title: Nitric oxide mediated endothelium-dependent relaxation induced by glibenclamide in rat isolated aorta.
abstract: OBJECTIVE
  Glibenclamide was found to act as both a selective ATP-sensitive K(+) channel blocker and a vasorelaxant. The exact mechanisms underlying the relaxant effect of glibenclamide are unknown. The present study was designed to examine the role of endothelium/nitric oxide in glibenclamide-induced relaxation in rat isolated aortic rings.
  
  
  METHODS
  A combination of experimental approaches including isometric force measurement, cell culture, Ca(2+) fluorescence measurement and radioimmunoassay were used to examine the vascular effect of glibenclamide.
  
  
  RESULTS
  Glibenclamide induced a concentration-dependent relaxation more effectively in rings with endothelium (IC(50) of 32+/-4 microM) than those without endothelium (IC(50) of 365+/-29 microM). Incubation with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue significantly reduced and L-arginine (3 mM) potentiated the glibenclamide-induced relaxation. L-Arginine (3 mM) partially antagonized the effect of L-NAME. Glibenclamide (100 microM) increased the cyclic GMP content of endothelium-intact tissues. Pretreatment with N(G)-nitro-L-arginine (100 microM) or removal of endothelium significantly suppressed the effect of glibenclamide on cyclic GMP production. Glibenclamide elevated the intracellular Ca(2+) levels in cultured rat aortic endothelial cells. Glibenclamide also inhibited the endothelium-independent contractile response to 60 mM K(+) (IC(50) of 137+/-21 microM) and caused a rightward shift in the concentration-contraction curve for CaCl(2). Besides, glibenclamide inhibited phorbol-12,13-diacetate (1 microM)-induced contraction in Ca(2+)-free Krebs solution.
  
  
  CONCLUSIONS
  These results indicate that glibenclamide-induced endothelium-dependent relaxation involves nitric oxide release and this effect may be related to its stimulatory effect on endothelial Ca(2+) levels. However, the glibenclamide-induced endothelium-independent relaxation may be associated with its inhibitory effect on Ca(2+) influx through Ca(2+) channels and on the protein kinase C-mediated contractile mechanism.
authors.affiliation: Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Chan
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.forename: W
authors.initials: W
authors.lastname: Ko
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001011:Aorta; D001120:Arginine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002122:Calcium Chloride / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D009569:Nitric Oxide; D000001:Calcimycin; D004533:Egtazic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D002122:Calcium Chloride; D013755:Tetradecanoylphorbol Acetate; D005905:Glyburide; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester