title: Nicorandil augments regional ischemia-induced monophasic action potential shortening and potassium accumulation without serious proarrhythmia.
abstract: Nicorandil is a clinically used nitrovasodilator that has a property as an opener of ATP-sensitive potassium (KATP) channels in vitro. We examined whether nicorandil at a clinically used dose augmented regional ischemia-induced monophasic action potential (MAP) shortening and increase in extracellular potassium concentration ([K+]o), and how it affected arrhythmia occurrence. Five-minute occlusion of a distal site of the left anterior descending coronary artery (LAD) was repeated at 30-min intervals in anesthetized open-chest dogs while recording MAP or measuring [K+]o with a potassium-sensitive valinomycin electrode from the epicardial center of the ischemic myocardium. Nicorandil (0.2-0.5 mg/kg) was administered intravenously (i.v.) 5 min before the third occlusion, and the data were compared with those during the second occlusion (control). During the second occlusion, MAP duration at 90% repolarization (APD90) shortened (mean rate for 5 min, 13 +/- 3%, n = 11) and [K+]o increased from 3.7 +/- 0.1 to 6.2 +/- 0.8 mM at 5 min (n = 12). These changes were reversed < or = 3 min after reperfusion. Before the third occlusion, baseline APD90 and [K+]o were not altered by nicorandil; however, the extent of occlusion-induced shortening of APD90 (25 +/- 4%) and [K+]o increase (7.8 +/- 1.6 mM) was augmented by the pretreatment. The drug effect was attenuated by a concomitant pretreatment with 5-hydroxydecanoate, a specific blocker of KATP channels (n = 2). The prevalence of ventricular fibrillation (VF) during occlusion/reperfusion sequence was reduced after nicorandil (1 of 25 vs. 5 of 25) without de novo VF. These results suggest that nicorandil at a clinical dose facilitates regional ischemia-induced activation of myocardial KATP channels without causing serious proarrhythmia. Such a property might help protect the myocardium against ischemia/reperfusion damage.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Moritani
authors.forename: S
authors.initials: S
authors.lastname: Miyoshi
authors.forename: M
authors.initials: M
authors.lastname: Asanagi
authors.forename: L S
authors.initials: LS
authors.lastname: Zhao
authors.forename: H
authors.initials: H
authors.lastname: Mitamura
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D020108:Nicorandil; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000517:prevention & control*
chemical_list: D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D011188:Potassium