The long term goal of the present proposal is to determine the role of ATP regulated potassium (KATP) channels in the antiischemic actions of volatile anesthetic agents in two different models of ischemia and reperfusion injury. Preliminary results indicate that several KATP channel opening drugs have direct effects to improve functional recovery and reduce infarct size following coronary artery occlusion and reperfusion. Conversely, KATP channel antagonists can block the beneficial actions of KATP channel openers. Coronary vasodilation by volatile anesthetic agents has recently been linked to KATP channel opening and is blocked by glibenclamide. Preliminary evidence from the applicants' laboratory indicates that the beneficial effect of volatile anesthetics to improve recovery of contractile function during reperfusion following coronary occlusion is antagonized by glibenclamide. The major objective of the present proposal will be to determine the role of opening of KATP channels in the beneficial effects of halothane and isoflurane on reversibly (stunned) or irreversibly injured (infarcted) myocardium of chronically instrumented dogs subjected to brief (15 minutes) or prolonged (60 minutes) coronary artery occlusion and be assessed by ultrasonic segment length gauges. The extent of irreversible tissue damage will be determined by the triphenyltetrazolium histochemical staining technique. In all experiments, reperfusion will be allowed for 24 hrs to determine if volatile anesthetics only delay or produce a prolonged reduction in myocardial injury. A second objective is to characterize the influence of halothane and isoflurane on ischemic preconditioning. Experiments are designed to test whether KATP channel opening by volatile anesthetics can mimic, enhance, or lower the threshold of ischemic preconditioning against stunning or myocardial infarction.
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