Blockage of the HERG human cardiac K+ channel by the gastrointestinal prokinetic agent cisapride

Saeed Mohammad, Zhengfeng Zhou, Qiuming Gong, Craig T. January

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    Abstract

    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-a-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 o 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.

    Original languageEnglish (US)
    Pages (from-to)H2534-H2538
    JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
    Volume273
    Issue number5 42-5
    StatePublished - Dec 9 1997

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    Keywords

    • Gastrointestinal motility
    • Potassium channels
    • Q-T interval
    • Rapidly activating delayed-rectifier potassium current
    • Torsades de pointes

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

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