HERG AND KVLQT1 ISK, THE CARDIAC K+ CHANNELS INVOLVED IN LONG QT SYNDROMES, ARE TARGETS FOR CALCIUM-CHANNEL BLOCKERS/

We examined the effects of the calcium channel blockers nitrendipine, diltiazem, verapamil, bepridil, and mibefradil on the cloned HERG and KvLQT1/lsK K+ channels. These channels generate the vapid and slow com ponents of the cardiac delayed rectifier K+ current, and mutations can affect them, which leads to long QT syndromes. When expressed in tran sfected COS cells, HERG is blocked in a concentration-dependent manner by bepridil (EC50 = 0.55 mu M), verapamil (EC50 = 0.83 mu M), and mib efradil (EC50 = 1.43 mu M), whereas nitrendipine and diltiazem have ne gligible effects. Steady state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. S imilarly, KvLQT1/lsK is inhibited by bepridil (EC50 = 10.0 mu M) and m ibefradil (EC50 = 11.8 mu M), while being insensitive to nitrendipine, diltiazem, or verapamil. These results demonstrate that both cloned K + channels HERG and KvLQT1/lsK, which represent together the cardiac d elayed 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 t he deleterious adverse cardiac events associated with bepridil.