Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum

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 (H₂S) in erection has recently been recognized and is receiving attention as a pharmacological target. Several studies have focused on the effect of H₂S on NO-dependent relaxation, but the role of NO on H₂S in penile tissue has not been studied yet. Unlike NO, H₂S is mainly synthesized from smooth muscle cells rather than endothelial cells. We hypothesized that H₂S 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 H₂S formation and vasorelaxation induced by l-cysteine, which is the substrate of the H₂S 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 H₂S 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 H₂S donor) in MCC was observed. L-NNA increased H₂S 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 H₂S plays a compensatory role in the absence of NO by enhancing the relaxation induced by endogenous H₂S through CSE and 3-MPST in MCC, without altering downstream mechanisms. We suggest that H₂S-targeting drugs may provide the maintenance of compensatory treatment in ED patients. This may be more relevant in ED with severe endothelial dysfunction, as H₂S is mainly derived from smooth muscle.