title: Cilostazol protects the heart against ischaemia reperfusion injury in a rabbit model of myocardial infarction: focus on adenosine, nitric oxide and mitochondrial ATP-sensitive potassium channels.
abstract: 1. The present study examined whether or not cilostazol reduces the myocardial infarct size, and investigated its mechanism in a rabbit model of myocardial infarction. 2. Japanese white rabbits underwent 30 min of coronary occlusion, followed by 48 h of reperfusion. Cilostazol (1 and 5 mg/kg) or vehicle was given intravenously 5 min before ischaemia. 8-p-sulfophenyl theophylline (8SPT; an adenosine receptor blocker, 7.5 mg/kg), Nω-nitro-L-arginine methylester (l-NAME; an NOS inhibitor, 10 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD; a mitochondrial ATP-sensitive potassium (KATP) channel blocker, 5 mg/kg) was given intravenously 5 min before cilostazol injection. Infarct size was determined as a percentage of the risk area. 3. The myocardial interstitial levels of adenosine and nitrogen oxide (NOx) during ischaemia and reperfusion, and the intensity of myocardial dihydroethidium staining were determined. 4. Infarct size was significantly reduced in the cilostazol 1 mg/kg (38.4% (2.9%)) and cilostazol 5 mg/kg (30.7% (4.7%)) groups compared with that in the control group (46.5% (4.2%)). The infarct size-reducing effect of cilostazol was completely abolished by 8SPT (46.6% (3.5%)), L-NAME (49.0% (5.5%)), or 5HD (48.5% (5.1%)). 8SPT, L-NAME or 5HD alone did not affect the infarct size. Cilostazol treatment significantly increased myocardial levels of adenosine and NOx during ischaemia, and attenuated the intensity of dihydroethidium staining during reperfusion. 5. These findings show that cilostazol reduces the myocardial infarct size by increasing adenosine and NOx levels, attenuating superoxide production and opening the mitochondrial KATP channels. Cilostazol might provide a new strategy for the treatment of coronary heart disease.
authors.affiliation: Department of Cardiology, Gifu University Graduate School of Medicine, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Bai
authors.lastname: Muqier
authors.forename: Hiroya
authors.initials: H
authors.lastname: Murakami
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iwasa
authors.forename: Shohei
authors.initials: S
authors.lastname: Sumi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ushikoshi
authors.forename: Takuma
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishigaki
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Bunji
authors.initials: B
authors.lastname: Uno
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077407:Cilostazol; D003652:Decanoic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology; D011817:Rabbits; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D026902:Potassium Channel Blockers; D058915:Purinergic P1 Receptor Antagonists; D013777:Tetrazoles; D013481:Superoxides; D009569:Nitric Oxide; C052853:5-hydroxydecanoic acid; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000241:Adenosine; D000077407:Cilostazol; D019331:NG-Nitroarginine Methyl Ester