Frequency-Dependent Electrophysiologic Actions of Amiodarone and Sematilide in Humans

Background The autonomic nervous system appears to play an important role in the development of clinical ventricular arrhythmias, and 3-adrenergic sympathetic stimulation may be important in modulating the electrophysiologic effects of class III antiarrhythmic agents. This study prospectively determined the effects of isoproterenol on the frequency-dependent actions of sematilide (a pure class III agent that selectively blocks the delayed rectifier potassium current) and amiodarone (a class III agent with a complex pharmacologic profile) on ventricular repolarization, refractoriness, and conduction. Methods and Results The frequency-dependent electrophysiologic effects of sematilide (n= 11) and amiodarone (n=22) were determined at (1) drug-free baseline, (2) during steadystate (>48 hours) dosing with sematilide (455+±5 mg/d [mean±SEM]) or after 10.5 days of amiodarone loading (1618±32 mg/d), and (3) during isoproterenol administration (35 ng/kg per minute) to patients receiving sematilide or amiodarone. Electrophysiologic determinations were made at paced cycle lengths of 300 to 500 ms. The two groups were similar in all clinical characteristics. The ventricular action potential duration at 90% repolarization (APD90) was significantly prolonged by sematilide (mean increase, 7±1%, P<.01 by ANOVA) and amiodarone (mean increase, 12±1%, P<.001). However, while sematilide-induced APD90 prolongation was fully reversed to baseline values during isoproterenol infusion, the APD90 in patients receiving amiodarone remained significantly prolonged by a mean of 6±1% compared with baseline (P=.005). The reduction in the APD,O was frequency dependent for both agents, with a greater reduction at longer than shorter paced cycle lengths (P<.02). During isoproterenol infusion the right ventricular effective refractory period (RVERP) in patients receiving sematilide was significantly reduced to mean values of 8±2% below baseline (P<.05),