Journal
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
Volume 80, Issue -, Pages 26-34Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vascn.2016.04.005
Keywords
ECG; Guinea pig hearts; Langendorff perfusion; Methods; Proarrhythmia; Rate corrected QT interval; Repolarization reserve; Safety screening; Synergism; Torsades de pointes
Categories
Funding
- Hungarian Scientific Research Fund [OTKA PD 105882, OTKA NK-104331]
- National Development Agency
- European Regional Fund [TAMOP-4.2.2-08/1-2008-0013, TAMOP-4.2.1/B-09/1/KONV-2010-0005, TAMOP-4.2.2/B-10/1-2010-0012, TAMOP-4.2.2. A-11/1/KONV-2012-0052, TAMOP-4.2.2.A-11/1/KONV-2012-0060, TAMOP-4.2.2.A-11/1/KONV-2012-0073]
- Hungary-Romania Cross-Border Cooperation Programme [HURO/1001/086/2.2.1_HURO-TWIN]
- Janos Bolyai fellowship of the Hungarian Academy of Sciences during this investigation [BO/00794/12]
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Introduction: Preclinical in vivo QT measurement as a proarrhythmia essay is expensive and not reliable enough. The aim of the present study was to develop a sensitive, cost-effective, Langendorff perfused guinea pig heart model for proarrhythmia safety screening. Methods: Low concentrations of dofetilide and cisapride (inhibitors of the rapid delayed rectifier potassium current, I-Kr) were tested alone and co-perfused with HMR-1556 (inhibitor of the slow delayed rectifier potassium current, I-Ks) in Langendorff perfused guinea pig hearts. The electrocardiographic rate corrected QT (QTc) interval, the T-peak-T-end interval and the beat-to-beat variability and instability (BVI) of the QT interval were determined in sinus rhythm. Results: Dofetilide and HMR-1556 alone or co-perfused, prolonged the QTc interval by 20 +/- 2%, 10 +/- 1% and 55 +/- 10%, respectively. Similarly, cisapride and HMR-1556 alone or co-perfused, prolonged the QTc interval by 11 +/- 3%, 11 +/- 4% and 38 +/- 6%, respectively. Catecholamine-induced fast heart rate abolished the QTc prolonging effects of the I-Kr inhibitors, but augmented the QTc prolongation during I-Ks inhibition. None of the drug perfusions increased significantly the T-peak-T-end interval and the sinus BVI of the QT interval. Discussion: I-Ks inhibition increased the QTc prolonging effect of I-Kr inhibitors in a super-additive (synergistic) manner, and the QTc interval was superior to other proarrhythmia biomarkers measured in sinus rhythm in isolated guinea pig hearts. The effect of catecholamines on the QTc facilitated differentiation between I-Kr and I-Ks inhibitors. Thus, QTc measurement in Langendorff perfused guinea pig hearts with pharmacologically attenuated repolarization reserve and periodic catecholamine perfusion seems to be suitable for preclinical proarrhythmia screening. (C) 2016 Elsevier Inc. All rights reserved.
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