A growing body of experimental and clinical evidence indicates that certain volatile anesthetics precondition the heart against irreversible ischemia/reperfusion injury by activating endogenous protective cellular mechanisms. This phenomenon has been termed the anesthetic-induced preconditioning (APC). During the previous grant cycle, we obtained data from guinea pig hearts to suggest that opening of the KA/ATP channel by anesthetics contributes to APC. Because APC may vary among species, it is important to establish the mechanisms responsible for APC in human myocardium. Therefore, the objective of our proposal is to investigate the signaling pathways responsible for APC in isolated human atrial myocytes and determine the respective roles of sarc and mitoK/ATP channels in cytoprotection produced by volatile anesthetics. This will be accomplished by the use of electrophysiological, biochemical, molecular and immunohistochemical techniques. The major hypothesis to be tested is that in human myocardium the sarc and mitoKar P channels are involved in cytoprotection afforded by acute APC. To pursue this hypothesis we will address the following specific aims:
Aim I : To identify cellular pathways by which acute APC modulates the sarCK/ATP channel in human atrial myocytes. Hypothesis: Volatile anesthetics modulate the human sarCK/ATP channel and its sensitivity to nucleotides, protein kinases (PKC, PTK, MAPK) and reactive oxygen species.
Aim II : To characterize how APC affects activity of mitOK/ATP channels in intact myocytes, mitochondrial function and mitoK/ATP channels in planar lipid bilayers. Hypothesis: Volatile anesthetics regulate mitochondrial function and activity of the human mitoKare channel via multiple signaling pathways.
Aim III : To characterize the efficacy of acute APC on survival of isolated human atrial myocytes. Hypothesis: Sarc and mitOK/ATP channels play a role in cellular protection against ischemic injury afforded by APC, and this protection is anesthetic specific. In summary, this research project will characterize the importance of the KATP channel in human atrial myocytes and evaluate specific signaling pathways that mediate APC in vitro. This proposal represents a comprehensive approach to the significant and clinically relevant phenomenon of volatile anesthetic-induced cardioprotection against ischemia/reperfusion injury.
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