Effects of BAY 41-2272 on smooth muscle tone, soluble guanylyl cyclase activity and NADPH oxidase activity/expression in corpus cavernosum from wild-type, neuronal and endothelial NOS null mice

We aimed to characterize the relaxation induced by the soluble guanylyl cyclase (sGC) stimulator BAY 41-2272 and its pharmacological interactions with nitric oxide (NO) in the corpus cavernosum (CC) from wild-type (WT), eNOS and nNOS mice. The effect of BAY 41-2272 on superoxide formation and NADPH oxidase expression was also investigated. Tissues were mounted in myographs for isometric force recording. Enzyme immunoassay kits were used for cGMP determination. sGC activity was determined in the supernatant fractions of the cavernosal samples by the conversion of GTP to cGMP. Superoxide formation and expression of NADPH oxidase subunits were studied using the reduction of ferricytochrome c and Western blot analysis, respectively. BAY 41-2272 (0.01-10 μM) relaxed CC with pEC50 values of 6.36 ± 0.07 (WT), 6.27 ± 0.06 (nNOS) and 5.88 ± 0.07 (eNOS). The relaxations were accompanied by increases in cGMP levels. L-NAME inhibited BAY 41-2272-evoked responses in CC from WT and nNOS, but not eNOS. ODQ reduced and sildenafil potentiated the relaxations induced by BAY 41-2272 in all groups. BAY 41-2272 enhanced NO (endogenous and exogenous)induced relaxations in a concentration-dependent manner. Expression and activity of sGC was similar among the different groups. Superoxide formation was reduced by BAY 41-2272 (0.1-1 μM). The compound also inhibited p22 and gp91 expression induced by U46619. Our results demonstrated that sGC activation in the penis by BAY 41-2272 directly or via enhancement of NO effects may provide a novel treatment for erectile dysfunction, particularly in the event of an increased intra-penile oxidative stress. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on June 27, 2007 as DOI: 10.1124/jpet.107.124594 at A PE T Jornals on Sptem er 3, 2017 jpet.asjournals.org D ow nladed from