Additive effects of the Rho kinase inhibitor Y-27632 and vardenafil on relaxation of the corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

Objectives To evaluate the expression of the Rho/Rho-associated protein kinase ( ROCK) pathway in the corpus cavernosum of patients with severe erectile dysfunction ( ED) compared with healthy human corpus cavernosum, and to test the functional effects of two Rho kinase inhibitors ( RKIs) on erectile tissue of patients with severe ED, which did not respond to phosphodiesterase type 5 inhibitors ( PDE5Is). Patients and Methods Human corpus cavernosum samples were obtained after consent from men undergoing penile prosthesis implantation ( n = 7 for organ bath experiments, n = 17 for quantitative PCR [ qPCR]). Potent control subjects ( n = 5) underwent penile needle biopsy. qPCR was performed for the expression of RhoA and ROCK subtypes 1 and 2. Immunohistochemistry staining against ROCK and α smooth muscle actin (α SMA) was performed on the corpus cavernosum of patients with ED. Tissue strips were precontracted with phenylephrine and incubated with 1 μ m of the PDE5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKIs azaindole or Y-27632 were added, and relaxation of tissue was quantified. Results The expression of ROCK1 was unchanged ( P > 0.05), while ROCK2 ( P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK1 and ROCK2 protein colocalized with α SMA, confirming the presence of this kinase in cavernous smooth muscle cells and/or myofibroblasts. After incubation with DMSO, 10 μ m azaindole and 10 μ m Y-27632 relaxed precontracted tissues with 49.5 ± 7.42% ( P = 0.1470 when compared with vehicle) and 85.9 ± 10.3% ( P = 0.0016 when compared with vehicle), respectively. Additive effects on relaxation of human corpus cavernosum were seen after preincubation with 1 μ m vardenafil. Conclusion The RKI Y-27632 causes a significant relaxation of corpus cavernosum in tissue strips of patients with severe ED. The additive effect of vardenafil and Y-27632 shows that a combined inhibition of Rho-kinase and phosphodiesterase type 5 could be a promising orally administered treatment for severe ED. [ABSTRACT FROM AUTHOR]