TRPM8 channel activation triggers relaxation of pudendal artery and corpus cavernosum with increased vascular sensitivity in spontaneously hypertensive rats: Is it a new target for erectile dysfunction?

Abstract

Background and PurposeErectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recently uncovered functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure. The aim of this study was to investigate the function of cold‐sensing TRPM8 channel in internal pudendal artery (IPA) in normotensive and hypertensive rats.Experimental ApproachWe performed experiments integrating physiological, pharmacological, biochemical, and cellular techniques.Key ResultsTRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA and corpus cavernosum (CC). In addition, TRPM8 activation, by both a cooling compound (icilin) and cold (thermal stimulus), induced relaxation in IPA and CC. In IPA, the concentration‐response curve to icilin was desensitized in different conditions, such as: the absence of vascular endothelium, the presence of L‐NAME (10−4 M) or indomethacin (10−5 M), a combination of charybdotoxin (10−7 M) and apamin (5×10−6 M), and Y27632 (10−6 M). Interestingly, icilin‐induced vasodilation was significantly higher in IPA from spontaneously hypertensive (SHR) compared to Wistar rats, despite no differences in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. In CC, the concentration‐response curve to icilin was shifted to the right in the presence of ROCK inhibitor Y27632, suggesting that ROCK, at least in part, is important to relaxation induced by TRPM8 activation. Supporting these functional data, we observed that the expression of RhoA and ROCK was not changed in CC treated with either vehicle, Phe, or Phe+icilin. However, MYPT1 phosphorylation was increased by Phe compared to control, and Phe+icilin reverted this effect, suggesting that TRPM8 activation inhibits RhoA/ROCK pathway in CC.ConclusionsThese data demonstrate, for the first time, the expression and function of TRPM8 channels in the IPA and CC involving, at least in part, endothelium‐derived relaxing factors and ROCK inhibition. Overall, this channel could potentially be a new target for the treatment of hypertension associated‐ED.Support or Funding InformationNational Council for Scientific and Technological Development (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES); NIDDK Diacomp Pilot & Feasibly Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.