Kui Péter, Orosz Szabolcs, Takács Hedvig, Sarusi Annamária, Csík Norbert, Rárosi Ferenc, Csekő Csongor, Varró András, Papp Julius Gy, Forster Tamás, Farkas Attila S, Farkas András
Dept. of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
Gedeon Richter Plc., Budapest, Hungary.
J Pharmacol Toxicol Methods. 2016 Jul-Aug;80:26-34. doi: 10.1016/j.vascn.2016.04.005. Epub 2016 Apr 5.
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.
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.
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.
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.
作为一种致心律失常试验，临床前体内QT测量成本高昂且可靠性不足。本研究的目的是开发一种用于致心律失常安全性筛查的灵敏、经济高效的Langendorff灌注豚鼠心脏模型。
在Langendorff灌注的豚鼠心脏中，单独测试低浓度的多非利特和西沙必利（快速延迟整流钾电流IKr抑制剂），并与HMR-1556（缓慢延迟整流钾电流IKs抑制剂）共同灌注。在窦性心律下测定心电图心率校正QT（QTc）间期、T峰-T末间期以及QT间期的逐搏变异性和不稳定性（BVI）。
单独或共同灌注时，多非利特和HMR-1556分别使QTc间期延长20±2%、10±1%和55±10%。同样，单独或共同灌注时，西沙必利和HMR-1556分别使QTc间期延长11±3%、11±4%和38±6%。儿茶酚胺诱导的快速心率消除了IKr抑制剂的QTc延长作用，但增强了IKs抑制期间的QTc延长。所有药物灌注均未显著增加T峰-T末间期和QT间期的窦性BVI。
IKs抑制以超相加（协同）方式增强了IKr抑制剂的QTc延长作用，并且QTc间期优于在离体豚鼠心脏窦性心律中测量的其他致心律失常生物标志物。儿茶酚胺对QTc的影响有助于区分IKr和IKs抑制剂。因此，在Langendorff灌注的豚鼠心脏中进行QT测量，同时药理学降低复极储备并定期进行儿茶酚胺灌注，似乎适用于临床前致心律失常筛查。
