TRPV1 Channel Stimulation Reduces the Mechanoreflex in Decerebrate Rats

Abstract

Background Mechanically-sensitive channels (MSCs) located on group III and IV thin fiber skeletal muscle afferents are stimulated by skeletal muscle contraction during exercise and contribute to reflex increases in sympathetic nervous system activity and blood pressure. This exercise-induced mechanically activated reflex, termed the mechanoreflex, is dependent on MSC stimulation produced by changes in muscle length and concurrent increases in intramuscular pressure during contraction. A relatively novel class of mechanically activated channel known as “piezo” is thought to contribute importantly to the generation of the mechanoreflex. For example, we found recently that hindlimb arterial injection of GsMTx4, a partially selective piezo channel inhibitor, reduced the pressor response to isolated dynamic mechanoreflex activation in rats. Recent work on the gating mechanics of piezo channels reveal that their activation can be regulated by changes in the phospholipid components of the cell membrane. Stimulation of transient receptor potential vanilloid 1 (TRPV1) has been shown to alter membrane concentrations of phospholipid component phosphatidylinositol 4,5-bisphosphate (PIP2). Specifically, stimulation of TRPV1 by capsaicin has been shown to completely inhibit piezo channel currents by depleting PIP2 in dorsal root ganglia neurons. Whether TRPV1 stimulation with capsaicin can modulate MSCs involved in mechanoreflex activation and reduce the reflex increase in blood pressure during dynamic hindlimb muscle stretch remains unknown. Purpose and Hypothesis Our purpose was to investigate the effect of TRPV1 stimulation produced by the injection of capsaicin into the arterial supply of the hindlimb on the mechanoreflex in healthy rats with patent femoral arteries (“freely perfused”, FP) and in a chronically ligated femoral artery rat model of simulated peripheral artery disease (“ligated”) in which the mechanoreflex is exaggerated. We tested the hypothesis that hindlimb arterial injection of capsaicin would reduce the pressor response to 30 s of 1 Hz dynamic hindlimb muscle stretch in both FP and ligated rats. Methods We compared (paired Student's t-tests) the pressor response (peak Δ mean arterial blood pressure) to muscle stretch before and 30 minutes after the injection of the TRPV1 agonist capsaicin (0.5 µg in 0.25ml) into the arterial supply of the hindlimb circulation of decerebrate, unanesthetized rats. Results Injection of capsaicin into the arterial supply of the hindlimb produced a pressor response in 57±14 mmHg in FP rats and 52±4 mmHg in ligated rats. More importantly, we found that capsaicin significantly reduced the peak pressor response to dynamic stretch in both FP (n=4, pre: 19±5, post: 5±1 mmHg, p=0.04) and ligated (n=7, pre: 27±3, post: 19±4 mmHg, p=0.01) rats. Conclusion We conclude that TRPV1 stimulation with capsaicin reduced the mechanoreflex evoked by dynamic stretch in both FP and ligated rats. These data provide additional, albeit indirect, evidence that piezo channels contribute importantly to the generation of the mechanoreflex and that TRPV1 stimulation-induced desensitization of piezo channels is capable of modulating mechanoreflex activation.