(Circulation. 1995;91:462-470.)
© 1995 American Heart Association, Inc.
Articles |
Sympatholytic Action of Intravenous Amiodarone in the Rat Heart
From the Alfred and Baker Medical Unit, Baker Medical Research Institute and Alfred Hospital, Melbourne, Australia.
Correspondence to Dr X-J Du, Alfred and Baker Medical Unit, Baker Medical Research Institute, Commercial Rd, Prahran, Victoria 3181, Australia.
Background Amiodarone is a commonly used antiarrhythmic agent with complex pharmacological effects. Although ventricular arrhythmias can be suppressed soon after intravenous amiodarone, the mechanisms responsible for this action are unclear. We studied the effects of acute treatment with amiodarone on the metabolism and release of norepinephrine (NE) in intact rats and in perfused rat hearts.
Methods and Results Experiments were performed in anesthetized rats and in perfused, innervated hearts with amiodarone administered intravascularly. NE release was induced by electrical stimulation of the sympathetic ganglion. Concentrations of NE and its intraneuronal metabolite dihydroxyphenylglycol (DHPG) in hearts, plasma, and coronary venous effluent were measured by high-performance liquid chromatography. Acute administration of amiodarone induced dose-dependent increases in DHPG concentrations in plasma (5 mg/kg, +48%; 15 mg/kg, +84%; and 50 mg/kg, +467%) and in coronary venous effluent (1 µmol/L, +37%; 3 µmol/L, +510%; and 10 µmol/L, +1100%) together with an unchanged basal overflow of NE. In perfused hearts, NE release evoked by nerve stimulation was inhibited by infusion of amiodarone (1 µmol/L, -16%; 3 µmol/L, -24%; and 10 µmol/L, -64%) or by intravenous amiodarone (50 mg/kg) given 1 hour before heart perfusion (-70%), and the extent of this suppression correlated well with levels of DHPG overflow present immediately before nerve stimulation. When given in vitro and in vivo, amiodarone also significantly reduced NE and increased DHPG content in the heart, leading to a raised DHPG/NE ratio. All these effects of amiodarone were similar to those found with reserpine but less potent. In contrast, oral amiodarone produced none of these effects.
Conclusions Acute administration of amiodarone in perfused hearts or intact rats induces partial NE depletion in the heart by interfering with vesicular NE storage and enhancing intraneuronal NE metabolism, effects associated with an impaired NE release during sympathetic activation. Oral dosing with amiodarone has no such effect. Further study is required to test whether this novel sympatholytic effect of amiodarone contributes to its antiarrhythmic action after intravenous administration.
Key Words: amiodarone • dihydroxyphenylglycol • norepinephrine • reserpine • nervous system
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