1 The effects of some guanidine derivatives, (-)-N-(1-phenylethyl) guanidine (PEG), guanethidine and debrisoquine have been investigated on the content and subcellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline from this organ during stimulation of the splenic nerve.2 PEG and guanethidine, at a dose of 5 mg/kg, produced adrenergic neurone blockade within 15 min and the same dose of debrisoquine produced blockade within 30 minutes.3 All three compounds produced a decrease of similar magnitude in the noradrenaline content of the high-speed particulate (P(2)) and supernatant (S) fractions of splenic homogenates; these actions were temporally correlated with the adrenergic neurone-blocking action of the compounds.4 PEG did not produce any further decrease in the noradrenaline content of the subcellular fractions at times up to 18 h after its administration; adrenergic neurone blockade was maintained throughout this period but had disappeared after 7 days when the noradrenaline content of the subcellular fractions was restored to control levels.5 Guanethidine, in contrast, caused a marked progressive loss of the transmitter from all subcellular fractions-an effect which was maximal 18 h after its administration but continued, as did the adrenergic neurone-blocking action, for at least 72 hours. This additional loss of noradrenaline, over and above that seen after 15 min, is unlikely to be connected with the adrenergic neurone-blocking action of the drug.6 Dexamphetamine both prevented and antagonized the neurone blockade and the subcellular noradrenaline-depleting action of PEG and guanethidine. The restoration of nerve function after administration of dexamphetamine to animals pretreated with 5 mg/kg of either of these compounds was temporally correlated with a selective repletion of the noradrenaline content of the supernatant fraction of the spleen.7 Larger doses (15 mg/kg) of PEG or guanethidine produced a selective depletion of noradrenaline in only the supernatant fraction of the spleen. This depletion was temporally correlated with the adrenergic neurone-blocking action of these compounds. The lack of effect of the compounds at this dose level on the noradrenaline contained in the P(2) fraction may be due to ;stabilization' of the store of noradrenaline in vivo which gives rise to this fraction on homogenization.8 It is suggested that the guanidine-type adrenergic neurone-blocking agents displace the noradrenaline which is readily available for release by nerve impulses, and that it is this action that may account for their sympathomimetic properties.9 The ability of these guanidines to impair the release of noradrenaline by nerve impulses could occur because whilst they are present within the neurone the ;nerve-releasable store', which may in these experiments appear in the supernatant fraction after homogenization, may be unable to refill with transmitter.