title: Nicorandil attenuates FeCl(3)-induced thrombus formation through the inhibition of reactive oxygen species production.
abstract: BACKGROUND
  Although nicorandil has a number of beneficial cardiovascular actions, its effects on endothelial cells in the context of thrombosis have not been elucidated.
  
  
  RESULTS
  Arterial thrombosis was induced by endothelial injury caused by FeCl(3) in the mouse testicular artery. Thrombus growth led to complete occlusion 12 min after endothelial injury in control mice. The antiplatelet agent, tirofiban, and nicorandil significantly slowed the growth of thrombi, resulting in arterial occlusion after 58 min and 55 min, respectively. In the absence of endothelial cells, nicorandil did not inhibit platelet aggregation. Diazoxide and high-dose isosorbide dinitrate both showed a similar effect to that of nicorandil. The beneficial effect of nicorandil was prevented by 5-hydroxydecanoate, but not by L-NAME. The production of reactive oxygen species by FeCl(3) treatment was measured with the specific fluorescent probe, dihydrorhodamine 123. After FeCl(3) treatment, nicorandil significantly inhibited the increase in fluorescence. In further experiments, incubation of human umbilical vein endothelial cells with nicorandil did not change the endothelial nitric oxide synthase (eNOS) mRNA levels, eNOS phosphorylation or nitrite production.
  
  
  CONCLUSIONS
  Nicorandil attenuates FeCl(3)-induced thrombus formation in the mouse testicular artery, which suggests that it may inhibit the generation of reactive oxygen species by FeCl(3)-treated endothelial cells through activation of the mitochondrial ATP-sensitive potassium channels.
authors.affiliation: Department of Physiology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Youko
authors.initials: Y
authors.lastname: Takahari
authors.forename: Naoko
authors.initials: N
authors.lastname: Higashijima
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ishizuka
authors.forename: Noriko
authors.initials: N
authors.lastname: Tamura
authors.forename: Yota
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ishida
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002712:Chlorides; D003094:Collagen; D003652:Decanoic Acids / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005290:Ferric Compounds / Q000633:toxicity; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020108:Nicorandil / Q000097:blood / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D002712:Chlorides; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D006880:Hydroxy Acids; D015221:Potassium Channels; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; C052853:5-hydroxydecanoic acid; D003094:Collagen; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D007548:Isosorbide Dinitrate; C024555:ferric chloride; D019331:NG-Nitroarginine Methyl Ester