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Section of Cardiology, Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792
Cisapride, a gastrointestinal prokinetic
agent, is known to cause long Q-T syndrome and ventricular
arrhythmias. The cellular mechanism is not known. The human
ether-á-go-go-related gene (HERG), which encodes the rapidly
activating delayed rectifier K+
current and is important in cardiac repolarization, may serve as a
target for the action of cisapride. We tested the hypothesis that
cisapride blocks HERG. The whole cell patch-clamp
recording technique was used to study HERG channels stably
expressed heterologously in HEK293 cells. Under voltage-clamp
conditions, cisapride block of HERG is dose dependent
with a half-maximal inhibitory concentration of 6.5 nM at 22°C
(n = 25 cells). Currents rapidly
recovered with drug washout. The onset of block by cisapride required
channel activation indicative of open or inactivated state blockage.
Block of HERG with cisapride after channel activation
was voltage dependent. At 
20 mV, 10 nM cisapride reduced HERG
tail-current amplitude by 5%, whereas, at +20 mV, the tail-current
amplitude was reduced by 45% (n = 4 cells). At 20 and +20 mV, 100 nM cisapride reduced tail-current
amplitude by 66 and 90%, respectively. We conclude that cisapride is a
potent blocker of HERG channels expressed in HEK293 cells. This effect
may account for the clinical occurrence of Q-T prolongation and
ventricular arrhythmias observed with cisapride.
rapidly activating delayed-rectifier potassium current; potassium channels; Q-T interval; torsades de pointes; gastrointestinal motility
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