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Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve

Baczkó, István and Jost, Norbert László and Virág, László and Bősze, Zsuzsanna and Varró, András (2016) Rabbit models as tools for preclinical cardiac electrophysiological safety testing: Importance of repolarization reserve. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY, 121 (2). pp. 157-168. ISSN 0079-6107

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Abstract

It is essential to more reliably assess the pro-arrhythmic liability of compounds in development. Current guidelines for pre-clinical and clinical testing of drug candidates advocate the use of healthy animals/tissues and healthy individuals and focus on the test compound's ability to block the hERG current and prolong cardiac ventricular repolarization. Also, pre-clinical safety tests utilize several species commonly used in cardiac electrophysiological studies. In this review, important species differences in cardiac ventricular repolarizing ion currents are considered, followed by the discussion on electrical remodeling associated with chronic cardiovascular diseases that leads to altered ion channel and transporter expression and densities in pathological settings. We argue that the choice of species strongly influences experimental outcome and extrapolation of results to human clinical settings. We suggest that based on cardiac cellular electrophysiology, the rabbit is a useful species for pharmacological pro-arrhythmic investigations. In addition to healthy animals and tissues, the use of animal models (e.g. those with impaired repolarization reserve) is suggested that more closely resemble subsets of patients exhibiting increased vulnerability towards the development of ventricular arrhythmias and sudden cardiac death.

Item Type: Article
Additional Information: \n Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary \n MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary \n Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary \n Cited By :7 \n Export Date: 29 November 2018 \n CODEN: PBIMA \n Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Funding Agency and Grant Number: Hungarian Scientific Research Fund [OTKA NN 110896, OTKA K 109610, OTKA NN 109904, OTKA NK 104397, OTKA NK 104331]; National Office for Research and Technology - Baross Programme [REG-DA-09-2-2009-0115-NCXINHIB]; Hungarian Academy of Sciences Funding text: This work was supported by the Hungarian Scientific Research Fund (OTKA NN 110896 and OTKA K 109610 to I.B., OTKA NN 109904 to N.J., OTKA NK 104397 to Z.B, OTKA NK 104331 to A.V.), by the National Office for Research and Technology - Baross Programme (REG-DA-09-2-2009-0115-NCXINHIB), and by the Hungarian Academy of Sciences. Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 17 September 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 23 September 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 24 September 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 26 September 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 30 September 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 4 October 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 31 October 2019 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 24 January 2020 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 27 January 2020 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 13 February 2020 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :7 Export Date: 14 February 2020 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu Funding Agency and Grant Number: Hungarian Scientific Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA NN 110896, OTKA K 109610, OTKA NN 109904, OTKA NK 104397, OTKA NK 104331]; National Office for Research and Technology - Baross Programme [REG-DA-09-2-2009-0115-NCXINHIB]; Hungarian Academy of SciencesHungarian Academy of Sciences Funding text: This work was supported by the Hungarian Scientific Research Fund (OTKA NN 110896 and OTKA K 109610 to I.B., OTKA NN 109904 to N.J., OTKA NK 104397 to Z.B, OTKA NK 104331 to A.V.), by the National Office for Research and Technology - Baross Programme (REG-DA-09-2-2009-0115-NCXINHIB), and by the Hungarian Academy of Sciences. Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Szeged, 6720, Hungary MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Dóm tér 12., Szeged, 6720, Hungary Rabbit Genome and Biomodel Group, NARIC-Agricultural Biotechnology Institute, Gödöllő, 2100, Hungary Cited By :14 Export Date: 1 December 2020 CODEN: PBIMA Correspondence Address: Baczkó, I.; Department of Pharmacology & Pharmacotherapy, University of Szeged, Dóm tér 12., Hungary; email: baczko.istvan@med.u-szeged.hu
Uncontrolled Keywords: Animals; Humans; SAFETY; SAFETY; RABBITS; PATHOPHYSIOLOGY; human; animal; Electrophysiology; Electrophysiology; physiology; HEART; HEART; Disease Models, Animal; Rabbit; Rabbit; heart arrhythmia; biological model; disease model; Models, Cardiovascular; Arrhythmias, Cardiac; repolarization reserve; cardiac arrhythmias; procedures; species differences; IKs; Pre-clinical safety testing;
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3020 Biophysics / biofizika
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 15:17
Last Modified: 07 Jan 2021 15:17
URI: http://real.mtak.hu/id/eprint/119295

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