The electrophysiological effects of E-3753, a new antiarrhythmic drug, were studied in guinea-pig papillary muscles. 2. E-3753 (10(-7) - 10(-4) M) produced a concentration-dependent decrease in the action potential amplitude and Vmax of the upstroke, shortened the action potential duration (APD) and shifted the resting membrane potential to less negative values. E-3753 also shortened the effective refractory period (ERP), lengthening the ERP relative to APD. 3. E-3753 (10(-5) M) shifted the membrane responsiveness curve along the voltage axis to more negative potentials. 4. In the presence of E-3753 (10(-5) M) trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (onset rate at 3 Hz, 0.05 +/- 0.009 per action potential), to a new steady-state level. This use-dependent Vmax block was augmented at higher rates of stimulation. The time constant for the recovery of Vmax from the use-dependent block was 41.1 +/- 4.8 s. 5. E-3753 (10(-5) - 10(-4) M) had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular fibres depolarized by 27 mM KCl. 6. The slow onset of use-dependent block during repetitive activity and the slow offset kinetics of use-dependent Vmax block suggest that E-3753 exhibits class Ic antiarrhythmic actions in ventricular muscle fibres but does not exhibit class IV (Ca antagonist) antiarrhythmic actions.
摘要
在豚鼠乳头肌中研究了新型抗心律失常药物E - 3753的电生理效应。2. E - 3753（10⁻⁷ - 10⁻⁴M）使动作电位幅度和除极上升支的Vmax呈浓度依赖性降低，缩短动作电位时程（APD），并使静息膜电位向负值减小的方向偏移。E - 3753还缩短了有效不应期（ERP），使ERP相对于APD延长。3. E - 3753（10⁻⁵M）使膜反应性曲线沿电压轴移向更负的电位。4. 在E - 3753（10⁻⁵M）存在的情况下，频率在0.5至3Hz之间的刺激 trains 导致Vmax呈指数下降（3Hz时的起始速率为每动作电位0.05±0.009），直至达到新的稳态水平。这种频率依赖性Vmax阻滞在较高刺激频率时增强。Vmax从频率依赖性阻滞恢复的时间常数为41.1±4.8秒。5. E - 3753（10⁻⁵ - 10⁻⁴M）对由异丙肾上腺素在27mM KCl使心室纤维去极化时诱发的慢动作电位的特征无影响。6. 重复活动期间频率依赖性阻滞的缓慢起始以及频率依赖性Vmax阻滞的缓慢消除动力学表明，E - 3753在心室肌纤维中表现出Ic类抗心律失常作用，但不表现出IV类（钙拮抗剂）抗心律失常作用。
