Antagonism Of Trpv4 Channels Decreases Neural Discharge And Pressor Responses To Mechanical Stimulation In Rats

Mechanical distortion of working skeletal muscle induces sympathoexcitation via thin fiber afferents, a reflex response known as the skeletal muscle mechanoreflex. However, to date, the receptor ion channels responsible for mechanotransduction within skeletal muscle sensory afferents remain largely undetermined. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel that plays an important role in mechanotransduction within various organs. We therefore hypothesized that the mechanoreflex is, in part, mediated by activation of TRPV4 in muscle afferents. PURPOSE: We examined whether application of a TRPV4 antagonist, HC067047, attenuates 1) responsiveness to mechanical stimuli in thin-fiber muscle afferents and 2) sympathetic and pressor responses to activation of the mechanoreflex via passive stretch of the hindlimb muscle in healthy rats. METHODS: The responsiveness of mechanically activated group IV fibers innervating skeletal muscle was assessed by obtaining ex vivo single-fiber recordings. Action potentials elicited by a mechanical stimulus (0-392 mN ramped stimulus) were recorded before and 5 min after intramuscular administration of HC067047 (1 μM, 5 μL) or Krebs buffer solution (vehicle control, 5 μL). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to passive stretch were measured in decerebrate Sprague-Dawley rats before and 10 min after intraarterial injection of either HC067047 (1 μM, 0.1 mL) or saline (vehicle control, 0.1 mL). RESULTS: HC067047 significantly reduced the response magnitude of mechanically-evoked action potentials in muscle group IV afferent fibers (P = 0.007). In the in vivo decerebrate rat preparation, the RSNA and MAP responses to passive stretch of hindlimb muscle were significantly attenuated by intraarterial injection of HC067047 (ΔRSNA: P = 0.019, ΔMAP: P = 0.002). CONCLUSION: The findings suggest that TRPV4 plays an important role in mechanotransduction contributing to sympathetic and pressor responses evoked by the skeletal muscle mechanoreflex during exercise.