The overall objective of the proposed research is to develop improved methods for cardiac preservation. This goal will be sought using in vivo and in vitro models. As the first objective, a heterotopic rat cardiac allograft model will be used to explore effects of cAMP analogues, nitroglycerin, antioxidants and antineutrophil antibodies on cardiac preservation and reperfusion. During 12-hours of cold storage the hearts will be preserved with UW solution with or without cAMP or cGMP/NO analogues or antioxidants or a combination of these. The hearts will then be transplanted into immunosuppressed allogenic recipients, some of which will receive monoclonal antibodies against cell adhesion molecules. The reperfused hearts will be evaluated for contractility, perfusion, leukocyte influx, vascular permeability and activation. The investigators will test various dosages and combinations with the goal of optimizing the prepreservation/ reperfusion regimen. The second objective is to evaluate the potential contribution of endothelium to the pathophysiology of preservation/reperfusion. The system to be studied consists of human umbilical vein endothelial cells exposed to severe hypoxia and in some cases returned to normoxia. Changes in metabolism of NO/oxidant production, IL-8, PAI-1, cyclic nucleotides (adrenergic receptor-G protein coupling) activation and adhesion of platelets will be investigated.
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