Presynaptic antisympathetic action of amiodarone and its metabolite desethylamiodarone

Amiodarone has a "reserpine-like" sympatholytic action in the heart. The ai ms of this study were to test whether desethylamiodarone (DEA), the in vivo bioactive metabolite of amiodarone, has this action and whether this actio n could be demonstrated in a neuronal preparation. Experiments were perform ed in intact rats, perfused hearts, or brain synaptosomes treated with DEA and amiodarone, and concentrations of norepinephrine (NE) and dihydroxyphen ylglycol (DHPG), the intraneuronal metabolite of NE, were assayed in plasma , coronary effluent, and synaptosomes. In perfused hearts, DEA at 1, 3, and 10 mu M increased DHPG overflow by threefold, sixfold, and ninefold, respe ctively (all p < 0.01 vs. control). DEA at 1 mu M was more potent than amio darone in increasing overflow. DEA at 1 and 3 mu M also inhibited NE releas e evoked by sympathetic nerve stimulation (p < 0.05). In intact rats, intra venous 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 a miodarone, DEA (both 10 mu M), and reserpine reduced synaptosomal NE conten t by 42, 45, and 60%, respectively. Thus similar to its parent drug, DEA ex erts a presynaptic sympatholytic action in rat hearts in vivo and in vitro. This action of amiodarone and DEA also was observed in synaptosomes.