New in vitro model for proarrhythmia safety screening: IKs inhibition potentiates the QTc prolonging effect of IKr inhibitors in isolated guinea pig hearts

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.