BIMAKALIM, AN ATP-SENSITIVE POTASSIUM CHANNEL OPENER, MIMICS THE EFFECTS OF ISCHEMIC PRECONDITIONING TO REDUCE INFARCT SIZE, ADENOSINE RELEASE, AND NEUTROPHIL FUNCTION IN DOGS

Background The primary goal of the present study was to determine whet her the infarct size-reducing effect of preconditioning is associated with an increase in adenosine release from the ischemic myocardium dur ing a prolonged occlusion period or the subsequent reperfusion period and by a decrease in neutrophil infiltration. A second objective was t o determine whether bimakalim, a KATP channel opener, mimics the effec ts of ischemic preconditioning. Methods and Results Barbital-anestheti zed open-chest dogs were subjected to 60 minutes of left anterior desc ending coronary artery (LAD) occlusion followed by 3 hours of reperfus ion. In the preconditioning group, 5 minutes of LAD occlusion followed by 10 minutes of reperfusion was elicited before the 60-minute occlus ion period. In two other groups, bimakalim 1 mu g/kg bolus followed by a 0.05 mu g . kg(-1). min(-1) infusion or an equivalent volume of sal ine was administered intravenously 15 minutes before occlusion and con tinued until the time of reperfusion. in a final group, bimakalim was administered 10 minutes before reperfusion and continued until the end of the experiment. To measure the release of adenosine from the ische mic region, coronary venous blood samples were collected at various ti mes during ischemia and after reperfusion, and the concentration of ad enosine was measured. Myocardial infarct size was determined by triphe nyl tetrazolium chloride; transmural myocardial blood flow, by radioac tive microspheres. Transmural myeloperoxidase (MPO) activity, an index of neutrophil infiltration in the area at risk, was also measured. Pr econditioning produced a marked reduction in infarct size (9.8+/-3.0% versus 28.6+/-5.2% in the control group, mean+/-SEM); adenosine releas e at 5, 10, 15, and 30 minutes of the 3-hour reperfusion period; and t ransmural MPO activity in the risk area. Similarly, pretreatment with bimakalim resulted in reductions in infarct size, adenosine release, a nd transmural MPO activity to an extent almost identical to that of pr econditioning. When bimakalim was administered 10 minutes before reper fusion, the drug also produced a significant reduction in infarct size and transmural MPO activity; however, no significant reduction in cor onary venous adenosine concentrations was observed. There were no sign ificant differences in collateral blood flow between groups. Conclusio ns These results indicate that myocardial preconditioning in the canin e heart produced by a short period of ischemia or a KATP channel opene r is not mediated by an increase in adenosine release, as measured by coronary venous adenosine concentrations, during 60 minutes of occlusi on or the initial 30 minutes of reperfusion. A significant reduction i n transmural MPO activity in the ischemic area also appears to result from KATP channel activation and may play a role, at least in part, in the reduction in infarct size observed, particularly when a KATP chan nel opener is administered just before reperfusion.