title: Cyclic guanosine monophosphate-enhancing reduces androgenic extracellular regulated protein kinases-phosphorylation/Rho kinase II-activation in benign prostate hyperplasia.
abstract: OBJECTIVE
  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.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Liu
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Fan
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lo
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D006162:Guanylate Cyclase / Q000187:drug effects / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D014970:Xanthines / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000187:drug effects / Q000502:physiology*
chemical_list: D010880:Piperidines; D018160:Receptors, Cytoplasmic and Nuclear; D014970:Xanthines; C439304:KMUP 1; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
keywords: benign prostatic hyperplasia; cyclic guanosine monophosphate; protein kinase; smooth muscle contractility; testosterone; α1A-adrenoceptor