The overall objective of this proposal is to improve cardioprotection in children undergoing surgery for repair of congenital heart defects. The majority of infants undergoing cardiac surgery exhibit varying degrees of cyanotic heart disease where the myocardium is chronically perfused with hypoxic blood. To investigate mechanisms of adaptation to chronic hypoxia and resistance to myocardial ischemia a non-surgical rabbit model of chronic hypoxia from birth has been developed. The relationship between protein kinases and nitric oxide synthase and whether they activate sarcolemmal or mitochondrial K/ATP channels to confer cardioprotection in chronically hypoxic hearts is unknown. We hypothesize that chronic hypoxia activates protein kinase signal transduction pathways leading to activation of nitric oxide synthase which confers cardioprotection by activation of sarcolemmal and mitochondrial K/ATP channels. We propose to test this hypothesis in isolated hearts and isolated myocytes from rabbits raised from birth in hypoxic and normoxic environments and in right atrial tissue from cyanotic and acyanotic infants undergoing surgical repair of congenital heart defects. We shall determine (1) whether protein kinases participate in the mechanism of adaptation to chronic hypoxia and resistance to ischemia in isolated hearts from normoxic and chronically hypoxic immature rabbits and in human hearts from infants with cyanotic and acyanotic heart defect, (2) the mechanisms by which chronic hypoxia controls nitric oxide production from nitric oxide synthase and resistance to subsequent ischemia and (3) the mechanisms by which protein kinases and nitric oxide synthase mediate the activity of the sarcolemmal and mitochondrial K/ATP channels and the involvement of cyclic GMP in controlling resistance to myocardial ischemia induced by chronic hypoxia. The findings from these studies should enhance our understanding of the cardioprotective mechanisms resulting from adaptation to chronic hypoxia in the immature heart and may lead to the development of new strategies to protect hearts of children undergoing surgical repair for congenital birth defects.
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