‘Class Ia’ anti-arrhythmic drugs produce moderate cardiac action potential prolongation, whereas class Ib and Ic agents are not commonly associated with this effect (e.g. Milne et al. 1984). Class Ia drugs such as quinidine and disopyramide inhibit cloned cardiac delayed rectifier channels encoded by HERG (human ether-a-go-go-related gene; Yang et al. 1997; Po et al. 1999; Lees-Miller et al. 2000; Paul et al. 2001), and this is likely to account for the increased action potential duration and associated prolongation of the QT interval of the electrocardiogram produced by these agents. The aim of the present study was to investigate the effects of the class Ic anti-arrhythmic agent flecainide on HERG potassium channels and to compare any observed action with that of the class Ia agent quinidine. Actions of the class Ib agent lignocaine on HERG were also determined.

Whole-cell patch-clamp measurements were made from a HEK-293 cell line stably expressing HERG channels (Zhou et al. 1998). Drug effects on the HERG current ‘tail’ (I_HERG) at -40 mV following depolarising test pulses were monitored. Each drug concentration was tested on a minimum of six different cells. Flecainide inhibited I_HERG in a concentration- and voltage-dependent fashion. For each of 3, 5 and 10 µM flecainide, inhibition was significantly less for test potentials between -40 and -20 mV than for pulses to more positive test potentials (P < 0.001, ANOVA). The half-maximal inhibitory concentration (IC₅₀) for flecainide on I_HERG following a test potential of +30 mV was 3.91 ± 0.68 µM (mean ± S.E.M.). By comparison, quinidine showed an IC₅₀ under our conditions of 0.41 ± 0.04 µM. In contrast, lignocaine was a comparatively weak blocker of HERG (IC₅₀ of 262.9 ± 22.4 µM). Our data indicate that flecainide inhibits HERG channels with lower potency than quinidine. The much lower potency of lignocaine is consistent with a lack of reported QT prolongation with this agent.This work was funded by the British Heart Foundation and Wellcome Trust.

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