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The purpose of these experiments was to determine the frequency dependence of the effects of amiodarone and its active desethyl metabolite on slow-channel tissues. Intravenous amiodarone and desethylamiodarone (10 or 25 mg/kg) increased atrioventricular conduction time (AVCT) and refractory period (AVERP) in open-chest, chloralose-anesthetized dogs. Drug effects on AVCT and AVERP were greatly augmented by increasing atrial stimulation frequency. The frequency dependence of drug effects was quantified by studying the response of atrioventricular (AV) conduction to changes in coupling interval. Under control conditions, premature atrial stimulation increased AVCT with a time constant of 70 msec. In the presence of amiodarone and desethylamiodarone, a biexponential relationship between AVCT and coupling interval was observed. One component had a time constant similar to control, and a slower component with a time constant of about 1 sec appeared. Slow-channel action potentials produced in canine cardiac false tendons by elevated potassium (25 mM) and isoproterenol in vitro showed interval-dependent changes in Vmax with a time constant averaging 74 msec in the absence of amiodarone. In the presence of amiodarone, a slower recovery phase of Vmax with a time constant averaging 0.94 sec was observed. These results indicate that amiodarone and its metabolite produce heart rate-dependent changes in AV nodal function in vivo and suggest use-dependent calcium-channel blockade as a mechanism of this action. Amiodarone's rate-related effects on slow-channel properties should produce selective depression of supraventricular tachyarrhythmias involving rapid activation of the AV node.

It has been suggested that some of the effects of long-term amiodarone therapy may be due to accumulation of a metabolite, desethylamiodarone. To evaluate the pharmacologic actions of the metabolite, we gave single intravenous doses (10 or 25 mg/kg) of amiodarone or desethylamiodarone to anesthetized dogs. The resulting plasma and myocardial concentrations of both agents were similar to levels achieved with long-term oral amiodarone therapy in man. Amiodarone and desethylamiodarone produced frequency-dependent slowing in ventricular and atrioventricular nodal conduction and increased atrial and ventricular refractory periods. The relative effects of these agents on fast- and slow-channel tissues differed, with amiodarone producing significantly greater prolongation of Wenckebach cycle length and desethylamiodarone producing larger increases in QRS duration, atrial refractory period, and ventricular refractory period. We conclude that desethylamiodarone has substantial electrophysiologic effects at clinically relevant concentrations and has relatively greater effect on fast-channel tissue in vivo than does amiodarone. The accumulation of desethylamiodarone probably accounts for some of the delayed electrophysiologic effects in patients receiving long-term treatment with amiodarone.