Cyclic guanosine monophosphate-enhancing reduces androgenic extracellular regulated protein kinases-phosphorylation/Rho kinase II-activation in benign prostate hyperplasia

Objectives To investigate whether 7‐[2‐[4‐(2‐chlorophenyl) piperazinyl] ethyl]‐1,3‐di‐methylxanthine (KMUP‐1) inhibits the effects of testosterone on the development of benign prostatic hyperplasia and sensitizes prostate contraction. Methods A benign prostatic hyperplasia animal model was established by subcutaneous injections of testosterone (3 mg/kg/day, s.c.) for 4 weeks in adult male Sprague–Dawley rats. Animals were divided into six groups: control, testosterone, testosterone with KMUP‐1 (2.5, 5 mg/kg/day), sildenafil (5 mg/kg/day) or doxazosin (5 mg/kg/day). After 4 weeks, the animals were killed, and prostate tissues were prepared for isometric tension measurement and western blotting analysis. KMUP‐1, Y27632, zaprinast, doxazosin or tamsulosin were used at various concentrations to determine the contractility sensitized by phenylephrine (10 μmol/L). Results KMUP‐1 inhibited testosterone‐induced phosphorylation of extracellular signal‐regulated phosphorylated protein kinase and mitogen‐activated protein kinase kinase and Rho kinase‐II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia‐induced mitogen‐activated protein kinase kinase and Rho kinase‐II activation. The decreased expressions of soluble guanylate cyclase α1 was reversed by KMUP‐1, doxazosin and sildenafil. Soluble guanylate cyclase β1 and protein kinase G were increased by KMUP‐1, doxazosin, and sildenafil in the testosterone‐treated benign prostatic hyperplasia group. Phosphodiesterase‐5A was increased by testosterone and inhibited by KMUP‐1 (5 mg/kg/day) or sildenafil (5 mg/kg/day). KMUP‐1 inhibited phenylephrine‐sensitized prostate contraction of rats treated with testosterone. Conclusions Mitogen‐activated protein kinase 1/extracellular regulated protein kinases kinase, soluble guanylate cyclase/cyclic guanosine monophosphate, protein kinase/protein kinase G and Rho kinase‐II are related to prostate smooth muscle tone and proliferation induced by testosterone. KMUP‐1 inhibits testosterone‐induced prostate hyper‐contractility and mitogen‐activated protein kinase 1/extracellular regulated protein kinases kinase‐phosphorylation, and it inactivates Rho kinase‐II by cyclic guanosine monophosphate, protein kinase and α1A‐adenergic blockade. Thus, KMUP‐1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.