TRPV4 and Piezo channel inhibition in the isolated carotid sinus comparably suppresses baroreflex function and acts synergistically at high arterial pressures in healthy male rats

Background and Purpose: The arterial baroreflex is a negative feedback mechanism that continuously adjusts autonomic nerve activity to regulate arterial pressure (AP) on a beat-by-beat basis at rest and during physical activity. Piezo channels are well recognized as key mechanosensitive ion channels. Importantly, a groundbreaking study using transgenic mice identified Piezo channels as essential baroreceptor mechanosensors for the acute regulation of AP. However, whether Piezo channels play a significant role in animals without genetic modifications remains unverified. Further, TRPV4 channels have been implicated in sensing mechanical forces across a variety of tissues. Nevertheless, their specific contribution to baroreceptor function has yet to be clarified. To this end, the present study aimed to determine how inhibition of Piezo and TRPV4 channels within the vascularly isolated carotid sinus region affects arterial baroreflex function in healthy, normal rats under open-loop baroreflex conditions. Methods: Fifty-eight healthy male Sprague-Dawley rats (Body weight: 378 ± 36 g) were initially anesthetized with an intraperitoneal injection of a urethane and α-chloralose cocktail. To establish an open-loop condition, the bilateral carotid sinus baroreceptors were surgically isolated from the systemic circulation. The isolated carotid sinus areas were perfused with one of the following solutions: saline (control solution, n = 11); GsMTx-4, a Piezo channel inhibitor, at 0.01 μM (n = 8), 0.1 μM (n = 8), or 1.0 μM (n = 6); HC067047, a TRPV4 inhibitor, at 0.5 μM (n = 6), 1.0 μM (n = 7), or 5.0 μM (n = 6); or a combination of 1.0 μM GsMTx-4 and 5.0 μM HC067047 (n = 6). Carotid sinus pressure (CSP) was increased stepwise from 60 mmHg to 180 mmHg in 20 mmHg increments per minute. Baroreflex function was assessed by recording renal sympathetic nerve activity (RSNA), AP, and heart rate (HR) responses to the stepwise CSP input. Results: In the control solution, RSNA, AP, and HR decreased significantly in response to the stepwise CSP input following an inverse sigmoid curve (P < 0.05). Consistent with pioneering work, GsMTx-4 significantly attenuated the neural arc (CSP–RSNA relationship) in a dose-dependent manner (P < 0.05) while having no significant effect on the peripheral arc (SNA–AP relationship) of the baroreflex. Notably, the TRPV4 inhibitor significantly reduced the cardiovascular responses to CSP in a dose-dependent manner (P < 0.05), without altering the peripheral arc, to a similar extent as the Piezo channel inhibitor. Moreover, the combination of GsMTx-4 and HC067047 produced a significantly greater reduction in the RSNA, AP, and HR responses to CSP — particularly at high CSP (180 mmHg) — than either inhibitor alone (P < 0.05). Conclusion: These findings suggest that TRPV4 channels play a critical role in baroreceptor function, comparable to that of Piezo channels, and that the two act synergistically at high AP ranges. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.