Guanethidine and related agents. I. Mechanism of the selective blockade of adrenergic neurons and its antagonism by drugs.

The mechanism of the selective action of guanethidine and related drugs on adrenergic neurons and the blockade of this action by desipramine were investigated. H 3 -bethanidine, guanethidine and debrisoquin are accumulated in the heart of the rat against a concentration gradient by an energy-requiring transport mechanism. The uptake of H 3 -bethanidine by heart slices was found to be inhibited competitively by norepinephrine. Guanethidine, debrisoquin and bretylium also inhibited uptake competitively, as did tyramine, metaraminol and desipramine. Antagonism of the catecholamine-depleting effect of guanethidine on the guinea-pig heart by desipramine in vivo is associated with inhibition of the uptake of guanethidine by the heart. These studies indicate that guanethidine and related drugs block adrenergic neurons selectively because they are concentrated within these neurons by the membrane transport system that pumps norepinephrine into the neuron after its release. The necessity of the transport system for guanethidine9s action is demonstrated by the loss of guanethidine9s effect when its uptake is inhibited. This is the basis for a significant drug-drug interaction in man.