The principal objective of this research is to establish the pathogenesis of irreversible myocardial cell injury. Prior studies using an in vivo ischemia model in dogs have suggested that loss of cell volume control and increased cell membrane permeability occur as early events in irreversible injury. We have recently developed an in vitro anoxic perfused rat heart model in which we can reproduce nearly identical biochemical and ultrastructural lesions in vitro. We wish to use this model to test the hyypothesis that rupture or loss of integrity of the cell plasma membrane is the critical event in irreversible anoxic and presumably also ischemic injury. We will determine the role of membrane permeability in induction of characteristic ultrastructural lesions of irreversibility as well as the mechanisms responsible for the observed loss of normal plasma membrane functions. Various agents which may stabilize membrane structure will be studied for their ability to delay or prevent irreversible injury. The model will also be evaluated as an in vitro method for screening agents of potential value in preventing or reduction of size of myocardial infarction. The results of this study will lead to further understanding of the basic mechanisms of cell death and may lead to development of rational therapies for acute myocardial infarction.