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

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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.

The 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.

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