British Journal of Pharmacology · 1999 · 61 citations · 34 references
MedicineMolecular BiologyPharmacologyElectrophysiologyIon Channel BiophysicsMolecular PharmacologyCardiac Ion ChannelsIon Channel PharmacologyIon Channel PhysiologyIon Channel RegulationIon ChannelsPotassium Channel BiophysicsChannelsMechanism Of Ion Channel BlockadePotassium Channel BlockadePotassium Channel FunctionPotassium Channel GatingPotassium Channel PharmacologyPotassium Channel PhysiologyTransient Expression
Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.
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A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
Mark Curran, Igor Splawski, Katherine W. Timothy et al. · Cell · 1995 · 2.3K citations · Full text
HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family
Matthew C. Trudeau, Jeffrey W. Warmke, Barry Ganetzky et al. · Science · 1995 · 1.2K citations