Berger F, Borchard U, Hafner D, Weis T M
Institute of Pharmacology, Heinrich-Heine-University of Düsseldorf, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Mar;357(3):291-8. doi: 10.1007/pl00005170.
Tedisamil has been described as a selective inhibitor of a fast inactivating transient outward current (i(to,f)) in rat ventricular myocytes. Because recent reports demonstrated the existence of a second slowly inactivating transient component (i(to,s)) we investigated i(to,s) and differentiated the effects of tedisamil on both transient outward current components and their influence on action potential duration. Standard electrophysiological techniques were used for whole cell recordings at 24-26 degrees C from enzymatically isolated myocytes. Inhibition of i(to,f) by tedisamil was the result of an acceleration of inactivation at positive test potentials with a concentration for half-maximal inhibition (EC50) of 4-7 micromol/l, which is confirmatory to reports from other investigators. Our new results show that i(to,s) is more sensitive to tedisamil with an EC50 of 0.5 micromol/l. Furthermore the pattern of i(to,s) inhibition is different compared with i(to,f), because inactivation of i(to,s) is not accelerated by tedisamil. Instead the amplitude of the steady state inactivation curve of i(to,s) is attenuated which indicates a reduction of maximally available current. I(to,s) was evaluated by three different methods as time-dependently inactivating current (7.5 s test pulse duration), voltage-dependently inactivated current and tedisamil-sensitive current. All approaches yield similar inactivation curves. The potential for halfmaximal inactivation of i(to,s) lies about 35 mV more negative than that for i(to,f) and the slope factor (K = -23 mV) is different to that of i(to,f) (K = -3 mV). Effectiveness of tedisamil-induced modulation of i(to,f) and i(to,s) on action potential repolarization was tested. Action potentials stimulated at 0.5 Hz were not prolonged by 1 micromol/l tedisamil (dominant i(to,s) block) at a repolarization level of 0 mV but prolonged to about 120% of control at -70 mV. This indicates that i(to,f) was sufficient to guarantee a regular early repolarization whereas decrease of i(to,s) delayed the final repolarization. In conclusion, the observation that tedisamil inhibits i(to,f) and i(to,s) differently supports the hypothesis that the two i(to)-components are related to two different channel populations expressed in rat ventricular myocytes.
替地沙米被描述为大鼠心室肌细胞中快速失活的瞬时外向电流（i(to,f)）的选择性抑制剂。由于最近的报告表明存在第二种缓慢失活的瞬时成分（i(to,s)），我们研究了i(to,s)，并区分了替地沙米对两种瞬时外向电流成分的影响及其对动作电位时程的影响。在24 - 26摄氏度下，使用标准电生理技术对酶分离的心肌细胞进行全细胞记录。替地沙米对i(to,f)的抑制作用是由于在正测试电位下失活加速，其半数最大抑制浓度（EC50）为4 - 7微摩尔/升，这与其他研究者的报告一致。我们的新结果表明，i(to,s)对替地沙米更敏感，EC50为0.5微摩尔/升。此外，与i(to,f)相比，i(to,s)的抑制模式不同，因为替地沙米不会加速i(to,s)的失活。相反，i(to,s)的稳态失活曲线的幅度减小，这表明最大可用电流减少。通过三种不同方法评估i(to,s)，即作为时间依赖性失活电流（测试脉冲持续时间7.5秒）、电压依赖性失活电流和替地沙米敏感性电流。所有方法得出的失活曲线相似。i(to,s)的半数最大失活电位比i(to,f)约负35毫伏，斜率因子（K = -23毫伏）与i(to,f)（K = -3毫伏）不同。测试了替地沙米诱导的i(to,f)和i(to,s)调制对动作电位复极化的有效性。在0 mV的复极化水平下，1微摩尔/升替地沙米（主要阻断i(to,s)）不会使0.5 Hz刺激的动作电位延长，但在 -70 mV时延长至对照的约120%。这表明i(to,f)足以保证正常的早期复极化，而i(to,s)的减少会延迟最终复极化。总之，替地沙米对i(to,f)和i(to,s)的抑制作用不同这一观察结果支持了这样的假设，即两种i(to)成分与大鼠心室肌细胞中表达的两种不同通道群体有关。
