TRPV4 channels mediate exacerbated response to mechanical cues in spontaneously hypertensive rats

Upon hypoosmotic stimulation, cardiomyocytes undergo a transient positive inotropic effect (Pie) associated with an increase in the amplitude of intracellular Ca2+ transients. However, the underlying mechanisms remain elusive. The Transient Receptor Vanilloid 4 channel (TRPV4) promotes Ca2+ entry and, thus, could contribute to hypotonic swelling-induced Pie. TRPV4 have not been studied in spontaneously hypertensive rats (SHRs). We aimed to determine if TRPV4 contributes to swelling-induced Pie in Wistar rats and if this response is altered in SHR. Cardiomyocytes were isolated from 8 to 12-month-old Wistar and SHR rats. Contractility was assessed by video-edge-detection in myocytes superfused with isotonic (309 mOsm) or hypotonic solution (217 mOsm). TRPV4 expression was assessed by western blot. The slow force response (SFR) was examined in papillary muscles from SHR stretched from 92 to 98% of their maximal length. While TRPV4 inhibition with GSK2193874 (GSK; 300 nmol/l) or HC067047 (1 μmol/l) did not affect the hypotonic solution induced Pie in Wistar myocytes, it was significantly reduced in SHR. Consistently, TRPV4 expression was enhanced in SHR hearts and myocytes. Disruption of caveolae with 5 mmol/l methyl-β-cyclodextrin and inhibition of microtubule polymerization with 10 μmol/l Colchicine, reduced the GSK-sensible component of the hypotonic solution induced Pie. GSK also blunted the SFR in SHR papillary muscles. We conclude that TRPV4 do not contribute to the hypotonic solution induced Pie in Wistar rats but provide Ca2+ entry that amplifies this response in SHR. Intact caveolae and microtubule integrity are required for TRPV4 activation in SHR myocytes. In SHR hearts, TRPV4 can be activated by cardiac stretch contributing to the SFR.