Guanethidine is often thought to act like bretylium and produce sympathetic blockade by interfering with the process by which nerve impulses invade sympathetic nerve terminals (Boura & Green, 1959;Cass & Spriggs, 1961). Guanethidine, in contrast to bretylium, impairs the capacity of tissues to store noradrenaline (Sheppard & Zimmerman, 1959;Cass, Kuntzman & Brodie, 1960), but this action of the drug is usually dismissed as distinct from its bretylium-like action since the degree of blockade does not parallel the loss of peripheral noradrenaline (Zaimis, 1964). Thus, guanethidine produces complete block of adrenergic transmission before it produces a measurable loss of noradrenaline stores, and the blockade disappears before the amine content is noticeably repleted (Cass & Spriggs, 1961;Sanan & Vogt, 1962). Additional evidence for the view that guanethidine and bretylium act by similar mechanisms is provided by recent studies which show that the sympatholytic effects of both drugs are inhibited by amphetamine-like drugs (Laurence & Rosenheim, 1960;Wilson & Long, 1960;Matsumoto & Horita, 1962).Since bretylium and guanethidine are often used as research tools in studies of adrenergic function, it is important to know whether they do, in fact, act by the same mechanism.Research carried out in this laboratory Schanker & Morrison, 1964;Chang, Costa & Brodie, 1965) indicates that guanethidine is retained in tissues by two processes. One process localizes the drug nonspecifically and is not affected by amphetamine or reserpine; the other involves a specific affinity of the drug for noradrenaline storage compartments and is suppressed by amphetamine or reserpine. The specific process is saturable and takes up three molecules of drug for each molecule of endogenous noradrenaline.Considerable evidence suggests that the adrenergic blockade is related to the amount of guanethidine that accumulates in sympathetic neurones and that the drug in sympathetic nerve endings elicits a persistent depolarization of presynaptic terminals. According to this view, depolarization would increase the permeability of terminal membranes and cause the loss of noradrenaline. The degree of blockade would not be directly related to the noradrenaline level but to the degree of depolarization that causes the amine loss.