonstrating that treatment with the VR1 receptor antagonist capsazepine in skeletal muscle of SHR reduced the reflex responses to ischemic contraction to a greater extent than in normotensive controls.…”