Abstract P229: Beyond Cooling Sensation: Topical Penile Administration Of The Trpm8 Agonist Improves Hypertension Associated-erectile Dysfunction

Abstract

Background and Purpose: Erectile dysfunction (ED) is an indicator for futurecardiovascular events. The search for new targets is crucial due to the low efficacy ofPDE5 inhibitors in patients with endothelial dysfunction. Menthol, a TRPM8 agonist, iswidely used in preparations to improve sensation during sexual intercourse, although nodata are reported for the improvement of ED. So, we hypothesize that chronic topicalactivation of TRPM8 improves hypertension associated-ED. Experimental Approach: Adult (9-12 weeks) male spontaneously hypertensive rats (SHR) and Wistar rats wereused for protein expression analysis and TRPM8 agonist curves in isolated CC. We alsotreated rats topically on the penis for 30 days with carbopol 940 (hydrogel, vehicle) ormenthol (carbopol 940 + menthol 0.1%). After treatment, we measured the mean bloodpressure (MBP), CC and iliac (IL) artery contractility. Key Results: Both strains of rathad similar TRPM8 expression in CC by western blotting and immunofluorescence.TRPM8 activation by cooling compounds, icilin (10 -8 –10 -4 M) or menthol (10 -7 –10 -3 M),relaxed CC strips pre-contracted by phenylephrine (PE, 10 -6 or 10 -5 M), but with reducedeffect in SHR. Interestingly, the topical penile treatment with menthol decreased the MBPof the SHR (151.8±6.8 mmHg, n=6) compared to the SHR vehicle group (174.6±2.6mmHg, n=5; p<0.05). In addition, in CC, the concentration-response curves to PE andthromboxane agonists were shifted to the left after menthol treatment. Interestingly, nochange in acetylcholine and sodium nitroprusside (SNP) relaxation were observed aftertopical penile treatment with menthol. The concentration-response curves to PE and SNPwere shifted to the left in IL arterial rings. This suggests topical menthol administrationinduced systemic vascular influence leading to a response like the normotensive Wistar. Conclusion: TRPM8 channels are expressed and functional in the CC, with decreasedsensitivity in SHR. Also, our data suggest that topical administration of menthol improvesthe reactivity of vascular tissue, demonstrating the potential of TRPM8 activation fortherapeutic benefits in hypertension associated-ED.