Inhibition of HERG Potassium Channel Current by the Class 1a Antiarrhythmic Agent Disopyramide

Paul, Ashok A; Witchel, Harry J.; Hancox, Jules C.

doi:10.1006/bbrc.2001.4269

Cited by 56 publications

(31 citation statements)

References 23 publications

(24 reference statements)

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“…This occurred without a signi®cant alteration to I K tail deactivation kinetics. A recent study from this laboratory also reported rapidly developing, time-and voltage-dependent blockade of I HERG by the Class Ia agent disopyramide (DISO; Paul et al, 2001). Thus, it seems likely that across Class I sub-divisions agents active against I HERG share a core similarity in producing a rapid, activation-dependent, open channel blockade.…”

Section: Herg and Ligmentioning

confidence: 96%

“…Figure 2B shows the normalized mean currentvoltage (I ± V) relations for I HERG tails in control solution and in the presence of FLEC. For each of 16 cells, I HERG tail amplitudes at each potential were normalized to the maximal I HERG tail in control conditions, as described recently (Paul et al, 2001). I ± V plots were constructed for each cell, and data from the di erent cells were also pooled in order to obtain the mean I ± V relations in control and drug.…”

Section: Voltage Dependence Of I Herg Inhibition By Flecmentioning

confidence: 99%

“…Po et al, 1998;Paul et al, 2001;Yang et al, 2001). Therefore, in order to contextualize our ®ndings with ecainide against those of other Class I agents, additional experiments with QUIN were performed; this Class Ia agent is known to block both native I Kr and heterologously expressed HERG (Po et al, 1998;Lees-Miller et al, 2000;Ishii et al, 2001).…”

Section: Comparison With Quinmentioning

confidence: 99%

“…Although we did not speci®cally examine any role for voltage-dependent inactivation in I HERG blockade by the agents under study in this report, some information on this issue is available. For both DISO and QUIN, a mutation to the HERG channel that vastly attenuates current inactivation (S631A) does not remove I HERG blockade (Lees-Miller et al, 2000;Paul et al, 2001). Channel inactivation is therefore not obligatory for I HERG blockade by two major Class Ia antiarrhythmic drugs.…”

Section: Herg and Ligmentioning

confidence: 99%

“…Disopyramide can also induce QT prolongation (e.g. Lima & Boudoulas, 1987), and block HERG/I Kr (Virag et al, 1998;Paul et al, 2001). Interestingly, intravenous administration of the Class Ic drug propafenone can also produce QT interval prolongation and torsade de pointes (e.g.…”

Section: Introductionmentioning

confidence: 99%

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

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

144

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1 The inhibition of the cardiac`rapid' delayed recti®er current (I Kr ) and its cloned equivalent HERG mediate QT interval prolonging e ects of a wide range of clinically used drugs. In this study, we investigated the e ects of the Class Ic antiarrhythmic agent¯ecainide (FLEC) on ionic current (I HERG ) mediated by cloned HERG channels at 378C . 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). 2 Whole cell voltage clamp recordings of I HERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I HERG`t ails' following test pulses to +30 mV with an IC 50 of 3.91+0.68 mM (mean+s.e.mean) and a Hill co-e cient 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 *75 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 signi®cantly altered by FLEC. 4 In experiments in which 10 s depolarizing pulses were applied from 780 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 ®rst 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 IC 50 of 0.41+0.04 mM and PROPAF inhibited I HERG with an IC 50 of 0.44+0.07 mM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6 LIG showed little e ect on I HERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC 50 was 262.90+22.40 mM. 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=PROPAF4FLEC44LIG. British Journal of Pharmacology (2002) 136, 717 ± 729 Keywords: Antiarrhythmic; Class Ia; Class Ib; Class Ic;¯ecainide; HERG; I Kr ; QT interval; QT prolongation; quinidine Abbreviations: ANOVA, analysis of variance; d, fractional distance in the transmembrane ®eld sensed at drug receptor site; DISO, disopyramide; FLEC,¯ecainide; HERG, Human ether-a-go-go related gene; IC 50 , half maximal inhibitory drug concentration; I Ca,L , L-type calcium current; I HERG , current mediated by the HERG channel; I K , delayed recti®er potassium current; I Kr`r apid' delayed recti®er potassium current; I Ks`s low' delayed recti®er potassium current; I to , transient outward potassium current; k, slope factor describing voltage de...

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Section: Herg and Ligmentioning

confidence: 96%

Section: Voltage Dependence Of I Herg Inhibition By Flecmentioning

confidence: 99%

Section: Comparison With Quinmentioning

confidence: 99%

Section: Herg and Ligmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

144

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hERG Channel Physiology and Drug‐Binding Structure–Activity Relationships

Dalibalta

Mitcheson

2008

Antitargets

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Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Polak¹,

Wiśniowska

Brandys³

2008

J of Applied Toxicology

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The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug-hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC(50)) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC(50) values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC(50) data available in accessible scientific literature to provide a high-quality data set for further studies.

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Inhibition of HERG Potassium Channel Current by the Class 1a Antiarrhythmic Agent Disopyramide

Cited by 56 publications

References 23 publications

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 comparison with quinidine, propafenone and lignocaine

hERG Channel Physiology and Drug‐Binding Structure–Activity Relationships

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

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