Evoked Efflux of 3H‐Bretylium by Sympathomimetic Amines from the Rat Vas Deferens in Vitro

Abstract

The tissue was preloaded with 3H-bretylium (2 .times. 10-7 M) and the efflux of bretylium to the incubation medium in the presence of the amines during 20 min was determined. The efflux evoked by (+)-amphetamine was almost abolished at 0.degree. and by desipramine. The dose response curves showed that some of the amines at high concentrations markedly antagonized their own effect. N-methylamphetamine and (+)-amphetamine at a high concentration also antagonized the efflux evoked by low external Na+ concentration. This effect is probably produced by inhibition of the outward transport of bretylium through the neuron membrane. The structure activity relationship obtained shows that the non-hydroxylated amines are most potent in evoking bretylium efflux and that the potency diminished with the number of hydroxyl groups. The tertiary amine analog of amphetamine is less active and the quaternary derivative is much less active than amphetamine and N-methylamphetamine. A hydroxyl group at 3-position gives a somewhat higher potency than that at 4-position. This structure activity relationship is similar to that previously reported for the sympathomimetic amines in reversing the adrenergic neuron blockade by bretylium; this reversal is probably induced by the reduction of the intraneuronal concentration of bretylium as a result of the evoked efflux.