The objects of these proposals are to establish the limits of metabolic adaptation in ischemic myocardium and to evaluate several interventions designed to improve energy production and/or mechanical function. We have observed previously that the damages of myocardial ischemia result not only from the loss in oxygen delivery, but also from an accumulation of several inhibitory metabolites. Nevertheless, manipulations which either modify or circumvent these products can be affected to stimulate residual oxidative phosphorylation. Studies in working swine hearts are planned to continue these investigations. Emphasis will be specifically directed at determining the effects of substrate enhancement, documenting the influence of agents designed to blunt the effects of fatty acid excess, and further detailing the impact of coronary washout. Alternate substrates which may have specific advantages in providing mitochondria with increased amount of acetyl-CoA and which will be evaluated in the coming grant year include: acetate, beta-hydroxybutyrate and pyruvate with dichloro acetate. Specific agents to be used in modifying fatty acid excess will be the various isomers (L, D and DL) of carnitine. Experiments will be formed to evaluate and determine the magnitude and distribution of the intracellular incorporation of carnitine, the effects of their isomeric stereospecificity, and their potential impact on modifying and hopefully improving energy production in ischemic tissue. Studies to evaluate the impact of coronary washout on preserving metabolic and mechanical functions are also planned. Studies will determine whether washout in ischemia alters vascular redistribution and oxygen content. It is hoped that a critical evaluation of cardiac metabolism and energy production with these several interventions will provide insights to possible future therapeutic options for protecting ischemic myocardium.
