A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide

Introduction. In conditions with severe deficiency of endogenous nitric oxide (NO), such as long-term diabetes and cavernosal nerve injury, phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in the treatment of erectile dysfunction. NO-releasing PDE5 inhibitors could be an alternative therapeutic approach in Such cases. Aim. We therefore aimed to compare sildenafil and NO-releasing sildenafil (NCX-911) in relaying human corpus cavernosum in the absence or presence of endogenous NO. Methods. The two compounds were compared in reducing the phenylephrine-induced tone of human cor us cavernosum in the presence or absence of an inhibitor of NO synthase (L-NAME; P 500 mu M) or an inhibitor of soluble guanylate cyclase (ODQ, 10 mu M). Results. NCX-911 was as potent as sildenafil in control conditions (EC(50) = 733.1 +/- 94.4 nM and 800.7 +/- 155.8 nM, respectively). The potency of NCX-911 was not altered but that of sildenafil decreased significantly in the presence of L-NAIME (EC(50) = 980.4 +/- 106.7 nM and 2446.7 +/- 256.8 n/M, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 mu M failed to induce relaxation in the presence of ODQ (EC(50) = 6578 +/- 1150 nM, and 6488 +/- 938 nim for NCX-911 and sildenafil, respectively). Conclusion. These results show that the potency of NCX-911 wis maintained unlike slidenafil in the absence of endogerious NO confirming the potential use of NO-releasing PDE5 inhibitors in NO-deficient conditions.