HERG and KvLQT1/IsK, the Cardiac K + Channels Involved in Long QT Syndromes, Are Targets for Calcium Channel Blockers CHRISTOPHE CHOUABE, MILOU-DANIEL DRICI, GEORGES ROMEY, JACQUES BARHANIN, and MICHEL LAZDUNSKI Institut de Pharmacologie Mole ´ culaire et Cellulaire, Centre National de la Recherche Scientifique, Sophia Antipolis, F-06560 Valbonne, France Received April 6, 1998; Accepted June 17, 1998 This paper is available online at http://www.molpharm.org ABSTRACT We examined the effects of the calcium channel blockers ni- trendipine, 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 de- layed 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 (EC 50 = 0.55 M), verapamil (EC 50 = 0.83 M), and mibefradil (EC 50 = 1.43 M), 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 (EC 50 = 10.0 M) and mibefradil (EC 50 = 11.8 M), 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. CCBs constitute an heterogeneous class of compounds with different chemical structures and varying potencies for block- ing voltage-dependent Ca 2+ channels (Hosey and Lazdunski, 1988). Their primary sites of action include cardiac muscle, systemic, and coronary arterial smooth muscle cells. Their largest domain of prescription is the management of hyper- tension, angina, and supraventricular arrhythmias. Accord- ing to the type of voltage-dependent Ca 2+ channel they block, one can distinguish T- or L-type calcium antagonists. Mibe- fradil is the only T-type calcium antagonist approved by the Food and Drug Administration (Clozel et al., 1997). L-type calcium antagonists include the 1,4-dihydropyridines such as nitrendipine and isradipine, the phenylalkylamines such as verapamil, and the benzothiazepines as typified by diltiazem. Many other drugs have effects on L-type Ca 2+ channels, like the diarylaminopropylamine bepridil. Verapamil, diltiazem, bepridil, and mibefradil block Ca 2+ channels in cardiac cells at clinically relevant concentrations, resulting in a decrease in heart rate and atrioventricular nodal conduction velocity. This forms the basis of their antiarrhythmic efficacy in reen- trant arrhythmias or in slowing the ventricular rate in the case of atrial flutter or fibrillation (at least for phenylalky- lamines and benzothiazepines) (Roden, 1996). With few ex- ceptions, calcium antagonists do shorten the cell action po- tential duration; this is why they do not prolong the refractory period and all except bepridil (Campbell et al., 1990) are considered ineffective as ventricular antiarrhyth- mic agents. Hence, verapamil, diltiazem, and mibefradil can increase the rate and duration of experimentally induced ventricular tachycardia (Billman and Hamlin, 1996), and inappropriate use of verapamil has been shown to jeopardize the outcome of Wolff-Parkinson-White syndrome by further shortening the refractory period of the accessory pathway and increasing the ventricular rate in the case of atrial fi- brillation (Gulamhusein et al., 1983). Conversely, verapamil also has been shown to be of use in certain forms of ventric- ular tachycardia known as “verapamil sensitive” that seem to be triggered by delayed afterdepolarizations (Lauer et al., 1992; Gill et al., 1993; Lee et al., 1996). Bepridil, because of its ability to prolong the refractory period of ventricular myocytes and the QT interval on the electrocardiogram, has been successfully used in ventricular arrhythmias (Roden, 1996). This classic feature of class III antiarrhythmic drugs results from a blockade of I K , which is considered to be an This work was supported by the Centre National de la Recherche Scienti- fique. C.C. is a recipient of a Grant from the Association Franc ¸aise contre les Myopathies. ABBREVIATIONS I K , cardiac delayed rectifier K + current; I Kr , rapidly activating component of cardiac delayed rectifier K + current; I Ks, slowly activating component of cardiac delayed rectifier K + current; EGTA, ethylene glycol bis(-aminoethyl ether)-N,N,N',N'-tetraacetic acid; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; CCB, calcium channel blocker. 0026-895X/98/040695-09$3.00/0 Copyright © by The American Society for Pharmacology and Experimental Therapeutics All rights of reproduction in any form reserved. MOLECULAR PHARMACOLOGY, 54:695–703 (1998). 695 at ASPET Journals on July 26, 2016 molpharm.aspetjournals.org Downloaded from