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Cyclic guanosine monophosphate‐enhancing reduces androgenic extracellular regulated protein kinases‐phosphorylation/Rho kinase II‐activation in benign prostate hyperplasia
Author(s) -
Liu ChiMing,
Fan YaChin,
Lo YiChing,
Wu BinNan,
Yeh JwuLai,
Chen IngJun
Publication year - 2014
Publication title -
international journal of urology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 67
eISSN - 1442-2042
pISSN - 0919-8172
DOI - 10.1111/iju.12195
Subject(s) - doxazosin , protein kinase a , endocrinology , medicine , kinase , sildenafil , cyclic guanosine monophosphate , mapk/erk pathway , pharmacology , chemistry , biochemistry , nitric oxide , blood pressure
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 S prague– D awley 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, Y 27632, 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 R ho kinase‐ II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia‐induced mitogen‐activated protein kinase kinase and R ho kinase‐ II activation. The decreased expressions of soluble guanylate cyclase α 1 was reversed by KMUP ‐1, doxazosin and sildenafil. Soluble guanylate cyclase β 1 and protein kinase G were increased by KMUP ‐1, doxazosin, and sildenafil in the testosterone‐treated benign prostatic hyperplasia group. Phosphodiesterase‐5 A 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 R ho 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 R ho kinase‐ II by cyclic guanosine monophosphate, protein kinase and α1 A ‐adenergic blockade. Thus, KMUP ‐1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.