A Nitric Oxide-Releasing PDE5 Inhibitor Relaxes Human Corpus Cavernosum in the Absence of Endogenous Nitric Oxide

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Abstract
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. We therefore aimed to compare sildenafil and NO‐releasing sildenafil (NCX‐911) in relaxing human corpus cavernosum in the absence or presence of endogenous NO. The two compounds were compared in reducing the phenylephrine‐induced tone of human corpus cavernosum in the presence or absence of an inhibitor of NO synthase (L‐NAME; 500 µM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 µM). NCX‐911 was as potent as sildenafil in control conditions (EC50 = 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‐NAME (EC50 = 980.4 ± 106.7 nM and 2446.7 ± 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 µM failed to induce relaxation in the presence of ODQ (EC50 = 6578 ± 1150 nM and 6488 ± 938 nM for NCX‐911 and sildenafil, respectively). These results show that the potency of NCX‐911 was maintained unlike sildenafil in the absence of endogenous NO confirming the potential use of NO‐releasing PDE5 inhibitors in NO‐deficient conditions.

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