Suessbrich H, Schönherr R, Heinemann S H, Lang F, Busch A E
Institute of Physiology I, Eberhard Karls University Tübingen, Germany.
FEBS Lett. 1997 Sep 8;414(2):435-8. doi: 10.1016/s0014-5793(97)01030-2.
The class III antiarrhythmic drug clofilium is known to block diverse delayed rectifier K+ channels at micromolar concentrations. In the present study we investigated the potency of clofilium and its tertiary analog LY97241 to inhibit K+ channels, encoded by the human ether-a-go-go related gene (HERG). Clofilium blocked HERG channels in a voltage-dependent fashion with an IC50 of 250 nM and 150 nM at 0 and +40 mV, respectively. LY97241 was almost 10-fold more potent (IC50 of 19 nM at +40 mV). Other cloned K+ channels which are also expressed in cardiac tissue, Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv4.2, Kir2.1, or I(Ks), were not affected by 100-fold higher concentrations. Block of HERG channels by LY97241 was voltage dependent and the rate of HERG inactivation was increased by LY97241. A rise of [K+]0 decreased both, rate of HERG inactivation and LY97241 affinity. The HERG S631A and S620T mutant channels which have a strongly reduced degree of inactivation were 7-fold and 33-fold less sensitive to LY97241 blockade, indicating that LY97241 binding is affected by HERG channel inactivation. In summary, the antiarrhythmic action of clofilium and its analog LY97241 appears to be caused by their potent, but distinct ability for blocking HERG channels.
Ⅲ类抗心律失常药物氯非铵在微摩尔浓度下可阻断多种延迟整流钾通道。在本研究中，我们研究了氯非铵及其叔胺类似物LY97241抑制由人类醚 - 去极化相关基因（HERG）编码的钾通道的效力。氯非铵以电压依赖性方式阻断HERG通道，在0和 +40 mV时的IC50分别为250 nM和150 nM。LY97241的效力几乎高10倍（在 +40 mV时IC50为19 nM）。其他也在心脏组织中表达的克隆钾通道，Kv1.1、Kv1.2、Kv1.4、Kv1.5、Kv4.2、Kir2.1或I(Ks)，不受高100倍浓度的影响。LY97241对HERG通道的阻断是电压依赖性的，并且LY97241增加了HERG失活的速率。[K + ]0的升高降低了HERG失活速率和LY97241的亲和力。具有强烈降低的失活程度的HERG S631A和S620T突变通道对LY97241阻断的敏感性分别降低了7倍和33倍，表明LY97241的结合受HERG通道失活的影响。总之，氯非铵及其类似物LY97241的抗心律失常作用似乎是由它们有效但不同的阻断HERG通道的能力引起的。
