1 Cisapride is a prokinetic agent which has been associated with QT prolongation, torsades de pointes and cardiac arrest. The cellular mechanism for these observations is high a nity blockade of I Kr (encoded by HERG). 2 In a chronic transfection model using CHO-K1 cells, cisapride inhibited HERG tail currents after a step to +25 mV with similar potency at room and physiological temperatures (IC 50 16.4 nM at 20 ± 228C and 23.6 nM at 378C). 3 Channel inhibition exhibited time-, voltage-and frequency-dependence. In an envelope of tails test, channel blockade increased from 27+8% after a 120 ms depolarizing step to 50+4% after a 1.0 s step. These ®ndings suggested a nity for open and/or inactivated channel states. 4 Inactivation was signi®cantly accelerated by cisapride in a concentration-dependent manner and there was a small (77 mV

1 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 eects was blockade of I Kr . 2 A stable transfection of HERG into a CHO-K1 cell line produced a delayed recti®er, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. 3 Perhexiline caused voltage-and frequency-dependent block of HERG (IC 50 7.8 mM). 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 anity for the inactivated state. Keywords: Perhexiline; human ether-a-go-go-related gene (HERG); Chinese hamster ovary (CHO-K1) cell; cardiac arrhythmia; torsades de pointesAbbreviations: CHO-K1, Chinese hamster ovary; CPT-1, carnitine palmitoyl transferase-1; E rev , reversal potential; HEPES, N-2-hydroxylethylpiperazine-N 1 -2-ethanesulphonic acid; HERG, human ether-a-go-go-related gene; IC 50 , drug concentration producing 50% channel blockade; I K , delayed recti®er potassium channel; I Kr , rapidly activating component of delayed recti®er potassium channel; I Ks , slowly activating component of delayed recti®er potassium channel; I Kur , ultra-rapidly activating potassium channel; V 1/2 , voltage of half maximal activation or inactivation