Chouabe C, Drici M D, Romey G, Barhanin J, Lazdunski M
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Sophia Antipolis, F-06560 Valbonne, France.
Mol Pharmacol. 1998 Oct;54(4):695-703.
We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/IsK K+ channels. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in transfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM), and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1/IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K+ channels HERG and KvLQT1/IsK, which represent together the cardiac delayed rectifier K+ current, are sensitive targets to calcium channel blockers. This work may help in understanding the mechanisms of action of verapamil in certain ventricular tachycardia, as well as some of the deleterious adverse cardiac events associated with bepridil.
我们研究了钙通道阻滞剂尼群地平、地尔硫䓬、维拉帕米、苄普地尔和米贝拉地尔对克隆的HERG和KvLQT1/IsK钾通道的影响。这些通道产生心脏延迟整流钾电流的快速和慢速成分，突变可影响它们，进而导致长QT综合征。当在转染的COS细胞中表达时，苄普地尔（EC50 = 0.55 microM）、维拉帕米（EC50 = 0.83 microM）和米贝拉地尔（EC50 = 1.43 microM）以浓度依赖性方式阻断HERG，而尼群地平和地尔硫䓬的影响可忽略不计。在存在阻滞剂的情况下，稳态激活和失活参数向更负值偏移。同样，KvLQT1/IsK受到苄普地尔（EC50 = 10.0 microM）和米贝拉地尔（EC50 = 11.8 microM）的抑制，而对尼群地平、地尔硫䓬或维拉帕米不敏感。这些结果表明，共同代表心脏延迟整流钾电流的克隆钾通道HERG和KvLQT1/IsK都是钙通道阻滞剂的敏感靶点。这项工作可能有助于理解维拉帕米在某些室性心动过速中的作用机制，以及与苄普地尔相关的一些有害心脏不良事件。
