Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

1 The inhibition of the cardiac 'rapid' delayed rectifier current (I-Kr) and its cloned equivalent HERG mediate QT interval prolonging effects of a wide range of clinically used drugs. In this study, we investigated the effects of the Class Ic antiarrhythmic agent flecainide (FLEC) on ionic current (I-HERG) mediated by cloned HERG channels at 37degreesC. We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class 1a); lignocaine (LIG, Class 1b) and propafenone (PROPAF, Class Ic). 2 Whole cell voltage clamp recordings Of I-HERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I-HERG 'tails' following test pulses to +30 mV with an IC50 Of 3.91 +/- 0.68 muM (mean +/- s.e.mean) and a Hill co-efficient close to 1 (0.76 +/- 0.09). 3 In experiments in which I-HERG tails were monitored following voltage commands to a range of test potentials, I-HERG inhibition by FLEC was observed to be voltage-dependent and to be associated with a similar to - 5 mV shift of the activation curve for the current. Voltage-dependence of inhibition was greatest over the range of potentials corresponding to the steep portion of the I-HERG activation curve. The time-course Of I-HERG tail deactivation was not significantly altered by FLEC. 4 In experiments in which 10 s depolarizing pulses were applied from - 80 to 0 mV, the level of current inhibition by FLEC did not increase between I and 10 s. Some time-dependence of inhibition was observed during the first 200-300 ms of depolarization. This observation and the voltage-dependence of inhibition are collectively consistent with FLEC exerting a rapid open channel state inhibition Of I-HERG 5 Under similar recording conditions QUIN inhibited I-HERG with an IC50 of 0.41 +/- 0.04 muM and PROPAF inhibited I-HERG with an IC50 of 0.44 +/- 0.07 muM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6 LIG showed little effect on I-HERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC50 was 262.90 +/- 22.40 muM. 7 Our data are consistent with FLEC, PROPAF and QUIN exerting I-HERG blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN = PROPAF > FLEC > > LIG.