Amiodarone has a "reserpine-like" sympatholytic action in the heart. The aims of this study were to test whether desethylamiodarone (DEA), the in vivo bioactive metabolite of amiodarone, has this action and whether this action could be demonstrated in a neuronal preparation. Experiments were performed in intact rats, perfused hearts, or brain synaptosomes treated with DEA and amiodarone, and concentrations of norepinephrine (NE) and dihydroxyphenylglycol (DHPG), the intraneuronal metabolite of NE, were assayed in plasma, coronary effluent, and synaptosomes. In perfused hearts, DEA at 1, 3, and 10 microM increased DHPG overflow by threefold, sixfold, and ninefold, respectively (all p < 0.01 vs. control). DEA at 1 microM was more potent than amiodarone in increasing DHPG overflow. DEA at 1 and 3 microM also inhibited NE release evoked by sympathetic nerve stimulation (p < 0.05). In intact rats, intravenous DEA at 15 mg/kg elicited onefold increase in plasma DHPG level, and oral pretreatment with amiodarone did not interfere with the sympatholytic action of intravenous amiodarone. In synaptosomes, 40-min incubation with amiodarone, DEA (both 10 microM), and reserpine reduced synaptosomal NE content by 42, 45, and 60%, respectively. Thus similar to its parent drug, DEA exerts a presynaptic sympatholytic action in rat hearts in vivo and in vitro. This action of amiodarone and DEA also was observed in synaptosomes.