Dukes I D, Cleemann L, Morad M
Department of Physiology, University of Pennsylvania, Philadelphia.
J Pharmacol Exp Ther. 1990 Aug;254(2):560-9.
The potassium currents in rat and guinea pig ventricular myocytes and mouse astrocytes were studied using tedisamil, a novel antiarrhythmic agent. A 1 to 20 microM dosage of tedisamil caused marked prolongation of the action potential in isolated rat ventricular myocytes, mimicking its reported effects on multicellular rat heart preparations. Under voltage clamp conditions, tedisamil caused a dose-dependent increase in the speed of inactivation of the transient outward K+ current (Ito), the predominant outward current in rat ventricular myocytes. In cardiac myocytes, the tedisamil block was neither use- nor voltage-dependent. The slow reversibility of drug action when applied from the outside, and its effectiveness when applied intracellularly, suggested an internal site of drug action. In guinea pig ventricular myocytes, tedisamil blocked the slowly developing time-dependent delayed rectifier K+ current (IK) over the same concentration range as that found for Ito in the rat myocytes. Tedisamil reduced this current without changing the characteristics of its slow (tau approximately 1 sec) activation. The effects of tedisamil on Ito and IK were independent of the phosphorylation state of the channel, as assessed by the equal effectiveness of the drug in the presence or absence of isoproterenol. Tedisamil also blocked the transient K+ current and the delayed rectifier current (IK) in mouse astrocytes over the same concentration range as that found in the cardiac myocytes and by a process that accelerated (transient K+ current) or mimicked (IK) inactivation. At concentrations of up to 50 microM, tedisamil had little effect on the time-dependent inward rectifier K+ current, or inward calcium current in rat or guinea pig ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
使用新型抗心律失常药物替地沙米，对大鼠、豚鼠心室肌细胞和小鼠星形胶质细胞的钾电流进行了研究。1至20微摩尔剂量的替地沙米可使离体大鼠心室肌细胞的动作电位显著延长，这与其对多细胞大鼠心脏制剂的报道作用相似。在电压钳制条件下，替地沙米可使瞬时外向钾电流（Ito）的失活速度呈剂量依赖性增加，Ito是大鼠心室肌细胞中的主要外向电流。在心肌细胞中，替地沙米的阻断作用既不依赖于使用情况，也不依赖于电压。从外部施加药物时，药物作用的缓慢可逆性以及细胞内施加时的有效性，提示药物作用位点在内部。在豚鼠心室肌细胞中，替地沙米在与大鼠心肌细胞中Ito相同的浓度范围内，阻断缓慢发展的时间依赖性延迟整流钾电流（IK）。替地沙米降低了该电流，但未改变其缓慢（时间常数约为1秒）激活的特性。通过在有无异丙肾上腺素存在时药物的同等有效性评估，替地沙米对Ito和IK的作用与通道的磷酸化状态无关。替地沙米在与心肌细胞相同的浓度范围内，也阻断了小鼠星形胶质细胞中的瞬时钾电流和延迟整流电流（IK），其作用过程是加速（瞬时钾电流）或模拟（IK）失活。在高达50微摩尔的浓度下，替地沙米对大鼠或豚鼠心室肌细胞中时间依赖性内向整流钾电流或内向钙电流几乎没有影响。（摘要截短于250字）
