NCX-911, a novel nitric oxide-releasing PDE5 inhibitor relaxes rabbit corpus cavernosum in the absence of endogenous nitric oxide

Abstract

Phosphodiesterase type 5 (PDE5) inhibitors have reduced efficacy in treating erectile dysfunction (ED) in conditions where there is a lack of endogenous nitric oxide (NO). Therefore, NO-releasing PDE5 inhibitors have been developed. Here we report the effect of such a compound, NCX-911, on the tone and nitrergic relaxations of rabbit corpus cavernosum in the absence or presence of a NO synthase inhibitor, N G -nitro-L-arginine methyl ester (L-NAME; 500 lM). NCX-911 was found to be as potent as sildenafil at inducing relaxation of rabbit cavernosum (EC 50 values 997.87195.7 and 1000.57140.8 nM, respectively). The potency of NCX-911 was not altered, but that of sildenafil decreased five-fold in the presence of L-NAME (EC 50 values 1281.27268.3 and 4959.17882.1, nM respectively, Po0.001 for sildenafil). Both compounds potentiated nitrergic relaxations with similar potencies. These results suggest that NO-releasing PDE5 inhibitors could potentially be more useful than PDE5 inhibitors in the treatment of ED in conditions where there is a lack of endogenous NO.

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

“…The ability of PDE5 inhibitors to relax isolated horse and human penile arteries and, rabbit and HCC, has been previously observed (Taher et al, 1997;Kalsi et al, 2004;Ruiz-Rubio et al, 2004;Angulo et al, 2010a). Relaxation of contracted HPRA and HCC caused by PDE5 inhibition is sensitive to blockade of NO synthesis or inhibition of soluble guanylyl cyclase, confirming the involvement of the NO/cGMP pathway in these responses.…”

Sexual dysfunction after pelvic surgery

“…They reported that NCX 4050 increase the guanyl cyclase activity and produce the smooth muscle relaxation in both human and rabbit cavernosal model. Recently, Kalsi et al 108 reported that NCX 911, a nitric-oxide-releasing PDE-5 inhibitor, produces the relaxation of cavernosal smooth muscle by increasing the endogenous NO. These two agents may be promising future options for patients with impaired NO release from the endothelium.…”

Pharmacological profile of a nitric oxide donor spermine NONOate in the mouse corpus cavernosum

“…Both S-NONOate and sildenafil increased the magnitude of nitrergic relaxations with similar potencies in the tissues. It was shown that sildenafil enhanced the nitrergic relaxations in the previous papers (27,31). It is also well known that the action of sildenafil in corpus cavernosum is dependent on the activation of the NO-cGMP system (5).…”

“…This result may suggest that S-NONOate does not synergize with endogenous nitric oxide and release of the NO from the S-NONOate compound potentiates the nitrergic relaxations via sGC activation in mice corpus cavernosum. On the other hand, some papers suggested that NO donors, NCX-911 or FPTO (4,7-dimethyl-1,2,5-oxadiazolo [3,4-d] pyridazine 1,5,6-trioxide) did not affect the nitrergic relaxations induced by EFS (14,27).…”