A ntagonism of the antihypertensive action of guanethidine by the tricyclic antidepressants, desipramine and protriptyline, has been demonstrated in controlled studies. These antidepressants also prevent the effect of the related ring-substituted guanidinium adrenergic neuron blockers, bethanidine and debrisoquin. That the rise in blood pressure when desipramine is added to guanethidine therapy is not due simply to a pressor action of the two drugs in combination was demonstrated by the lack of an increase in blood pressure when guanethidine was added to desipramine therapy.Investigations were conducted to determine whether antagonism of guanethidine's clinical effect could result from blockade by the tricyclic antidepressants of the norepinephrine pump in the adrenergic neuron membrane, thereby preventing the uptake of guanethidine into the neuron by this pump. Like guanethidine, the indirectly acting pressor amine, tyramine, enters the neuron via the norepinephrine pump. Desipramine, protriptyline, and amitriptyline in clinical doses all were found to block the pressor action of tyramine while potentiating the pressor effect of norepinephrine. The amino acid, methyldopa, does not enter the neuron via the norepinephrine pump, and its antihypertensive action is not altered by concomitant administration of tricyclic antidepressants. It is concluded from the evidence in this investigation together with the results of previous studies in experimental animals that clinical doses of desipramine-like drugs inhibit the norepinephrine pump in the peripheral adrenergic neuron in man and thereby prevent uptake of guanethidine to its site of action.