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, IKr) were tested alone and co-perfused with HMR-1556 (inhibitor of the slow delayed rectifier potassium current, IKs) in Langendorff perfused guinea pig hearts. The electrocardiographic rate corrected QT (QTc) interval, the Tpeak-Tend 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 IKr inhibitors, but augmented the QTc prolongation during IKs inhibition. None of the drug perfusions increased significantly the Tpeak-Tend interval and the sinus BVI of the QT interval.


DISCUSSION
IKs inhibition increased the QTc prolonging effect of IKr 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 IKr and IKs 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.
['Kui|Péter|P|', 'Orosz|Szabolcs|S|', 'Takács|Hedvig|H|', 'Sarusi|Annamária|A|', 'Csík|Norbert|N|', 'Rárosi|Ferenc|F|', 'Csekő|Csongor|C|', 'Varró|András|A|', 'Papp|Julius Gy|JG|', 'Forster|Tamás|T|', 'Farkas|Attila S|AS|', 'Farkas|András|A|']
D000818:Animals D001145:Arrhythmias, Cardiac D002395:Catecholamines D002839:Chromans D020117:Cisapride D003326:Coronary Circulation D051668:Delayed Rectifier Potassium Channels D004353:Drug Evaluation, Preclinical D004347:Drug Interactions D004562:Electrocardiography D005260:Female D006168:Guinea Pigs D006321:Heart D006339:Heart Rate D066298:In Vitro Techniques D008133:Long QT Syndrome D010627:Phenethylamines D026902:Potassium Channel Blockers D013449:Sulfonamides D016171:Torsades de Pointes
Proarrhythmia Safety screening Guinea pig hearts Langendorff perfusion Methods Repolarization reserve ECG Rate corrected QT interval Synergism Torsades de pointes