Cardiac KATP Channels in Anesthetic-Induced Preconditioning

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The overall goal of this project is to characterize the effects of anesthetic-induced preconditioning (APC) on sarcolemmal and mitochondrial ATP-sensitive potassium (K(ATP) channels in cardiac myocytes, mitochondrial K(ATP) channels incorporated into lipid bilayers and recombinant K(ATP) channels expressed in the mammalian HEK293 cell line. Results from our laboratory suggest that K(ATP) channels are critical elements in cardioprotection produced by volatile anesthetics against ischemia and reperfusion injury. Although some studies have indicated that isoflurane and other volatile anesthetics can mimic ischemic preconditioning and this action is sensitive to K(ATP) channel blockers, there is no direct evidence of the interaction between volatile anesthetics and the K(ATP) channel. Such an interaction is clinically important because volatile anesthetics may enhance or mimic the protective mechanisms of K(ATP) channel opening. Each of the three projects proposed in this Program will characterize fundamental mechanisms by which adenosine, protein kinase C, protein tyrosine kinase and mitogen-activated protein kinase-mediated pathways and reactive oxygen species interact and participate in cardioprotection by volatile anesthetics. The overall hypothesis of this work is that volatile anesthetics are cardioprotective during ischemia and reperfusion by modulating the activity of sarcolemmal and mitochondrial K(ATP) channels. To pursue this general hypothesis we will address the following specific aims: Aim I- To establish the cellular pathways by which volatile anesthetics modulate sarcolemmal K(ATP) channel activity in rat myocytes and recombinant K(ATP) channel expressed in the HEK293 mammalian cell line. Aim II- To characterize how volatile anesthetics alter the sensitivity of the mitochondrial K(ATP) channel to modulators in rat myocytes and lipid bilayers. Aim III- To determine the sensitivity of sarcolemmal and mitochondrial K(ATP) channels to channel modulators after APC in vivo (hearts obtained from Project I). In summary, Prqiect II will complement Projects I and III by examining the direct effects of volatile anesthetics on K(ATP) channels in the absence and presence of K(ATP) channel modulators. The long-term goal of this Project will be directed to translational research in which our findings concerning the cardioprotective role of volatile anesthetics can be applied to human investigation.