Inhibition of fatty acid oxidation in normal and hypoxic perfused rat hearts by 2-tetradecylglycidic acid

Abstract

Studies with a new fatty acid oxidation inhibitor, 2-tetradecylglycidic acid, showed that half-maximal inhibition of oleate oxidation occurred at concentrations of 3 × 10 −6 m. 2-Tetradecylglycidic acid also inhibited endogenous fatty acid oxidation, but had little effect on octanoate oxidation. The inhibition of long chain fatty acid oxidation produced by 2-tetradecylglycidic acid depended on its time exposure to the hearts. At low work loads it had no effect on left ventricular pressure development or aortic output, but was inhibitory at high work loads when the capacity for glucose oxidation was exceeded. The relationship of oleate concentration (with 2% albumin present) to pyridine nucleotide fluorescence and to the stimulation of oxygen consumption was examined using hearts perfused with glucose. Pyridine nucleotide fluorescence and oxygen consumption were both increased, with half-maximal effects occurring at 0.08 m m and 0.2 m m oleate, respectively. Oleate addition, both in the absence and presence of insulin, increased oxygen consumption to a greater degree than expected from the theoretical decrease of the P O ratio associated with fatty acid oxidation. At fatty acid/albumin molar ratios of 2.5 or greater, contractility was impaired and oxygen consumption increased even further. Pyridine nucleotides remained reduced indicating the absence of an uncoupling effect on oxidative phosphorylation. The oxygen wasting effect of fatty acids is interpreted as caused by long chain fatty acyl-CoA formation and hydrolysis. In working heart preparations made hypoxic by lowering the perfusate oxygen content to about 35%, addition of 1 m m oleate to the perfusate resulted in a reversible decrease in left ventricular pressure development and aortic output. Perfusion with 5 × 10 −5 m 2-tetradecylglycidic acid for 40 min before oleate addition prevented this deleterious effect of oleate during hypoxia. Photographs of the surface pyridine nucleotide fluorescence showed that addition of oleate to the hypoxic heart resulted in an increase in the size and number of anoxic areas. Subsequent addition of 10 −5 m 2-tetradecylglycidic acid caused the anoxic areas to disappear. These results indicate that the deleterious effects of fatty acids on the hypoxic myocardium are due to an increased oxygen demand resulting from accelerated fatty acid oxidation.