Sager P T, Follmer C, Uppal P, Pruitt C, Godfrey R
Division of Cardiology, Veterans Affairs Medical Center of West Los Angeles, CA 90073.
Circulation. 1994 Oct;90(4):1811-9. doi: 10.1161/01.cir.90.4.1811.
The autonomic nervous system appears to play an important role in the development of clinical ventricular arrhythmias, and beta-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.
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) 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 APD90 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), whereas the RVERP in patients receiving amiodarone remained significantly prolonged by a mean of 7 +/- 1% above baseline values (P = .01). Sematilide and sematilide/isoproterenol had no effect on ventricular 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-induced 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 for the sustained VT cycle length to be reduced below baseline in patients 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).
Isoproterenol fully reversed the effects of selective potassium channel block with sematilide on the APD90 and further reduced the RVERP to values significantly below baseline; it partially attenuated but did not fully reverse amiodarone-induced prolongation of the APD90 and RVERP, which remained significantly prolonged beyond baseline values. Isoproterenol exerted frequency-dependent effects in both patient groups on the APD90; it modestly attenuated amiodarone-induced conduction slowing without frequency-dependent actions; and the sustained VT cycle length remained significantly prolonged during isoproterenol administration to patients receiving amiodarone but not in those receiving sematilide. These findings may have important clinical implications regarding protection from arrhythmia development in patients receiving pure class III agents or amiodarone.
自主神经系统似乎在临床室性心律失常的发生中起重要作用，β-肾上腺素能交感神经刺激可能在调节Ⅲ类抗心律失常药物的电生理效应方面很重要。本研究前瞻性地确定了异丙肾上腺素对司美利特（一种选择性阻断延迟整流钾电流的纯Ⅲ类药物）和胺碘酮（一种具有复杂药理特性的Ⅲ类药物）对心室复极、不应期和传导的频率依赖性作用。
在以下情况下测定司美利特（n = 11）和胺碘酮（n = 22）的频率依赖性电生理效应：（1）无药物基线时；（2）在司美利特稳态（> 48小时）给药期间（455 +/- 5 mg/d [平均值 +/- 标准误]）或胺碘酮负荷10.5天后（1618 +/- 32 mg/d）；（3）在接受司美利特或胺碘酮治疗的患者静脉输注异丙肾上腺素（35 ng/kg每分钟）期间。在300至500 ms的起搏周期长度下进行电生理测定。两组在所有临床特征方面相似。司美利特（平均增加7 +/- 1%，方差分析P <.01）和胺碘酮（平均增加12 +/- 1%，P <.001）使90%复极时的心室动作电位时程（APD90）显著延长。然而，虽然在静脉输注异丙肾上腺素期间，司美利特诱导的APD90延长完全恢复到基线值，但与基线相比，接受胺碘酮治疗的患者的APD90仍显著延长，平均延长6 +/- 1%（P =.005）。两种药物导致的APD90缩短均呈频率依赖性，在较长起搏周期长度时的缩短幅度大于较短起搏周期长度时（P <.02）。在静脉输注异丙肾上腺素期间，接受司美利特治疗的患者的右心室有效不应期（RVERP）显著降低至比基线低8 +/- 2%的平均值（P <.05），而接受胺碘酮治疗的患者的RVERP仍比基线值显著延长，平均延长7 +/- 1%（P =.01）。司美利特和司美利特/异丙肾上腺素对心室传导无影响。与基线值相比，胺碘酮使QRS时限增加14 +/- 4%（起搏周期长度500 ms）至32 +/- 5%（起搏周期长度300 ms）。异丙肾上腺素使胺碘酮诱导的QRS延长平均减轻5 +/- 1%（P =.005），无频率依赖性效应，这与异丙肾上腺素诱导的钠电流增加一致。在静脉输注异丙肾上腺素期间，接受司美利特治疗的患者的持续性室性心动过速周期长度有低于基线的趋势（275 +/- 16对298 +/- 55 ms，P =.06），而接受胺碘酮治疗的患者的持续性室性心动过速周期长度与基线相比仍显著延长（327 +/- 17对257 +/- 12 ms，P <.001）。
异丙肾上腺素完全逆转了司美利特选择性钾通道阻滞对APD90的影响，并进一步将RVERP降低至显著低于基线的值；它部分减轻但未完全逆转胺碘酮诱导的APD90和RVERP延长，后者仍显著延长超过基线值。异丙肾上腺素在两组患者中对APD90均产生频率依赖性效应；它适度减轻了胺碘酮诱导的传导减慢且无频率依赖性作用；在接受胺碘酮治疗的患者静脉输注异丙肾上腺素期间，持续性室性心动过速周期长度仍显著延长，而在接受司美利特治疗的患者中则不然。这些发现可能对接受纯Ⅲ类药物或胺碘酮治疗的患者预防心律失常发生具有重要临床意义。
