Nicorandil augments regional ischemia-induced monophasic action potential shortening and potassium accumulation without serious proarrhythmia

Author(s): Moritani, K., Miyoshi, S., Asanagi, M., Zhao, L. S., Mitamura, H., Ogawa, S.

Journal/Book: J Cardiovasc Pharmacol. 1995; 26: 227 East Washington Sq, Philadelphia, PA 19106. Raven Press. 949-956.

Abstract: Nicorandil is a clinically used nitrovasodilator that has a property as an opener of ATP-sensitive potassium (K-ATP) 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 (APD(90)) 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 less than or equal to 3 min after reperfusion. Before the third occlusion, baseline APD(90) and [K+]o were not altered by nicorandil; however, the extent of occlusion-induced shortening of APD(90) (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 K-ATP 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 K-ATP channels without causing serious proarrhythmia. Such a property might help protect the myocardium against ischemia/reperfusion damage.

Note: Article T Miyazaki, Keio Univ, Sch Med, Dept Internal Med, Div Cardiopulm, Shinjuku Ku, 35 Shinanomachi, Tokyo 160, Japan

Keyword(s): ATP-sensitive potassium channels; potassium channel opener; coronary occlusion-reperfusion; ventricular fibrillation; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY LIGATION; SENSITIVE K+ CHANNELS; VENTRICULAR ARRHYTHMIAS; SYMPATHETIC-STIMULATION; RAT HEARTS; ACTIVATION; MODULATION; PINACIDIL; FIBRILLATION

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