THE EFFECTS OF BETA-ADRENERGIC STIMULATION ON THE FREQUENCY-DEPENDENTELECTROPHYSIOLOGIC ACTIONS OF AMIODARONE AND SEMATILIDE IN HUMANS

Background The autonomic nervous system appears to play an important r ole in the development of clinical ventricular arrhythmias, and beta-a drenergic sympathetic stimulation may be important in modulating the e lectrophysiologic effects of class III antiarrhythmic agents. This stu dy prospectively determined the effects of isoproterenol on the freque ncy-dependent actions of sematilide (a pure class III agent that selec tively blocks the delayed rectifier potassium current) and amiodarone (a class III agent with a complex pharmacologic profile) on ventricula r 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 steady state (>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) t o patients receiving sematilide or amiodarone. Electrophysiologic dete rminations were made at paced cycle lengths of 300 to 500 ms. The two groups were similar in all clinical characteristics. The ventricular a ction potential duration at 90% repolarization (APD(90)) was significa ntly prolonged by sematilide (mean increase, 7+/-1%, P<.01 by ANOVA) a nd amiodarone (mean increase, 12+/-1%, P<.001). However, while sematil ide-induced APD(90) prolongation was fully reversed to baseline values during isoproterenol infusion, the APD(90) in patients receiving amio darone remained significantly prolonged by a mean of 6+/-1% compared w ith baseline (P=.005). The reduction in the APD(90) was frequency depe ndent 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 ba seline (P<.05), whereas the RVERP in patients receiving amiodarone rem ained significantly prolonged by a mean of 7+/-1% above baseline value s (P=.01). Sematilide and sematilide/isoproterenol had no effect on ve ntricular conduction. Amiodarone increased the QRS duration by 14+/-4% (paced cycle length, 500 ms) to 32+/-5% (paced cycle length, 300 ms) compared with baseline values. Isoproterenol attenuated amiodarone-ind uced QRS prolongation by a mean of 5+/-1% (P=.005), without frequency- dependent effects, consistent with isoproterenol-induced increases in the sodium current. During isoproterenol infusion there was a trend fo r the sustained VT cycle length to be reduced below baseline in patien ts receiving sematilide (275+/-16 versus 298+/-55 ms, P=.06), whereas it remained significantly prolonged compared with baseline in patients receiving amiodarone (327+/-17 versus 257+/-12 ms, P<.001). Conclusio ns Isoproterenol fully reversed the effects of selective potassium cha nnel block with sematilide on the APD(90) and further reduced the RVER P to values significantly below baseline; it partially attenuated but did not fully reverse amiodarone-induced prolongation of the APD(90) a nd RVERP, which remained significantly prolonged beyond baseline value s. Isoproterenol exerted frequency-dependent effects in both patient g roups on the APD(90); it modestly attenuated amiodarone-induced conduc tion slowing without frequency-dependent actions; and the sustained VT cycle length remained significantly prolonged during isoproterenol ad ministration to patients receiving amiodarone but not in those receivi ng sematilide. These findings may have important clinical implications regarding protection from arrhythmia development in patients receivin g pure class III agents or amiodarone.