The relative contributions 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 sought to investigate the effects of administration of
ATP-sensitive K(+) channel (K(
ATP)) openers (
nicorandil and
minoxidil), 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
coronary occlusion as well as prior to 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=88), occlusion of the left main coronary artery and hence,
myocardial ischemia-induced arrhythmias was achieved by tightening a previously placed loose
silk ligature for 30 min. In Group II (n=206), arrhythmias were induced by reperfusion following a 20-min
ligation of the left main coronary artery. Both in Group I and Group II, intravenous (i.v.) administration of
nicorandil (0.47 mg/kg),
minoxidil (0.5 mg/kg),
HMR 1883 (3 mg/kg)/
nicorandil and
HMR 1883 (3 mg/kg)/
minoxidil before coronary artery occlusion increased survival rate (86%, 75%, 75% and 86% vs. 55% in the control subgroup in Group I; 75%, 67%, 67% and 75% vs. 46% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias. In Group II, i.v. administration of
nicorandil and
minoxidil before coronary artery occlusion significantly decreased
myocardial infarct size. However, i.v. administration of
nicorandil or
minoxidil before reperfusion did neither increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both
nicorandil and
minoxidil were abolished by pretreating the rabbits with 5-HD (5 mg/kg, i.v. bolus), a selective
mitochondrial K(ATP) channel blocker but not by
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 necrotic zone of myocardium in all the 16 subgroups in Group II suggest little anti-
free radical property of
nicorandil and
minoxidil. We conclude that intervention by
intravenous administration of
nicorandil and
minoxidil (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
coronary occlusion. The cardiomyocyte
mitochondrial K(ATP) channel may be a pharmacologically modulable target of cardioprotection and antiarrhythmic activity.