Use‐Dependent Effects of Amiodarone.Amiodarone is a highly effective antiarrhythmic agent. However, its exact mechanism of action remains uncertain. Prior studies suggest that intravenous amiodarone produces different electrophysiologic effects than chronic amiodarone administration. In addition, the effects of other antiarrhythmic agents andβ‐adrenergic stimulation on the electrophysiologic effects of amiodarone have not been well defined. In this study, we sought to evaluate the use‐dependent effects of intravenous (acute) versus oral (chronic) amiodarone administration on His‐Purkinje conduction in a closed‐chest canine model. We also sought to evaluate the effects of intravenous lidocaine and isoproterenol on the use‐dependent effects of chronically administered oral amiodarone. We found: (1) Acutely administered intravenous amiodarone (5 mg/kg bolus, followed by a 0.05 mg/kg/min infusion) does not produce a significant use‐dependent effect on His‐Purkinje conduction (serum amiodarone level 2.7 ± 1.1 mg/L), and acute beta blockade did not enhance use‐dependent effects of amiodarone; (2) Chronically administered oral amiodarone (1,000 mg/day ± 2 weeks) produced significant use‐dependent effects on His‐Purkinje conduction at similar serum drug concentrations (mean level 2.6 ± 1.5 mg/L; (3) Intravenous lidocaine (10 mg/kg bolus, 0.2 mg/kg/min infusion) produced significant additional use‐dependent effects to that of chronic oral amiodarone but only at rapid paced rates (cycle length 300‐210 msec); and (4) Isoproterenol (5μg/min infusion) significantly attenuated the use‐dependent effects of chronically administered amiodarone. The mechanism of action of acutely administered intravenous amiodarone appears to be different from that of chronic oral amiodarone. In addition, the marked use‐dependent effects observed after chronic amiodarone administration were reversed after catecholamine administration suggesting that attenuation of use dependence by sympathetic stimulation may negate some