Stimulation of fatty acid oxidation by phosphodiesterase III inhibitors in rat myocytes.
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.
Abdel-aleem
S
S
Department of Pharmacology, Glaxo Inc., Research Triangle Park, North Carolina.
Frangakis
C
C
D000818:Animals; D002478:Cells, Cultured; D017335:Enoximone; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D020105:Milrinone; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D007093:Imidazoles; D010168:Palmitates; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D017335:Enoximone; D020105:Milrinone