Major, Péter and Baczkó, István and Hiripi, László and Odening, K. E. and Juhász, Viktor and Kohajda, Zsófia and Horváth, András and Seprényi, György and Kovács, Mária and Virág, László and Jost, Norbert László and Prorok, János and Ördög, Balázs and Doleschall, Zoltán and Varró, András and Bősze, Zsuzsanna (2016) A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of KCNE1 gene. BRITISH JOURNAL OF PHARMACOLOGY, 173 (12). pp. 2046-2061. ISSN 0007-1188
|
Text
MajorPBritJPharmacol2016.pdf Download (2MB) | Preview |
Abstract
BACKGROUND AND PURPOSE: The reliable assessment of proarrhythmic risk of compounds under development remains elusive. Current safety-guidelines focus on KCNH2/HERG blocking effects in tissues and animals with intact repolarization. Novel models with better predictive value are needed that reflect patients with cardiac remodelling and reduced repolarization reserve. EXPERIMENTAL APPROACH: We created a rabbit model for long-QT syndrome type-5 (LQT5) with cardiac-specific overexpression of a mutant (G52R) KCNE1 beta-subunit of the slow delayed-rectifier K+ -channel (IKs ). ECG parameters, including short-term variability of the QT interval (STVQT ), a biomarker for proarrhythmic risk, and arrhythmia development were recorded. In vivo arrhythmia-susceptibility was evaluated by i.v. administration of the IKr blocker dofetilide. K+ currents were measured with the patch-clamp technique. KEY RESULTS: Patch-clamp studies in isolated ventricular myocytes revealed accelerated IKs and IKr deactivation-kinetics in LQT5 rabbits. At baseline, LQT5 animals exhibited slightly but significantly prolonged heart-rate corrected QT index (QTi) and increased STVQT . Dofetilide provoked Torsade-de-Pointes arrhythmia in a greater proportion of LQT5 rabbits, paralleled by a further increase in STVQT . CONCLUSION AND IMPLICATIONS: We have created a novel transgenic LQT5 rabbit model with increased susceptibility to drug-induced arrhythmias that may represent a useful model for testing proarrhythmic potential and for investigations of mechanisms underlying arrhythmias and sudden cardiac death due to repolarization disturbances. This article is protected by copyright. All rights reserved.
| Item Type: | Article |
|---|---|
| Additional Information: | Megjegyzés-26538499 N1 Funding details: OTKA, Hungarian Scientific Research Fund N1 Funding text: This work was supported by the Hungarian Scientific Research Fund (OTKA CNK 77855 and OTKA NK 104331 to A.V., OTKA NN 110896 to I.B., OTKA NN 109904 to N.J. and OTKA NK 104397 to Z.B.), by the National Office for Research and Technology - Baross Programme (REG-DA-09-2-2009-0115-NCXINHIB), by the Hungarian National Development Agency (TAMOP-4.2.6-15/1-2015-0002 and TAMOP-4.2.1.C-14/1/KONV-2015-0013 projects). Megjegyzés-26655808 N1 Funding details: OTKA, Hungarian Scientific Research Fund N1 Funding text: This work was supported by the Hungarian Scientific Research Fund (OTKA CNK 77855 and OTKA NK 104331 to A.V., OTKA NN 110896 to I.B., OTKA NN 109904 to N.J. and OTKA NK 104397 to Z.B.), by the National Office for Research and Technology - Baross Programme (REG-DA-09-2-2009-0115-NCXINHIB), by the Hungarian National Development Agency (TAMOP-4.2.6-15/1-2015-0002 and TAMOP-4.2.1.C-14/1/KONV-2015-0013 projects). Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology Institute, Gödöllõ, H-2100, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary Department of Cardiology and Angiology i, Heart Center University of Freiburg, Freiburg, Germany Department of Biology, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany Cited By :15 Export Date: 17 September 2019 CODEN: BJPCB Correspondence Address: Bõsze, Z.; Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology InstituteHungary; email: bosze@abc.hu Chemicals/CAS: KCNE1 protein, human; Potassium Channels, Voltage-Gated Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology Institute, Gödöllõ, H-2100, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary Department of Cardiology and Angiology i, Heart Center University of Freiburg, Freiburg, Germany Department of Biology, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany Cited By :15 Export Date: 3 October 2019 CODEN: BJPCB Correspondence Address: Bõsze, Z.; Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology InstituteHungary; email: bosze@abc.hu Chemicals/CAS: KCNE1 protein, human; Potassium Channels, Voltage-Gated Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology Institute, Gödöllõ, H-2100, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary Department of Cardiology and Angiology i, Heart Center University of Freiburg, Freiburg, Germany Department of Biology, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany Cited By :15 Export Date: 31 October 2019 CODEN: BJPCB Correspondence Address: Bõsze, Z.; Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology InstituteHungary; email: bosze@abc.hu Chemicals/CAS: KCNE1 protein, human; Potassium Channels, Voltage-Gated Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology Institute, Gödöllõ, H-2100, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary Department of Cardiology and Angiology i, Heart Center University of Freiburg, Freiburg, Germany Department of Biology, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany Cited By :15 Export Date: 24 January 2020 CODEN: BJPCB Correspondence Address: Bõsze, Z.; Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology InstituteHungary; email: bosze@abc.hu Chemicals/CAS: KCNE1 protein, human; Potassium Channels, Voltage-Gated Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology Institute, Gödöllõ, H-2100, Hungary Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary Department of Cardiology and Angiology i, Heart Center University of Freiburg, Freiburg, Germany Department of Biology, University of Szeged, Szeged, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary Department of Pathogenetics, National Institute of Oncology, Budapest, Hungary Department of Medicine, Montreal Heart Institute, Université de Montréal, Canada Department of Pharmacology and Therapeutics, McGill University, Montréal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany Cited By :15 Export Date: 27 January 2020 CODEN: BJPCB Correspondence Address: Bõsze, Z.; Rabbit Genome and Biomodel Group, Animal Biotechnology Department, NARIC - Agricultural Biotechnology InstituteHungary; email: bosze@abc.hu Chemicals/CAS: KCNE1 protein, human; Potassium Channels, Voltage-Gated |
| Subjects: | R Medicine / orvostudomány > RC Internal medicine / belgyógyászat R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 07 Jan 2021 15:37 |
| Last Modified: | 07 Jan 2021 15:37 |
| URI: | http://real.mtak.hu/id/eprint/119294 |
Actions (login required)
 |
Edit Item |
