The long-term objective of the proposed research is to develop a strategy for conducting extracorporeal circulation in immature cyanotic subjects that will avoid of reduce perioperative cardiac dysfunction. The hypothesis to be tested is that improvement in arterial oxygenation by initiation of cardiopulmonary bypass in hypoxemic immature subjects causes a heretofore unrecognized reoxygenation injury which targets endothelial and myocardial cells, and results in cardiac dysfunction that may partially offset the immediate benefits of correcting underlying congenital heart defect causing hypoxemia. We postulate two mechanisms: (1) reoxygenation injury occurs due to enhanced production of reaCtive oxygen species; (2) these oxygen intermediates can react subsequently with endothelium derived nitric oxide (.NO) and form additional toxic products. We propose that these biochemical events can be reduced or prevented by either pretreatment before bypass and/or adjusting the priming solution in the extracorporeal circuit with interventions that (a) reduce formation of superoxide anion (O2-) and/or expedite the degradation of other cytotoxic O2 species, (b) limit the production or increase the destruction of endothelium derived .NO, or (c) minimize the Interaction between O2- and .NO. These interventions will include (i) L-arginine structural analogs that act as competitive inhibitors of NO synthase to limit intracellular formation of NO from L-arginine, (2) introducing graded hypocalcemia on bypass to limit the activation of constitutive NO synthase, (3) employing site-directed superoxide dismutase (SOD) to characterize the role of O2- and its interaction with .NO in locations predominantly in the membrane and cytosol, (4) using scavengers of peroxynitrite (OONO-), the toxic product of O2-.NO interaction, to prevent oxidant injury, and (6) using catalase (CAT) which localizes predominantly in the membranes or cytosol to distinguish the relative contribution of the Haber-Weiss pathway to reoxygenation injury. An existing clinically relevant acute and chronic model of the neonatal hypoxemic piglet will be used to study first, the effects of cardiopulmonary bypass alone, and then will be used in conjunction with deep hypothermia and circulatory arrest to study conditions that simulate those during cardiac surgery.
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