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.

METHODS AND 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: Yu Eguchi, Youko Takahari, Naoko Higashijima, Nobuhiko Ishizuka, Noriko Tamura, Yota Kawamura, Hideyuki Ishida
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 73 Issue 3 Pg. 554-61 (Mar 2009) ISSN: 1346-9843 [Print] Japan
• PMID: 19179768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Chlorides
• Decanoic Acids
• Enzyme Inhibitors
• Ferric Compounds
• Hydroxy Acids
• Potassium Channels
• Reactive Oxygen Species
• Vasodilator Agents
• mitochondrial K(ATP) channel
• Nicorandil
• 5-hydroxydecanoic acid
• Collagen
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Isosorbide Dinitrate
• ferric chloride
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Arteries (drug effects, metabolism)
• Cells, Cultured
• Chlorides
• Collagen
• Decanoic Acids (pharmacology)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Enzyme Inhibitors (pharmacology)
• Ferric Compounds (toxicity)
• Humans
• Hydroxy Acids (pharmacology)
• Isosorbide Dinitrate (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Mitochondria (metabolism)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Nicorandil (blood, pharmacology)
• Nitric Oxide Synthase Type III (metabolism)
• Oxidative Stress (drug effects)
• Platelet Aggregation (drug effects)
• Potassium Channels (metabolism)
• Reactive Oxygen Species (metabolism)
• Thrombosis (chemically induced, drug therapy, metabolism)
• Umbilical Veins (cytology)
• Vasodilator Agents (blood, pharmacology)