ArticleBritish journal of pharmacology2006
Blockade of HERG human K+ channels and IKr of guinea-pig cardiomyocytes by the antipsychotic drug clozapine.
Article in British journal of pharmacology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Second-generation antipsychotics - Cardiac ion channel modulation and QT interval disturbances: A review.Biomolecules & biomedicine · 2025Review
- Article
- Harnessing AlphaFold to reveal hERG channel conformational state secrets.bioRxiv : the preprint server for biology · 2025Article
- Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia.International journal of molecular sciences · 2022Review
- Inhibitory effects of the atypical antipsychotic, clozapine, on voltage-dependent KThe Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2022Article
- Characterization and functional role of rapid- and slow-activating delayed rectifier KPflugers Archiv : European journal of physiology · 2021Article
- A greedy classifier optimization strategy to assess ion channel blocking activity and pro-arrhythmia in hiPSC-cardiomyocytes.PLoS computational biology · 2020Article
- Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications.European heart journal · 2019Review
- Usefulness of Bnet, a Simple Linear Metric in Discerning Torsades De Pointes Risks in 28 CiPA Drugs.Frontiers in pharmacology · 2019Article
- Safety of antipsychotics for the treatment of schizophrenia: a focus on the adverse effects of clozapine.Therapeutic advances in drug safety · 2018Review
- Cardiovascular Disease in Clozapine-Treated Patients: Evidence, Mechanisms and Management.CNS drugs · 2017Review
- Predicting the potency of hERG K⁺ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models.Journal of molecular modeling · 2012Article
- Clinical impact of fluvoxamine-mediated long QTU syndrome.European journal of clinical pharmacology · 2012Article
- Inhibitory actions of HERG currents by the immunosuppressant drug cyclosporin a.The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology · 2011Article
- Sudden death in patients receiving drugs tending to prolong the QT interval.British journal of clinical pharmacology · 2009Article
- Ether-a-go-go-related gene potassium channels: what's all the buzz about?Schizophrenia bulletin · 2007Review
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5 authors.
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Abstract
Clozapine, a commonly used antipsychotic drug, can induce QT prolongation, which may lead to torsades de pointes and sudden death. To investigate the arrhythmogenic side effects of clozapine, we studied the impact of clozapine on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus oocytes and HEK293 cells, and on the delayed rectifier K(+) currents of guinea-pig cardiomyocytes. Clozapine dose-dependently decreased the amplitudes of the currents at the end of voltage steps, and the tail currents of HERG. The IC(50) for the clozapine blockade of HERG currents in Xenopus oocytes progressively decreased relative to depolarization (39.9 microM at -40 mV, 28.3 microM at 0 mV and 22.9 microM at +40 mV), whereas the IC(50) for the clozapine-induced blockade of HERG currents in HEK293 cells at 36 degrees C was 2.5 microM at +20 mV. The clozapine-induced blockade of HERG currents was time dependent: the fractional current was 0.903 of the control at the beginning of the pulse, but declined to 0.412 after 4 s at a test potential of 0 mV. The clozapine-induced blockade of HERG currents was use-dependent, exhibiting more rapid onset and greater steady state blockade at higher frequencies of activation, with a partial relief of blockade observed when the frequency of activation was decreased. In guinea-pig ventricular myocytes held at 36 degrees C, treatment with 1 and 5 microM clozapine blocked the rapidly activating delayed rectifier K(+) current (I(Kr)) by 24.7 and 79.6%, respectively, but did not significantly block the slowly activating delayed rectifier K(+) current (I(Ks)). Our findings collectively suggest that blockade of HERG currents and I(Kr), but not I(Ks), may contribute to the arrhythmogenic side effects of clozapine.
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