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Vol. 286, Issue 2, 788-793, August 1998
Hoechst Marion Roussel, Inc., Cincinnati, Ohio (D.R., M.K.M., J.G.)
and
Nippon Hoechst Marion Roussel, Tokyo 107, Japan (E.W.L.)
Acquired long QT syndrome is a side effect seen with some
pharmacological agents, including antipsychotic drugs, and is
associated with the development of ventricular arrhythmias. This
syndrome is often caused by the blockade of repolarizing potassium
channels the human heart. A new antipsychotic agent, sertindole, has
been shown to produce QT prolongation after therapeutic doses in
humans. We therefore examined the effects of sertindole on two cloned human cardiac potassium channels, the human
ether-a-go-go-related gene (HERG) and Kv1.5, stably transfected
into mammalian cell lines. Using patch clamp electrophysiology, we
found sertindole blocked HERG currents with an IC50 value
of 14.0 nM when tail currents at 
40 mV were measured after a 2-sec
depolarization to +20 mV. When currents were measured at the end of
prolonged (20 sec) depolarizing pulses, the IC50 of
sertindole measured 2.99 nM. Sertindole enhanced the rate of current
decay during these prolonged voltage steps and displayed a positive
voltage dependence. Sertindole was approximately 1000-fold less active at blocking Kv1.5 displaying an IC50 value of 2.12 µM. By
comparison, the potent class III antiarrhythmic agent dofetilde blocked
HERG with an IC50 value of 9.50 nM but did not enhance HERG current decay or block Kv1.5 channel currents. It is concluded that sertindole is a high affinity antagonist of the human cardiac potassium channel HERG and that this blockade underlies the prolongation of QT interval observed with this drug. Furthermore, the sertindole molecule may
provide a useful starting point for the development of very high
affinity ligands for HERG.
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