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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
Author(s) -
Uvin Pieter,
Albersen Maarten,
Bollen Ine,
Falter Maarten,
Weyne Emmanuel,
Linsen Loes,
Tinel Hanna,
Sandner Peter,
Bivalacqua Trinity J.,
De Ridder Dirk J. M. K.,
Van der Aa Frank,
Brône Bert,
Van Renterghem Koenraad
Publication year - 2017
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/bju.13691
Subject(s) - rho associated protein kinase , rhoa , erectile dysfunction , rock2 , sildenafil , medicine , vardenafil , rho kinase inhibitor , cgmp specific phosphodiesterase type 5 , erectile tissue , protein kinase a , phosphodiesterase inhibitor , phenylephrine , endocrinology , kinase , andrology , chemistry , tadalafil , signal transduction , biochemistry , blood pressure
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 ( RKI s) on erectile tissue of patients with severe ED , which did not respond to phosphodiesterase type 5 inhibitors ( PDE 5Is). 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 PDE 5I vardenafil or with DMSO (control). Subsequently, increasing concentrations of the RKI s azaindole or Y‐27632 were added, and relaxation of tissue was quantified. Results The expression of ROCK 1 was unchanged ( P > 0.05), while ROCK 2 ( P < 0.05) was significantly upregulated in patients with ED compared with controls. ROCK 1 and ROCK 2 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 .