TRPM8 channel activation induces relaxation in pudendal artery and corpus cavernosum: Can TRPM8 channel be a target to improve diabetic erectile dysfunction?

Abstract

Erectile dysfunction (ED) is one of the most common and underestimated complications of diabetes. Previous studies have shown that TRPM8 activation triggers relaxation of internal pudendal arteries (IPA) with increased sensitivity in hypertensive rats. Despite the correlation between ED and diabetes, research on the role of TRPM8 channels in the IPA and corpus cavernosum (CC) in diabetes still needs to be elucidated. We hypothesized that preserved TRPM8 channel function in diabetic mice could be a therapeutic target for the treatment of ED. Male lean and db/db mice were euthanized, and the IPA were mounted on DMT wire myographs and CC were mounted on AVS organ bath for the measurement of isometric force. Concentration-response curves to icilin or menthol (TRPM8 agonists) were obtained. The CC TRPM8 channels expression was evaluated by western blot. Second harmonic generation was used to evaluate collagen deposition in IPA. Data are expressed as mean ± S.E.M of 3-5 mice. Non-linear regression curve was performed, and the maximum response (Emax) was analyzed using Student’s t test (p<0.05). Similar TRPM8 channel expression was observed in the CC from lean and db/db mice. Menthol-induced relaxation of the CC was reduced in diabetic mice (Emax: 105.00 ± 5.00%) compared to lean mice (Emax: 139.44 ± 15.91%) . Relaxant effect induced by icilin and menthol was similar between IPA from db/db (Emax icilin: 95.56 ± 0.86% and Emax menthol: 93.88 ± 2.33%) and lean (Emax icilin: 97.05 ± 0.87% and Emax menthol: 101.10 ± 1.75%) mice. Interestingly, pre-incubation with icilin (10-4M) for 30 minutes decreased the potency of phenylephrine-induced contraction compared to untreated IPA rings in both db/db and lean mice. In the IPA, diabetes decreased the sensitivity to acetylcholine compared to lean. However, the relaxation induced by acetylcholine was not changed by pre-incubation with icilin. Diabetic mice (db/db) IPA tended to have a decrease in arterial collagen content compared to lean mice. Although menthol-induced relaxation of the CC was reduced in diabetic mice, icilin and menthol were able to promote similar relaxation in IPA from diabetic and lean mice. In this way, TRPM8 function was preserved in IPA from diabetic mice. Icilin reduced sensitivity to phenylephrine in IPA from both mice. These data suggest that activation of TRPM8 could be a therapeutic target for the treatment of ED. SMSNA, NIH (RO1DK132948) and FAPESB This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.