Chronic administration of an oral Rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model

Introduction. It has been shown that the Rho/Rho kinase calcium sensitizing pathway has been implicated in the pathogenesis of erectile dysfunction as well as systemic atherosclerosis. Aims. To test whether chronic treatment of an oral Rho kinase inhibitor (fasudil, 5-Isoquinolinesulfonyl homopiperazine) could prevent the development of both vasculogenic erectile dysfunction and pelvic atherosclerosis in a rat model. Methods. Rats (3 months old) were divided into three groups (N = 10 in each group): control (group 1); atherosclerosis (group 2); and fasudil-treated (group 3). Groups 2 and 3 received atherosclerosis-prone treatment (6 weeks of 1% cholesterol diet and early 2 weeks of N-G-nitro-L-arginine methyl ester [3 mg/mL/day] treatment, but group 3 was concurrently treated with fasudil (30 mg/kg/day) for 6 weeks. Main Outcome Measures. The amount of systemic endothelial injury (plasma von Willebrand factor) and pelvic atherosclerosis was determined. Erectile function, cavernosal Rho kinase activity, and expressions of total and phosphorylated endothelial nitric oxide synthase (eNOS) were also determined. Results. Group 2 showed a significant amount of pelvic atherosclerosis and endothelial injury. The rats also showed elevated cavernosal Rho kinase activity and impaired erectile function. Immunoblot showed a decreased total as well as phosphorylated eNOS expression. The treatment with fasudil partly but significantly ameliorated the development of pelvic atherosclerosis and plasma level of von Willebrand factor. The treatment also normalized the erectile function, cavernosal Rho kinase activity, and total eNOS expression. The overexpression of phospho-eNOS was observed in group 3. Conclusions. These results indicate that the Rho/Rho kinase pathway is substantially involved in the development of erectile dysfunction and pelvic atherosclerosis, both of which could be prevented by chronic treatment with fasudil. Thus, Rho kinase might be considered a novel target for the prevention of vasculogenic erectile dysfunction.