The isolated perfused rat heart was used to study the effect of therapeutic concentrations of sodium salicylate and acetylsalicylate with respect to their potential cardioprotective property described in some clinical studies and experiments in vivo. Salicylates were added to the perfusion medium (Krebs-Henseleit buffer plus 5.5 mM glucose) in final concentrations ranging from 0.1 to 3.2 mM. In lower concentrations sodium salicylate reduced release of lactate dehydrogenase from the heart associated with delayed cleavage of endogenous triglycerides and a reduction of heart rate. A significant increase in lactate production, undoubtedly an expression of the uncoupling effect of sodium salicylate noted at 1.6 mM or higher concentration was accompanied by an increased uptake of glucose from the medium and increased coronary flow. In the presence of epinephrine (5.5 microM) sodium salicylate (0.1 and 0.5 mM) reduced only the total number of heart beats. Equimolar doses of acetylsalicylic acid failed to mimick salicylate effects. The results suggest that potentially cardioprotective effects of salicylate followed in these experiments by myocardial membrane leakage may be in part explained by the direct action of salicylate on the myocardium due to its antilipolytic and negative chronotropic effect. We failed to demonstrate this protective effect of salicylate against cardiotoxic doses of exogenous epinephrine.