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

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 37°C . We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class Ia); lignocaine (LIG, Class Ib) and propafenone (PROPAF, Class Ic). 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 IC 50 of 3.91±0.68 μ M (mean±s.e.mean) and a Hill co‐efficient close to 1 (0.76±0.09). 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 ∼−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. 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 1 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 . Under similar recording conditions QUIN inhibited I HERG with an IC 50 of 0.41±0.04 μ M and PROPAF inhibited I HERG with an IC 50 of 0.44±0.07 μ M . Similar to FLEC, both QUIN and PROPAF showed voltage‐dependence of inhibition and blockade developed rapidly during a sustained depolarization. LIG showed little effect on I HERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC 50 was 262.90±22.40 μ M . 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.British Journal of Pharmacology (2002) 136 , 717–729; doi: 10.1038/sj.bjp.0704784