The long-term objective of this developmental proposal is to determine the role of adenosine triphosphate-regulated potassium (K-ATP) channels in the antiischemic actions of chronic, modest ethanol exposure in canine models of ischemia and reperfusion injury and myocardial infarction. This and other laboratories have previously demonstrated that K-ATP channel activation reduces the extent of reversible (stunned) and irreversible (infarcted) ischemic injury during experiments using brief or prolonged periods of coronary artery occlusion and reperfusion. This laboratory has also shown that myocardial protection against ischemic injury produced by K-ATP channel activation is coupled to adenosine type 1 (A1) receptors in vivo. Recent evidence suggests that chronic, modest ethanol consumption may reduce myocardial ischemia- reperfusion injury and mimic the protective effects of ischemic preconditioning by activating A1 receptors. Whether K-ATP channels are involved in mediating this ethanol-induced myocardial protection via stimulation of A1 receptors has yet to be evaluated. Adenosine type 3 (A3) receptor activation also protects against myocardial stunning and infarction, however, whether A3 receptors are involved in ethanol-induced cardioprotection is unknown. The major hypothesis to be tested is that opening of K-ATP channels mediates the antiischemic actions of chronic, modest ethanol exposure in chronically instrumented canine models of postischemic, reperfusion injury and myocardial infarction. This problem is clinically relevant because regular ethanol drinkers are more likely to survive after myocardial infarction than non drinkers. Dogs will undergo brief (15 min to produce stunning) or prolonged (60 min to produce infarction) periods of coronary occlusion with and without pretreatment (4 to 12 weeks) with daily intravenous doses of ethanol required to produce peak plasma concentrations between 5 and 10 mM. Regional systolic and diastolic function will be evaluated using left ventricular pressure-segment length diagrams. Regional myocardial perfusion (radioactive microspheres) and myocardial oxygen consumption will be measured at selected intervals in each experiment. Myocardial infarct size will be quantified with triphenyltetrazolium histochemical staining. The results will help to clarify the mechanism of the antiischemic effects of chronic, modest ethanol exposure and will provide exciting new information about the unique role of K-ATP channels in reversible and irreversible ischemic injury.
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