Characterization of recombinant hERG K+ channel inhibition by the active metabolite of amiodarone desethyl-amiodarone

Zhang, Y.H.; Cheng, Hongwei; Alexeenko, Vadim; Dempsey, Christopher E.; Hancox, Jules C.

doi:10.1016/j.jelectrocard.2010.04.007

Cited by 26 publications

(53 citation statements)

References 22 publications

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“…An envelope of tails protocol (inset of Fig. 3G; see also [33]) was used to compare time-dependence of activation of I hERG between the two channels at + 20 mV. Mono-exponential fitting of mean normalized tail currents elicited by the protocol (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The hERG K+ channel S4 domain L532P mutation: Characterization at 37°C

Zhang

Colenso

Sessions

et al. 2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

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hERG (human Ether-à-go-go Related Gene) is responsible for ion channels mediating rapid delayed rectifier potassium current, IKr, which is key to cardiac action potential repolarization. Gain-of-function hERG mutations give rise to the SQT1 variant of the Short QT Syndrome (SQTS). Reggae mutant zebrafish, with a S4 zERG mutation (Leucine499Proline; L499P), display arrhythmic features analogous to those seen in the SQTS. The affected S4 domain ERG residue is highly conserved. This study was executed to determine how the homologous hERG mutation (L532P) influences channel function at 37 °C. Whole-cell measurements of current (IhERG) were made from HEK 293 cells expressing WT or L532P hERG. The half maximal activation voltage (V0.5) of L532P IhERG was positively shifted by ~+36 mV compared to WT IhERG; however at negative voltages a pronounced L532P IhERG was observed. Both activation and deactivation time-courses were accelerated for L532P IhERG. The inactivation V0.5 for L532P IhERG was shifted by ~+32 mV. Under action potential (AP) voltage-clamp, L532P IhERG exhibited a dome-shaped current peaking at ~+16 mV, compared to ~−31 mV for WT-IhERG. The L532P mutation produced an ~ 5-fold increase in the IC50 for dronedarone inhibition of IhERG. Homology modeling indicated that the L532 residue within the S4 helix lies closely apposed to the S5 region of an adjacent hERG subunit. Alterations to the S4 domain structure and, potentially, to interactions between adjacent hERG subunits are likely to account for the functional effects of this mutation.

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Section: Resultsmentioning

confidence: 99%

“…Whole cell conventional and human action potential (AP) voltage clamp recordings of hERG current (I hERG ) were made at 37 ± 1 °C as previously reported [33]. Data digitization rates were 10–25 kHz during all protocols and an appropriate bandwidth of 2–10 kHz was set on the amplifier.…”

Section: Methodsmentioning

confidence: 99%

The hERG K+ channel S4 domain L532P mutation: Characterization at 37°C

Zhang

Colenso

Sessions

et al. 2011

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…The R-enantiomer was not directly investigated in that study [27]. We have compared S(+), R(-) citalopram enantiomers and the racemic mixture on hERG channels using patch clamp recording at physiological temperature to elicit I hERG (cf [28]). As shown in Figures 1A-C, equal concentrations of citalopram, escitalopram and R-citalopram produced similar levels of I hERG inhibition and concentration response relations (shown in Fig.…”

Section: Citalopram and Herg Channel Inhibitionmentioning

confidence: 99%

Towards limiting QT interval prolongation and arrhythmia risk in citalopram use

2014

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“…The main metabolite is desethylamiodarone (DEA), which also has antiarrhythmic properties as the parent compound [20]. Therefore, we also studied the effects of DEA on I KAS .…”

Section: Resultsmentioning

confidence: 99%

Amiodarone Inhibits Apamin-Sensitive Potassium Currents

Turker

Chang

et al. 2013

PLoS ONE

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BackgroundApamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca2+-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles.ObjectiveTo test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells.MethodsWe used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.ResultsAmiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of I KAS.ConclusionBoth amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.

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Characterization of recombinant hERG K+ channel inhibition by the active metabolite of amiodarone desethyl-amiodarone

Cited by 26 publications

References 22 publications

The hERG K+ channel S4 domain L532P mutation: Characterization at 37°C

The hERG K+ channel S4 domain L532P mutation: Characterization at 37°C

Towards limiting QT interval prolongation and arrhythmia risk in citalopram use

Amiodarone Inhibits Apamin-Sensitive Potassium Currents

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