Inhibition by (Aminooxy)acetate of the Malate-Aspartate Cycle in the Isolated Working Guinea Pig Heart

Abstract

The quantitative importance of the malate-aspartate cycle and the sn-glycerol 3-phosphate cycle, with respect to the flux of cytosolic reducing equivalents across the mitochondrial membrane, was studied in isolated perfused guinea pig hearts. The heart preparations performed pressure-volume work and metabolized glucose, lactate, pyruvate or 3-hydroxybutyrate. With glucose or lactate as the substrate, (aminooxy)acetate, an inhibitor of the malate-aspartate cycle, caused left ventricular failure, manifested by reduced aortic pressure and cardiac output, in association with a decrease in myocardial oxygen consumption and a depletion of high energy phosphate stores; lactate and particularly sn glycerol 3-phosphate accumulated in the myocardium. Moreover, lactate release rates increased more than 10-fold in presence of glucose and (aminooxy)acetate. Pretreatment of the animals with high doses of triiodothyronine did not prevent the hemodynamic and metabolic alterations caused by (aminooxy)acetate. In contrast, (aminooxy)acetate did not affect performance and energy-yielding metabolism when hearts metabolized pyruvate or 3-hydroxybutyrate as the substrate. From the findings it is concluded that the malate-aspartate cycle preponderates over the sn-glycerol 3-phosphate cycle in the working guinea pig heart, even when sn-glycerol 3-phosphate accumulates.