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

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and... The inhibition of the cardiac ‘rapid’ delayed rectifier current (IKr) 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 (IHERG) 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 IHERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited IHERG ‘tails’ following test pulses to +30 mV with an IC50 of 3.91±0.68 μM (mean±s.e.mean) and a Hill co‐efficient close to 1 (0.76±0.09). In experiments in which IHERG tails were monitored following voltage commands to a range of test potentials, IHERG 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 IHERG activation curve. The time‐course of IHERG 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 IHERG. Under similar recording conditions QUIN inhibited IHERG with an IC50 of 0.41±0.04 μM and PROPAF inhibited IHERG with an IC50 of 0.44±0.07 μM. 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 IHERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC50 was 262.90±22.40 μM. Our data are consistent with FLEC, PROPAF and QUIN exerting IHERG 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 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

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

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References (70)

Publisher
Wiley
Copyright
2002 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0704784
pmid
12086981
Publisher site
See Article on Publisher Site

Abstract

The inhibition of the cardiac ‘rapid’ delayed rectifier current (IKr) 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 (IHERG) 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 IHERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited IHERG ‘tails’ following test pulses to +30 mV with an IC50 of 3.91±0.68 μM (mean±s.e.mean) and a Hill co‐efficient close to 1 (0.76±0.09). In experiments in which IHERG tails were monitored following voltage commands to a range of test potentials, IHERG 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 IHERG activation curve. The time‐course of IHERG 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 IHERG. Under similar recording conditions QUIN inhibited IHERG with an IC50 of 0.41±0.04 μM and PROPAF inhibited IHERG with an IC50 of 0.44±0.07 μM. 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 IHERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC50 was 262.90±22.40 μM. Our data are consistent with FLEC, PROPAF and QUIN exerting IHERG 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

Journal

British Journal of Pharmacology – Wiley

Published: Jul 1, 2002

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