title: New in vitro model for proarrhythmia safety screening: IKs inhibition potentiates the QTc prolonging effect of IKr inhibitors in isolated guinea pig hearts.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dept. of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Kui
authors.affiliation: Gedeon Richter Plc., Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Orosz
authors.affiliation: 2nd Dept. of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Takács
authors.affiliation: Dept. of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Annamária
authors.initials: A
authors.lastname: Sarusi
authors.affiliation: Department of Electrical Engineering and Cybernetics, Kecskemét College, Kecskemét, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Csík
authors.affiliation: Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary; Bolyai Institute, University of Szeged, Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Rárosi
authors.affiliation: Gedeon Richter Plc., Budapest, Hungary.
authors.forename: Csongor
authors.initials: C
authors.lastname: Csekő
authors.affiliation: Dept. of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.affiliation: Dept. of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; MTA-SZTE Research Group of Cardiovascular Pharmacology, Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Julius Gy
authors.initials: JG
authors.lastname: Papp
authors.affiliation: 2nd Dept. of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Forster
authors.affiliation: 2nd Dept. of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary. Electronic address: farkasamed@gmail.com.
authors.forename: Attila S
authors.initials: AS
authors.lastname: Farkas
authors.affiliation: 2nd Dept. of Medicine and Cardiology Centre, University of Szeged, Szeged, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Farkas
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002395:Catecholamines / Q000494:pharmacology; D002839:Chromans / Q000633:toxicity; D020117:Cisapride / Q000633:toxicity; D003326:Coronary Circulation / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced*; D010627:Phenethylamines / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000633:toxicity*; D013449:Sulfonamides / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced
chemical_list: D002395:Catecholamines; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; C420023:HMR 1556; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide; D020117:Cisapride
keywords: ECG; Guinea pig hearts; Langendorff perfusion; Methods; Proarrhythmia; Rate corrected QT interval; Repolarization reserve; Safety screening; Synergism; Torsades de pointes