title: Nicorandil inhibits angiotensin-II-induced proliferation of cultured rat cardiac fibroblasts.
abstract: OBJECTIVE
  Nicorandil, an ATP-sensitive potassium (K(ATP)) channel opener, nitric oxide (NO) donor and antioxidant, was shown to exert a variety of pharmacological effects including cardioprotective properties. However, its mechanisms of action are not completely understood. The aims of this study were to examine whether nicorandil may alter angiotensin-II (Ang II)-induced cell proliferation and to identify the putative underlying signaling pathways in rat cardiac fibroblasts.
  
  
  METHODS
  Cultured rat cardiac fibroblasts were pretreated with nicorandil, then stimulated with Ang II, and cell proliferation and endothelin-1 (ET-1) expression were examined. The effects of nicorandil on Ang-II-induced reactive oxygen species (ROS) formation and extracellular signal-regulated kinase (ERK) phosphorylation were also examined. In addition, the effects of nicorandil on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation were tested to elucidate the intracellular mechanism.
  
  
  RESULTS
  Nicorandil (0.1-10 μmol/l) caused a concentration-dependent inhibition of Ang-II-increased cell proliferation and ET-1 expression which were prevented by the K(ATP) channel blocker glibenclamide (1 μmol/l). Nicorandil also inhibited Ang-II-increased ROS and ERK phosphorylation. In addition, nicorandil was found to increase the NO and eNOS phosphorylation. N-nitro-L-arginine methyl ester, an inhibitor of NOS, and the short interfering RNA transfection for eNOS markedly attenuated the inhibitory effect of nicorandil on Ang-II-induced cell proliferation.
  
  
  CONCLUSIONS
  Our results suggest that nicorandil prevents cardiac fibroblast proliferation, and the inhibitory effect might be associated with the opening K(ATP) channels, by interfering with the generation of ROS, and the activation of the eNOS-NO pathway.
authors.affiliation: Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC.
authors.forename: Jer-Young
authors.initials: JY
authors.lastname: Liou
authors.forename: Hong-Jye
authors.initials: HJ
authors.lastname: Hong
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Sung
authors.forename: Hung-Hsing
authors.initials: HH
authors.lastname: Chao
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Chen
authors.forename: Tzu-Hurng
authors.initials: TH
authors.lastname: Cheng
authors.forename: Paul
authors.initials: P
authors.lastname: Chan
authors.forename: Ju-Chi
authors.initials: JC
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020108:Nicorandil / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D020108:Nicorandil; D009569:Nitric Oxide