Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum

Abstract Erectile dysfunction (ED) is considered as a marker for cardiovascular diseases. Nitric oxide (NO) deficiency is the major cause of erectile dysfunction (ED). The role of hydrogen sulfide (H 2 S) in erection has recently been recognized and is receiving attention as a pharmacological target. Several studies have focused on the effect of H 2 S on NO-dependent relaxation, but the role of NO on H 2 S in penile tissue has not been studied yet. Unlike NO, H 2 S is mainly synthesized from smooth muscle cells rather than endothelial cells. We hypothesized that H 2 S may compensate for the decreased NO bioavailability and may be beneficial in severe ED where endothelial dysfunction is present. Thus we studied the effect of NO deficiency on H 2 S formation and vasorelaxation induced by l -cysteine, which is the substrate of the H 2 S producing enzymes in mice corpus cavernosum (MCC). NO deficiency induced by Nω-Nitro- l -arginine (L-NNA) was confirmed by the inhibition of acetylcholine-induced relaxation. l -cysteine, the substrate for the endogenous H 2 S production, caused a concentration-dependent relaxation that was reduced by CBS/CSE inhibitor aminooxyacetic acid (AOAA) in MCC strips. L-NNA caused a significant increase in l -cysteine-induced relaxation, and this effect was reversed by AOAA. On the contrary, no change in relaxation to NaHS (exogenous H 2 S donor) in MCC was observed. L-NNA increased H 2 S formation stimulated by l -cysteine in wild type MCC but not in CSE −/− mice. In parallel, the expression of both cysthationine γ lyase (CSE) and 3-mercaptopyruvate sulphurtransferase (3-MST) was increased, whereas cysthationine-β synthase (CBS) was decreased in eNOS −/− MCC. We conclude that H 2 S plays a compensatory role in the absence of NO by enhancing the relaxation induced by endogenous H 2 S through CSE and 3-MPST in MCC, without altering downstream mechanisms. We suggest that H 2 S-targeting drugs may provide the maintenance of compensatory treatment in ED patients. This may be more relevant in ED with severe endothelial dysfunction, as H 2 S is mainly derived from smooth muscle.