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Vol. 54, Issue 4, 695-703, October 1998
Institut de Pharmacologie Moléculaire et Cellulaire, Centre
National de la Recherche Scientifique, Sophia Antipolis, F-06560
Valbonne, France
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 µM), verapamil (EC50 = 0.83 µM), and mibefradil (EC50 = 1.43 µM), 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 µM) and mibefradil (EC50 = 11.8 µM), 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.
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