Studies of the effects of beta-adrenergic agonists on the regulation of pyruvate dehydrogenase in the perfused rat heart.

The effects of &adrenergic agonists (e.g. epinephrine and isoproterenol) on the metabolic flux through, and the activation state of the pyruvate dehydrogenase multienzyme complex, were investigated in the isolated perfused rat heart. Infusion of epinephrine caused an inhibition of pyruvate decarboxylation at low (0.1 m ~ ) pyruvate concentrations in the perfusion medium, a stimulation of flux at intermediate (0.6 m ~ ) pyruvate concentrations and relatively little change occurred at high pyruvate levels (10 m ~ ) . However, in the presence of an alternate oxidizable substrate such as 8-hydroxybutyrate, epinephrine or isoproterenol stimulated pyruvate decarboxylation about 2.6-fold. Such a stimulation of flux through the pyruvate dehydrogenase reaction was accompanied by an extensive interconversion of the enzyme complex to its active form. Interconversion of the pyruvate dehydrogenase to its active form (e.g. 28% to 72% active) upon addition of the 8-agonist likely was not caused by effects of alterations in the levels of various tissue metabolites on the kinase/phosphatase interconversion system. Perfusion conditions and agents which alter the normal distribution of calcium in the perfused heart preparation prevented or reversed the effect of the 8-agonists on the metabolic flux through the pyruvate dehydrogenase reaction. While the data in this study are consistent with an activation of the enzyme complex via calcium stimulation of the pyruvate dehydrogenase phosphatase, we cannot distinguish between direct and indirect effects of calcium on the interconversion system of the pyruvate dehydrogenase complex.