title: A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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 microM) or an inhibitor of soluble guanylate cyclase (ODQ, 10 microM).
  
  
  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-NAME (EC(50) = 980.4 +/- 106.7 nM and 2446.7 +/- 256.8 nM, respectively; P < 0.001 for sildenafil vs. control). Both compounds below 1 microM failed to induce relaxation in the presence of ODQ (EC(50) = 6,578 +/- 1150 nM and 6,488 +/- 938 nM for NCX-911 and sildenafil, respectively).
  
  
  CONCLUSIONS
  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.
authors.affiliation: The St. Peter's Andrology Centre and Wolfson Institute for Biomedical Research, University College London, UK.
authors.forename: Jasjit S
authors.initials: JS
authors.lastname: Kalsi
authors.forename: David J
authors.initials: DJ
authors.lastname: Ralph
authors.forename: Phil
authors.initials: P
authors.lastname: Thomas
authors.forename: James
authors.initials: J
authors.lastname: Bellringer
authors.forename: Suks
authors.initials: S
authors.lastname: Minhas
authors.forename: Phil D
authors.initials: PD
authors.lastname: Kell
authors.forename: Selim
authors.initials: S
authors.lastname: Cellek
mesh_terms: D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000172:deficiency; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D020030:Nitric Oxide Donors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate