EFFECT OF DRUGS UPON MYOCARDIAL HYPOXIA

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The long term goal of the present proposal is to determine the role of potassium (K) channels, particularly adenosine triphosphate-regulated potassium (KATP) channels in the regulation of regional myocardial blood flow, cardiac muscle function and cell viability in different models of ischemia. Preliminary results indicate that several novel K channel openers (KCOs) have a different cardiac effect to improve functional and metabolic recovery of the heart and reduce infarct size following ischemia and reperfusion at nonhypotensive doses. Conversely, we have also shown that the KATP-dependent channel antagonist, glyburide, blocks the beneficial actions of the KCOs and may even exacerbate ischemic injury. Thus, the major objective of the present proposal will be to determine the function of opening or blocking KATP channels in the reversibly injured ("stunned") or irreversibly injured ("infarcted") myocardium of anesthetized dogs subjected to brief (15 minutes ) of prolonged (90 minutes) periods of coronary artery occlusion followed by reperfusion and the mechanisms involved. In stunned myocardium, regional wall motion will be assessed by ultrasonic dimension gauges, regional myocardial blood flow by radioactive microspheres and metabolic status by tissue biopsies obtained at various times during ischemia and reperfusion. In infarct size studies, the extent of tissue death will be determined by the triphenyltetrazolium histochemical technique. Reperfusion will be allowed for 5 or 24 hours to determine if KCOs only delay or produce a prolonged reduction in infarct size. Myeloperoxidose will be used as an index of neutrophil infiltration into normal, ischemic non-infarcted and infarcted myocardium and in vitro experiments will examine the role of KATP channels on neutrophil function as assessed by chemiluminescence. Preliminary studies have shown that several KCOs reduce neutrophil infiltration into ischemic myocardium in vivo and inhibit superoxide production in activated neurophils in vitro. The pro- or antiarrhythmic properties of the KCOs or antagonists will also be assessed by Holter monitoring. Since the major determinant of functional recovery in stunned myocardium and tissue survival in infarcted myocardium is the amount of collateral blood flow, a second major objective will be to determine the effects of KCOs on the coronary collateral circulation in dogs with different degrees of collateral development. Coronary arteriolar and collateral resistances will be calculated to determine relative selectivity of KCOs for these vessels in vivo. Isolated large coronary and mature collateral vessels will be isolated and studied in vitro to further characterize the selectivity of KCOs to dilate collateral vessels. KATP channel antagonists, glyburide, tolbutamide, sodium 5-hydroxydeconoate, will be used to determine if channels selective to these agents are responsible for the beneficial actions of the KCOs in collateral vessels. The results of these studies will provide exciting new data on the unique role of KATP channels in myocardial ischemia-reperfusion injury.