REDUCTION IN MYOCARDIAL INFARCT SIZE BY THE NEW POTASSIUM CHANNEL OPENER BIMAKALIM

We examined the effect of a new potassium channel opener, bimakalim, on myocardial infarct size (IS) in dogs. Barbital-anesthetized dogs were subjected to 90 min of left circumflex coronary artery (LCX) occlusion followed by 5-h reperfusion. Bimakalim (3 mug/kg bolus followed by 0.1 mug/kg/min intravenously, i.v.) was initiated either 15 min before LCX occlusion and continued throughout the experiments in one group of animals or initiated 5 min before and throughout reperfusion in a second group. A third group of dogs received i.v. vehicle (control) 15 minutes before LCX occlusion and throughout the remainder of the experiment. IS was determined by triphenyltetrazolium histochemical staining, regional myocardial blood flow (RMBF) by the radioactive microsphere technique, and neutrophil migration by measurement of tissue myeloperoxidase (MPO) activity. Bimakalim reduced mean aortic blood pressure (MBP, 25 mm Hg) during the occlusion and reperfusion periods in the group of dogs that received the drug throughout the experiment and reduced in BP, during reperfusion when administered immediately before the reperfusion period. In addition, bimakalim increased LCX coronary artery blood flow (CBF) and increased regional myocardial blood flow (RMBF) primarily during reperfusion in both drug-treated groups, with the greatest increase to the subepicardial region. During occlusion, however, bimakalim had no effect on collateral blood flow to the ischemic region. In all three groups, left ventricular (LV) mass, area at risk (AAR) mass, and percentage of the left ventricle at risk were similar. As compared with the control group, bimakalim reduced myocardial IS (31% reduction) as a percentage of the AAR when administered during both the occlusion and reperfusion periods (32 +/- 1 vs. 46 +/- 3), although it had no beneficial effect when administered during the reperfusion period only (41 +/- 7). Bimakalim also reduced MPO activity in tissue bordering the infarcted region when administered by either treatment protocol. Bimaklim is effective at reducing myocardial IS in dogs. The mechanism of this beneficial effect may be a result of decreased oxygen consumption during ischemia and/or a direct cardioprotective action secondary to myocardial K(ATP) channel activation.