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Br J Pharmacol
2013 Mar 01;1685:1215-29. doi: 10.1111/bph.12002.
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Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K(+) channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells.
Jehle J
,
Ficker E
,
Wan X
,
Deschenes I
,
Kisselbach J
,
Wiedmann F
,
Staudacher I
,
Schmidt C
,
Schweizer PA
,
Becker R
,
Katus HA
,
Thomas D
.
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BACKGROUND AND PURPOSE: Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/I(Kr) currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K(+) channels.
EXPERIMENTAL APPROACH: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes.
KEY RESULTS: Zolpidem caused acute hERG channel blockade in oocytes (IC(50) = 61.5 μM) and in HEK 293 cells (IC(50) = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I-V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes.
CONCLUSIONS AND IMPLICATIONS: Zolpidem inhibits cardiac hERG K(+) channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose.
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Bianchi,
herg encodes a K+ current highly conserved in tumors of different histogenesis: a selective advantage for cancer cells?
1998,
Pubmed
,
Xenbase
Caspi,
In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes.
2009,
Pubmed
Cherubini,
HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium.
2000,
Pubmed
Claycomb,
HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte.
1998,
Pubmed
Dennis,
Antidepressant-induced ubiquitination and degradation of the cardiac potassium channel hERG.
2011,
Pubmed
Drover,
Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone.
2004,
Pubmed
Dündar,
Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.
2004,
Pubmed
El Harchi,
Molecular determinants of hERG potassium channel inhibition by disopyramide.
2012,
Pubmed
Ficker,
Mechanisms of arsenic-induced prolongation of cardiac repolarization.
2004,
Pubmed
Ficker,
Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG.
2003,
Pubmed
Gierten,
Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein.
2008,
Pubmed
,
Xenbase
Gong,
HERG K+ channel related chemosensitivity to sparfloxacin in colon cancer cells.
2010,
Pubmed
Greenblatt,
Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo.
2006,
Pubmed
Guo,
Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes.
2007,
Pubmed
Hajak,
Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data.
2003,
Pubmed
Hausken,
Starting insomnia treatment: the use of benzodiazepines versus z-hypnotics. A prescription database study of predictors.
2009,
Pubmed
Hondeghem,
Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct.
2008,
Pubmed
Itzhaki,
Modelling the long QT syndrome with induced pluripotent stem cells.
2011,
Pubmed
Jehle,
Novel roles for hERG K(+) channels in cell proliferation and apoptosis.
2011,
Pubmed
Jones,
Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results.
2007,
Pubmed
Kiehn,
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
1999,
Pubmed
,
Xenbase
Letsas,
QT interval prolongation and Torsades de Pointes in a patient receiving zolpidem and amiodarone.
2006,
Pubmed
Lugenbiel,
Biological Heart Rate Reduction Through Genetic Suppression of Gα(s) Protein in the Sinoatrial Node.
2012,
Pubmed
Ma,
High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents.
2011,
Pubmed
McGrath,
Guidelines for reporting experiments involving animals: the ARRIVE guidelines.
2010,
Pubmed
Mitcheson,
A structural basis for drug-induced long QT syndrome.
2000,
Pubmed
,
Xenbase
Moretti,
Patient-specific induced pluripotent stem-cell models for long-QT syndrome.
2010,
Pubmed
Nicholson,
Hypnotic activity of an imidazo-pyridine (zolpidem).
1986,
Pubmed
Obers,
Multiple mechanisms of hERG liability: K+ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine.
2010,
Pubmed
,
Xenbase
Peng,
The action potential and comparative pharmacology of stem cell-derived human cardiomyocytes.
2010,
Pubmed
Rajamani,
Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine.
2006,
Pubmed
Redfern,
Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.
2003,
Pubmed
Roden,
Repolarization reserve: a moving target.
2008,
Pubmed
Salvà,
Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications.
1995,
Pubmed
Sanguinetti,
hERG potassium channels and cardiac arrhythmia.
2006,
Pubmed
Seyler,
TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.
2012,
Pubmed
,
Xenbase
Smith,
Functional up-regulation of HERG K+ channels in neoplastic hematopoietic cells.
2002,
Pubmed
Soucek,
Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant.
2012,
Pubmed
Staudacher,
hERG: protein trafficking and potential for therapy and drug side effects.
2010,
Pubmed
Staudacher,
Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels.
2011,
Pubmed
,
Xenbase
Staudacher,
hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine.
2011,
Pubmed
,
Xenbase
Takemasa,
Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome.
2008,
Pubmed
Thomas,
Doxazosin induces apoptosis of cells expressing hERG K+ channels.
2008,
Pubmed
Thomas,
Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing.
2003,
Pubmed
Thomas,
Inhibition of human ether-a-go-go-related gene potassium channels by alpha 1-adrenoceptor antagonists prazosin, doxazosin, and terazosin.
2004,
Pubmed
,
Xenbase
Thomas,
High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.
2001,
Pubmed
,
Xenbase
Thomas,
The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications.
2006,
Pubmed
Thomas,
Inhibition of cloned HERG potassium channels by the antiestrogen tamoxifen.
2003,
Pubmed
,
Xenbase
Thomas,
Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A.
1999,
Pubmed
,
Xenbase
Trappe,
Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study.
2013,
Pubmed
Viskin,
Long QT syndromes and torsade de pointes.
1999,
Pubmed
Wang,
Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.
2007,
Pubmed
Wang,
HERG K+ channel, a regulator of tumor cell apoptosis and proliferation.
2002,
Pubmed
Zhang,
Characterization of recombinant hERG K(+) channel inhibition by the active metabolite of amiodarone desethyl-amiodarone.
2010,
Pubmed
Zitron,
Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone.
2004,
Pubmed
,
Xenbase
de Haas,
Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.
2010,
Pubmed
van der Heyden,
Drugs and trafficking of ion channels: a new pro-arrhythmic threat on the horizon?
2008,
Pubmed
