Mitochondrial K_ATP channel activation is important in the antiarrhythmic and cardioprotective effects of non-hypotensive doses of nicorandil and cromakalim during ischemia/reperfusion: A study in an intact anesthetized rabbit model

The roles of cardiomyocyte sarcolemmal ATP-sensitive K⁺ (K_ATP) and mitochondrial K_ATP channels in the cardioprotection and antiarrhythmic activity induced by K_ATP channel openers remain obscure, though the mitochondrial K_ATP channels have been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of administration of non-hypotensive doses of ATP-sensitive K⁺ channel (K_ATP) openers (nicorandil and cromakalim), a specific mitochondrial K_ATP channel blocker (5-hydroxydecanoate (5-HD)) 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 30min. In Group II (n=184), arrhythmias were induced by reperfusion following a 20min ligation of the left main coronary artery. Both in Groups I and II, early intravenous infusion of nicorandil (100μg/kg bolus+10μg/kg/min), cromakalim (0.2μg/kg/min), HMR 1883 (3mg/kg)/nicorandil and HMR 1883 (3mg/kg)/cromakalim just prior to and during ischemia increased survival rate (75%, 67%, 86% and 75% versus 60% in the control subgroup in Group I; 75%, 75%, 75% and 67% versus 50% 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 cromakalim at the onset and during reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and cromakalim were abolished by pretreating the rabbits with 5-HD (5mg/kg, i.v. bolus), a selective mitochondrial K_ATP channel blocker but not by HMR 1883 (3mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-free radical property of nicorandil and cromakalim. We, therefore, conclude that intervention by intravenous administration of nicorandil and cromakalim (through the selective activation of mitochondrial K_ATP channels), increased survival rate and exhibited 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 a potential site of cardioprotection and antiarrhythmic activity.