Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate

1 Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades df pointes. We hypothesized that the cellular basis for these effects was blockade of I-Kr. 2 A stable transfection of HERG into a CHO-KI cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. 3 Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 mu M). 4 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. 5 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.