Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model.
Recent evidence suggests that the mitochondrial K(ATP) channels may be involved as a subcellular mediator in cardioprotection afforded by ischemic and pharmacological preconditioning by K(ATP) activators. The present study investigated the effects of administration of non-hypotensive doses of ATP-sensitive K(+) channel (K(ATP)) openers, nicorandil (NIC) and pinacidil (PIN), and specific blockers of mitochondrial (5-hydroxydecanoate) and sarcolemmal (1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methyl-thiourea, HMR 1883) K(ATP) channels prior to and during coronary occlusion and post-ischemic reperfusion on survival rate, ischemia- and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized rabbits. In Group I, myocardial ischemia-induced arrhythmias were provoked by tightening a ligature over the left main coronary artery for 30 min. In Group II, arrhythmias were induced by reperfusion following a 20 min ligation of the same artery. Both in Group I and Group II, early iv administration of NIC (0.47 mg/kg), PIN (0.1 mg/kg), HMR 1883 (3 mg/kg)/NIC and HMR 1883/PIN just prior to and during ischemia increased survival rate (75%, 86%, 75% and 75%, respectively, vs. 55% in the control in Group I; 75%, 75%, 75% and 67%, respectively, vs. 50% in the control in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late iv administration of NIC or PIN just prior to reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects were abolished by pretreating rabbits with 5-hydroxy-decanoate (5 mg/kg, iv bolus). In the present study, higher levels of malondialdehyde and lower levels of reduced glutathione and superoxide dismutase in necrotic zone of myocardium in all subgroups in Group II suggest little anti-free radical property of NIC and PIN. Therefore, it may be assumed that mitochondrial K(ATP) channel opening leads to mitochondrial generation and release of ROS providing for IPC and antiarrhythmic activity. The mitochondrial rather than sarcolemmal K(ATP) channel may represent a potential site of cardioprotection and antiarrhythmic activity.
Das
Biswadeep
B
Department of Pharmacology, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok-737 102 Sikkim, India. biswadeepdas@hotmail.com
Sarkar
Chayna
C
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000293:injuries; D003652:Decanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004338:Drug Combinations; D005978:Glutathione / Q000096:biosynthesis / Q000737:chemistry; D006880:Hydroxy Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008929:Mitochondria, Heart / Q000502:physiology*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000737:chemistry*; D020108:Nicorandil / Q000008:administration & dosage / Q000493:pharmacokinetics; D018384:Oxidative Stress / Q000187:drug effects; D020110:Pinacidil / Q000008:administration & dosage / Q000493:pharmacokinetics; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying / Q000008:administration & dosage / Q000187:drug effects* / Q000493:pharmacokinetics; D011292:Premedication; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D013482:Superoxide Dismutase / Q000737:chemistry; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D003652:Decanoic Acids; D004338:Drug Combinations; D006880:Hydroxy Acids; D008565:Membrane Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013449:Sulfonamides; C117780:mitochondrial K(ATP) channel; D020108:Nicorandil; D008315:Malondialdehyde; C052853:5-hydroxydecanoic acid; D020110:Pinacidil; C114623:clamikalant; D013482:Superoxide Dismutase; D005978:Glutathione; D013890:Thiourea