Myocardium subjected to a brief period of ischemia exhibits prolonged dysfunction after reflow, despite the absence of necrosis. This proposal will study how abnormal high energy phosphate metabolism may be related to post-ischemic """"""""stunned"""""""" myocardium. Repeated brief occlusions of the anterior descending coronary artery will be performed in the anesthetized dog to produce severe regional dysfunction (measured by sonomicrometry) without necrosis. In this model we will determine (1) the extent to which dysfunction can be reversed by cardiac glycosides and what changes in tissue adenine nucleotides (AN) and nucleosides (measured in biopsies by HPLC) occur during maximal inotropic stimulation, (2) whether tissue AN and function are correlated during progressively severe post-ischemic dysfunction, and (3) whether function can be restored by agents which increase tissue levels of AN. The recovery of post-ischemic dysfunction will also be determined in conscious instrumented dogs over a 2 week period under resting conditions and during increased afterload (phenylephrine). In isolated rabbit hearts, reperfused after a relatively mild global ischemic insult, 31-P NMR will be used to determine: (1) the metabolic reserve of the dysfunctional post-ischemic heart during stress, (2) the bioenergetic status of the post-ischemic heart, using levels of free ADP calculated from the creatine kinase equilibrium equation to make important thermodynamic calculations, (3) the extent of inhibition of adenine nucleotide translocase, (4) ATP and phosphocreatine production rates at different levels of cardiac performance using saturation transfer techniques. These data will provide evidence for or against uncoupling of oxidative phosphorylation futile ATP cycling or an abnormality of mitochondrial creatine kinase in the post-ischemic heart. The experiments outlined will further the understanding of the causes of post-ischemic dysfunction and could lead to new therapeutic approaches for preserving ventricular function in ischemic heart disease.
