In the present work, we tested the hypothesis that the development of myocardial infarction in the isolated perfused working rat hearts could be influenced by the nature of the substrate reaching the infarction zone. We measured cardiac output and rates of release of lactate dehydrogenase (LDH) after coronary artery ligation in hearts perfused with different substrates: glucose; palmitate, oleate, linoleate bound to albumin; palmitate-albumin plus glucose and/or insulin. Cardiac ouptut after ligation was lowest with palmitate and highest with glucose. LDH release was 5-10 times greater with FFA than with glucose, but was significantly reduced by the addition of glucose or insulin to the palmitate-albumin solution. Our results argue for an important role for substrate effects on the metabolic outocme of experimental myocardial infarction.