INTERACTIONS OF BRETYLIUM AND OTHER DRUGS ON GUINEA-PIG ATRIA: EVIDENCE FOR INHIBITION OF NEURONAL MONOAMINE OXIDASE BY BRETYLIUM

¹ Department of Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York

Bretylium pretreatment (25 µg/ml for 5 to 10 minutes) of the normal electrically driven to three hours after the bretylium wahout. Bretylium pretreatment also potentiated the ability of NE to restore responsiveness to other indirectly acting sympathomimetic agents, including bretylium itself. The effects of bretylium pretreatment resemble those produced by pretreatment with the monoamine oxidase inhibitors, iproniasid and pheniprasine. The net uptake of NE by normal and reserpine-treated atria was increased after bretylium pre- treatment. The increased net uptake by the reserpine-treated atrium after bretylium was as great as that after iproniazid or pheniprasine when incubation was with 0.25 µg/ml of NE for five minutes. Both effects of bretylium pretreatment on the reserpine-treated atrium (potentiation of the restoring action of NE and enhancement of net uptake) could be largely reversed by 20 minutes of exposure to 10 µg/ml of tyramine. If bretylium pretreatment. preceded either iproniasid or pheniprasine pretreatment, it could largely protect against the ir- reversible effects of the latter pretreatment. It is proposed that bretylium, on being actively transported into adrenergic nerve terminals, reaches a free concentration which competitively inhibits intraneuronal monoamine oxidase. This concentration falls only slowly after washout because of both reuptake of some bretylium diffusing out and replacement from a "reservoir" of intraneuronal bound bretylium. Tyramine, by competing with bretylium for both intraneuronal binding sites and for the transport site, accelerates the loss of bretylium and reverses the inhibition of monoamine oxidase.