In order to study the regulation of fatty acid oxidation in the heart, the effects of some phosphodiesterase III inhibitors, such as enoximone and milrinone, on the oxidation of [1-14C]palmitic acid, [1-14C]octanoic acid, and [2-14C]pyruvate were studied in adult rat myocytes. Enoximone and milrinone, at a concentration of 0.25 mM, increased palmitate oxidation significantly, by 70 and 40%, respectively. Also, enoximone increased octanoate oxidation by 45%. In contrast, pyruvate oxidation was decreased by 60% by enoximone. To investigate the effects of enoximone or milrinone on the pathway of fatty acid oxidation, their effects on the oxidation of either [1-14C]palmitoyl-CoA or [1-14C]palmitoylcarnitine were studied with rat heart homogenates. Neither enoximone nor milrinone had any effects on the oxidation of these compounds. Compounds known to elevate intracellular [Ca2+] or cyclic AMP, such as the calcium ionophore A23187, ionomycin, dibutyryl cyclic AMP, or isoproterenol, had no effect on palmitate oxidation. Enoximone, at a concentration of 0.25 mM, increased palmitate uptake by 40% in rat myocytes. These results suggest that enoximone and milrinone increase fatty acid oxidation in myocytes by increasing their cellular transport, and they also show the usefulness of these compounds as a tool to study the regulation of this vital pathway in heart.
