Selective cardiac plasma-membrane K(ATP) channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion.
ATP-dependent potassium channels (K(ATP)) have been implicated in cardioprotection both during myocardial ischemia and reperfusion. We compared the effect of a non-selective K(ATP) inhibitor glibenclamide, a selective mitochondrial K(ATP) inhibitor 5-hydroxy-decanoate (5-HD) and a selective sarcolemmal K(ATP) blocker HMR 1883, on survival and incidence of arrhythmias during myocardial ischemia in conscious, and during ischemia-reperfusion in pentobarbitone anesthetized rats. Glibenclamide (5 mg/kg i.p.) or HMR 1883 (3 mg/kg i.v.) reduced ischemia-induced irreversible ventricular fibrillation and improved survival during myocardial ischemia (64% and 61% vs. 23% in controls, respectively). 5-HD (5 mg/kg i.v.) did not influence survival and the incidence of ventricular arrhythmias. The incidence of reperfusion-induced arrhythmias was reduced by both glibenclamide and HMR 1883 (3 or 10 mg/kg) resulting in improved survival during reperfusion (81%, 82% and 96% vs. 24% in controls, respectively) in anesthetized rats. 5-HD did not reduce the incidence of lethal reperfusion arrhythmias. Glibenclamide and HMR 1883 prolonged (89+/-4.6 and 89+/-4.9 ms vs. 60+/-2.4 ms in controls), while 5-HD did not change the QT interval. In conclusion, inhibition of sarcolemmal K(ATP) reduces the incidence of lethal ventricular arrhythmias and improves survival both during acute myocardial ischemia and reperfusion in rats. This beneficial effect correlates with the prolongation of repolarization. Inhibition of mitochondrial K(ATP) does not improve survival or reduce the occurrence of ischemia and/or reperfusion-induced arrhythmias and does not prolong the QT interval. The present results also suggest that the antiarrhythmic effect of K(ATP) inhibitors is not influenced by pentobarbitone anesthesia.
Vajda
Szilvia
S
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged, Hungary.
Baczkó
István
I
Leprán
István
I
D000208:Acute Disease; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001341:Autonomic Nervous System / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D003652:Decanoic Acids / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D008297:Male; D009928:Organ Specificity; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D012508:Sarcolemma / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013534:Survival; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C052853:5-hydroxydecanoic acid; C114623:clamikalant; D013890:Thiourea; D005905:Glyburide