The antiarrhythmic and cardioprotective effects of non-hypotensive doses of nicorandil and celikalim during ischemia/reperfusion in anesthetized rabbits is due to selective mitochondrial KATP channel activation

We investigated the effects of administration of non-hypotensive doses of ATP-sensitive K⁺ channel (K_ATP) openers (nicorandil and celikalim), and a specific mitochondrial K_ATP channel blocker (5-hydroxydecanoate) 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, 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 minutes. In Group II, arrhythmias were induced by reperfusion following a 20 minute ligation of the left main coronary artery. Both in Group I and Group II, early intravenous infusion of nicorandil (100 μg/kg bolus + 10 μ/kg/min) or celikalim (0.2 μg/kg/min) just prior to and during ischemia increased survival rate (75% & 67% vs 60% in the control subgroup in Group I; 86% & 75% vs 55% 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 celikalim at the onset and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and celikalim were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial K_ATP channel blocker. 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 of the myocardium in all twelve subgroups of Group II suggest little anti-free radical property of nicorandil and celikalim. In conclusion, intervention by intravenous administration of nicorandil and celikalim (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.