The effects of alpha-adrenergic agonists on the regulation of the branched chain alpha-ketoacid oxidation in the perfused rat liver.

The effect of a-adrenergic agonists on the regulation of the branched chain a-ketoacid dehydrogenase reaction was measured in the isolated perfused rat liver.The metabolic flux through the b r a n c h e d chain complex, the oxidation-reduction state of the mitochondrial c o m p a r t m e n t as indicated b y the P-hydroxybutyrate/ acetoacetate ratio of the effluent perfusate, and the rate of hepatic glucose production were measured under various metabolic conditions.Using tu-ket~[l-'~C] isocaproate as a substrate, infusion of an a-adrenergic agonist such as epinephrine or phenylephrine caused a significant but transient inhibition of I4CO2 production.This type of inhibitory effect was much less m a r k e d when a-ket~[l-'~C]isovalerate was utilized to monitor the metabolic flux through the branched chain complex.The inhibition of a-ketoisocaproate flux upon phenylephrine infusion was paralleled by transient increases in the P-hydroxybutyrate/acetoacetate ratio in the effluent perfusate and hepatic glucose output.Lowering the calcium concentration of the perfusion medium minimized the magnitude of both the inhibition of the branched chain flux and the increase in the mitochondrial redox change; a strong correlation was observed between these two parameters.However, subsequent experiments demonstrated that the branched chain flux changes could occur independently of changes in the mitochondrial oxidation-reduction state.The time course of flux changes and the changes in the mitochondrial redox state correlated well with transient changes in both calcium and glucose output by the liver.Perfusion experiments using the divalent metal cationophore A23187 in conjunction with ethylene glycol bis(P-aminoethyl ether)-N,NJV'JV'-tetraacetic acid provided evidence that the redistribution of intracellular calcium, especially in the mitochondrial compartment, may regulate the metabolic flux through the branched chain tu-ketoacid dehydrogenase reaction in the liver.