Balser J R, Bennett P B, Hondeghem L M, Roden D M
Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232-6602.
Circ Res. 1991 Aug;69(2):519-29. doi: 10.1161/01.res.69.2.519.
Prolongation of cardiac action potentials may mediate some of the arrhythmia-suppressing and arrhythmia-aggravating actions of antiarrhythmic agents. In this study, suppression of time-dependent outward current by quinidine and amiodarone was assessed in guinea pig ventricular myocytes. The net time-dependent outward current contained at least two components: a slowly activating, La(3+)-resistant delayed rectifier current (IK) and a rapidly activating, La(3+)-sensitive current. Quinidine block of total time-dependent outward current during clamp steps to positive potentials was relieved as a function of time, whereas that induced by amiodarone was enhanced. In contrast, at negative potentials, suppression of current, whereas amiodarone reduced IK but not the La(3+)-sensitive current, suggesting that differential block of the two components of time-dependent current underlies the distinct effects of the two agents. In contrast to these disparate effects on total time-dependent outward current, steady-state reduction of IK by both drugs increased at positive voltages and saturated at approximately +40 mV; the voltage dependence of block by quinidine (17% per decade, +10 to +30 mV) was steeper than that by amiodarone (5% per decade, +10 to +20 mV). Block by quinidine was time dependent at negative potentials: on stepping from +50 to -30 mV, block initially increased very rapidly, and subsequent deactivation of IK was slowed. This effect was not seen with amiodarone. At -80 mV, quinidine block was relieved with a time constant of 40 +/- 15 msec (n = 4, twin-pulse protocol). The effects of quinidine on IK were compatible with neither a purely voltage-dependent model of quinidine binding nor a model incorporating both voltage- and state-dependent binding of quinidine to delayed rectifier channels having only one open state. The voltage- and time-dependent features of quinidine block were well described by a model in which quinidine has greater affinity for one of two open states of the channel. We conclude that the effects of quinidine and amiodarone on time-dependent outward current reflects block of multiple channels. Quinidine block of IK was far more voltage dependent than that produced by amiodarone, suggesting the drugs act by different mechanisms.
心脏动作电位的延长可能介导了抗心律失常药物的一些抗心律失常和促心律失常作用。在本研究中，评估了奎尼丁和胺碘酮对豚鼠心室肌细胞时间依赖性外向电流的抑制作用。总的时间依赖性外向电流至少包含两个成分：一个缓慢激活、对La(3+)耐药的延迟整流电流（IK）和一个快速激活、对La(3+)敏感的电流。在钳制到正电位的过程中，奎尼丁对总时间依赖性外向电流的阻断随时间缓解，而胺碘酮诱导的阻断则增强。相反，在负电位时，电流受到抑制，而胺碘酮降低了IK，但未降低对La(3+)敏感的电流，这表明时间依赖性电流的两个成分的差异阻断是这两种药物产生不同作用的基础。与对总时间依赖性外向电流的这些不同影响相反，两种药物对IK的稳态降低在正电压时增加，并在约+40 mV时达到饱和；奎尼丁阻断的电压依赖性（每十年17%，+10至+30 mV）比胺碘酮（每十年5%，+10至+20 mV）更陡峭。奎尼丁在负电位时的阻断具有时间依赖性：从+50 mV跃变为-30 mV时，阻断最初迅速增加，随后IK的失活减慢。胺碘酮未观察到这种效应。在-80 mV时，奎尼丁阻断以40±15毫秒的时间常数缓解（n = 4，双脉冲方案）。奎尼丁对IK的作用既不符合奎尼丁结合的纯电压依赖性模型，也不符合包含奎尼丁与仅具有一个开放状态的延迟整流通道的电压和状态依赖性结合的模型。奎尼丁阻断的电压和时间依赖性特征可以通过一个模型很好地描述，在该模型中，奎尼丁对通道的两个开放状态之一具有更高的亲和力。我们得出结论，奎尼丁和胺碘酮对时间依赖性外向电流的影响反映了对多个通道的阻断。奎尼丁对IK的阻断比胺碘酮产生的阻断更依赖电压，表明这两种药物的作用机制不同。
