P640New in vitro model for proarrhythmia screening: iks inhibition potentiates the qtc prolonging effect of ikr inhibitors in isolated guinea pig hearts

Purpose: We hypothesised that Langendorff-perfused guinea pig hearts with pharmacologically reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. We tested the electrocardiographic QT interval prolonging effect of the IKr K+ channel inhibitors dofetilide and cisapride in such experimental setting, and examined whether selective inhibition of the IKs K+ current by HMR-1556 can augment IKr-blocker-induced QT prolongation. Methods: Low concentration of IKr blockers were used for testing the sensitivity of the model. In the first set of experiments, hearts were perfused with: solvent, or 10 nM dofetilide, or 700 nM HMR-1556, or the combination of 10 nM dofetilide+700 nM HMR-1556. In the second set of experiments, hearts were perfused with: solvent, or 20 nM cisapride, or 700 nM HMR-1556, or the combination of 20 nM cisapride+700 nM HMR-1556. ECG was recorded; the ECG intervals and arrhythmia incidences were measured in a blinded manner; the rate corrected QT (QTc) intervals were calculated. Results: HMR-1556 and dofetilide prolonged QTc intervals significantly (10% and 20% vs control, respectively, p<0.05). However, co-administration of HMR-1556 and dofetilide potentiated the QTc prolonging effect of dofetilide (55% vs. Control, p<0.05). In the second set of experiments, HMR-1556 and cisapride prolonged QTc intervals equally (11% and 11% vs control, p<0.05). As found in the first set of experiments, the co-administration of HMR-1556 and cisapride prolonged QTc in a super-additive manner (38 % vs. Control, p<0.05). Conclusions: Reduction of the repolarization reserve with pharmacological inhibition of the IKs K+ current augmented the QTc prolonging effect of the IKr blockers dofetilide and cisapride in a super-additive manner in isolated guinea pig hearts. Thus, the model seems to be suitable for revealing latent QTc prolonging effect of drugs in cardiac safety pharmacological investigations. This work was supported by Hungarian Scientific Research Found (OTKA PD 105882) and Bolyai fellowship (BO/00794/12).