The long-term objective of this work is a comprehensive analysis of the cardioprotective effects of volatile anesthetics. These agents are capable of reducing the contractile deficit (myocardial stunning) following a brief period of ischemia and the extent of myocardial infarction following a prolonged period of coronary artery occlusion. Recently, it was found that a prior, brief exposure to the volatile anesthetic, isoflurane, could reduce myocardial infarct size after its discontinuation. This phenomenon has a strong similarity to ischemic preconditioning, in which a brief period of coronary artery occlusion and reperfusion renders myocardium resistant to infarction after a subsequent prolonged ischemia insult. Anesthetic-induced preconditioning (APC) demonstrates a powerful cardioprotective effect with short and long-term memories. The major hypothesis to be tested in the present investigation is that volatile anesthetics directly produce early and late preconditioning against both myocardial stunning and infarction via enhanced opening of ATP-dependent potassium (KATP) channels. Signal transduction pathways including adenosine receptors and protein kinase C serving as a mechanism(s) for APC will be characterized. APC-induced alterations in the interstitial concentration of adenosine and translocation of PKC isoforms will be measured in ischemic and control myocardium. Cardioprotective effects of the anesthetics will be studied in in vivo canine models of myocardial ventricular pressure-segment length diagrams, and myocardial infarct size will be measured by triphenyl tetrazolium histochemical staining. Alterations in potassium conductance through KATP channels will be studied directly by means of modification of the patch clamp technique in normal and previously ischemic ventricular myocytes. Because of the large number of patients with coronary artery disease undergoing infarction, the proposed research represents an investigation into a clinically relevant problem. Isoflurane has recently been shown to produce APC in patients undergoing coronary artery bypass graft surgery. Thus, this proposal will delineate mechanisms responsible for the novel and unique cardioprotective effects of volatile anesthetics against ischemia and reperfusion injury in vivo and provide direct evidence of the involvement of specific signal transduction pathways modulating the KATP channel in vitro.
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