Selective mitochondrial K-ATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (K-ATP) and mitochondrial K-ATP channels in cardioprotection and antiarrhythmic activity induced by K-ATP channel openers remain obscure. However, it has been suggested that the mitochondrial K-ATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (K-ATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial K-ATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal K-ATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation (if the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 mug/kg bolus + 10 mug/kg/min), 3-pyridyl pinacidil (3.0 mug/kg bolus + 1.0 mug/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg/ 3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial K-ATP channel blocker but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial K-ATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial K-ATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity. (C) 2003 Prous Science.