Molecular Pharmacology, Vol 9, 748-755, Copyright © 1973 by the American Society for Pharmacology and Experimental Therapeutics

Reserpine-Like Effects of Harmine on Isolated Adrenal Medullary Vesicles

¹ Department of Physiology and Pharmacology, Duke University, Medical Center, Durham, North Carolina 27710

Because of its structural similarities to reserpine, the actions of harmine on adrenal medullary vesicles were examined in order to clarify the mechanisms involved in drug effects on amine uptake and storage. Harmine markedly inhibited the ATP-Mg²⁺-dependent incorporation of epinephrine into isolated rat adrenal medullary vesicles. The inhibition was both competitive and reversible; K_m for epinephrine was 37 µM and K_i for harmine was 3.2 µM. Metaraminol incorporation, which is predominantly ATP-Mg²⁺-independent and reserpine-insensitive, was decreased only 23% by equimolar concentrations of harmine (which caused 85% inhibition of epinephrine incorporation). Harmine had no effect on efflux of epinephrine from adrenal medullary vesicles, indicating that the effect on incorporation was due solely to inhibition of uptake. No temperature-dependent uptake of harmine into the vesicles was detected, implying that the effects on the uptake system are purely inhibitory. Harmine in equimolar concentrations inhibited binding of epinephrine and serotonin to bovine adrenal vesicle membranes by 43% and 13%, respectively, but did not inhibit binding of metaraminol. Harmine strongly inhibited monoamine oxidase but had no effect on the activities of the catecholamine-synthesizing enzymes tyrosine hydroxylase, dopa decarboxylase, and dopamine -hydroxylase. The data suggest that the -carboline section of the harmine and reserpine structures is responsible for affinity for the amine uptake mechanism and for inhibition of uptake, while the remainder of the reserpine molecule confers irreversibility. A mobile carrier in the adrenal vesicle membrane may be the site of action.