Studies on the Interactions of Guanethidine and Bretylium With Noradrenaline Stores

The blockade is preceded by a sympathomimetic effect because of the release of noradrenaline (Abbs, 1966), guanethidine causing a more sustained effect than bretylium.Guanethidine was also shown to deplete tissue catecholamine (Sheppard & Zimmerman, 1959) and it was suggested that the loss of adrenergic function was attributable to loss of amine from the nerve endings (Cass, Kuntzman & Brodie, 1960).In contrast, a dose of bretylium which causes adrenergic blockade does not affect the tissue content of noradrenaline (Brodie & Kuntzman, 1960; Cass & Spriggs, 1961; Davey & Farmer, 1963; Spriggs, 1966).Since the noradrenaline content of tissues is little affected by guanethidine at the time when the adrenergic neurone blockade occurs (Cass & Spriggs, 1961; Gaffney, Chidsey & Braunwald, 1963; Spriggs, 1966) it is generally agreed that the neurone blocking action of guanethidine is not due to the depletion of noradrenaline but may be due to a mechanism similar to that of bretylium (Zaimis, 1964).However, differences between guanethidine and bretylium in their adrenergic neurone blocking effect at various frequencies of nerve stimulation were noted by Boura & Green (1959, 1962) and by Green & Robson (1964), suggesting different modes of action may be involved for these two agents.Brodie, Chang & Costa (1965) have shown that guanethidine and bretylium are incorporated into different sites of tissues.Binding of guanethidine to a specific site was shown to be closely related to its effect on noradrenaline stores (Chang, Costa & Brodie, 1965).Furthermore, only guanethidine was found to be retained in the particulate fraction of hearts (Costa, Chang & Brodie, 1964).Thus the adrenergic neurone blocking effect of guanethidine may be related in some way to the storage mechanism of nor- adrenaline in the sympathetic nerves, although it is not related to the depletion of the amine from tissues.The present paper describes the effects of guanethidine and bretylium on the subcellular distribution of noradrenaline in the rat vas deferens and heart.The results show that guanethidine rapidly displaced noradrenaline of the particulate fraction, which was shown to contain the functional pool of noradrenaline (Chang & Chang, 1965; Chang & Su, 1967).This effect of guanethidine is prevented by amphetamine but not by bretylium.