The prolongation of reserpine-induced cardiac norepinephrine depletion by metabolic inhibitors

Abstract

Levels of cardiac norepinephrine (NE) in the rat were determined at various times after the intraperitoneal administration of 2 mg/kg reserpine phosphate. The rate of repletion of NE was decreased by the administration of certain metabolic inhibitors [thioacetamide; 2,2-dichloro- N-(β-hydroxy-α-(hydroxymethyl) - p-methylsulfonyl-phenethyl) acetamide; β-diethylaminoethyl-diphenylpropyl acetate (SKF 525-A); actinomycin d] in proper dosage schedules. None of these agents significantly affected the endogenous NE concentration in the heart of the nonreserpinized rat. In animals pretreated with phenobarbital prior to reserpine, the levels of cardiac NE returned to normal more rapidly than did those of animals receiving no prior barbiturate. SKF 525-A decreased the levels of 3H-reserpine found in the heart and liver, and did not affect the concentration of 3H-reserpine in the carcass of animals 4 days after 2 mg/kg 3H-reserpine. Thioacetamide did not alter the capacity of the heart to retain tritiated NE after i.v. administration. Actinomycin d did not interfere with the rate of NE synthesis in the heart, nor did it change the characteristics of the NE uptake process of isolated perfused hearts from reserpinized animals. Repletion of adrenal NE in reserpinized animals was not affected by administration of actinomycin d. It was concluded that the slow repletion of the cardiac NE after reserpine administration may be due to the necessity for the synthesis of new NE storage sites in the heart, and that the metabolic inhibitors retard the return of normal NE levels by inhibiting the synthesis of these storage sites.