TRPM8 channel activation triggers relaxation of pudendal artery with increased sensitivity in the hypertensive rats

Introduction: Erectile dysfunction (ED) is frequently encountered in patients with arterial hypertension and there is a recent functional correlation between the expression of thermoreceptor channels TRPM8 (melastatin 8) and alterations in blood pressure in hypertension. The aim of this study was to investigate the function of cold-sensing TRPM8 channel in internal pudendal artery (IPA) in both normotensive and hypertensive rats. Methods: We performed experiments integrating physiological, pharmacological, biochemical and cellular techniques. Results: TRPM8 channels are expressed in the IPA and in vascular smooth muscle cells from IPA. In addition, TRPM8 activation, by both a cooling compound icilin (82.1 ± 3.0%, n = 6) and cold temperature [thermal stimulus, basal tone (25 °C, 41.2 ± 3.4%, n = 5) or pre-contracted tone induced by phenylephrine (25 °C, 87.0 ± 3.6%, n = 7)], induced relaxation in IPA. Furthermore, the results showed that the concentration-response curve to icilin was significantly shifted to the right in different conditions, such as: the absence of the vascular endothelium, in the presence of L-NAME (10⁻⁴ M), or indomethacin (10⁻⁵ M) or by 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, E₁₀ ⁻⁴ _{M =} 75.3 ± 1.7%) compared to wistar rats (E₁₀ ⁻⁴ _{M =} 56.4 ± 2.6%), despite no changes in the TRPM8 expression in IPA between the strains, suggesting that the sensitivity of TRPM8 channels is higher in SHR. Conclusions: These data demonstrate for the first time, the expression and function of TRPM8 channels in the IPA 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.