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

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• 作者：Pé ; ter Kui^a ; ¹ ; Szabolcs Orosz^b ; ¹ ; Hedvig Taká ; cs^c ; Annamá ; ria Sarusi^a ; Norbert Csí ; k^d ; Ferenc Rá ; rosi^e ; ^f ; Csongor Csekő^b ; Andrá ; s Varró ; ^a ; ^g ; Julius Gy. Papp^a ; ^g ; Tamá ; s Forster^c ; Attila S. Farkas^c ; ² ; ^{farkasamed@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Andrá ; s Farkas^c ; ²
• 关键词：ECG ; Guinea pig hearts ; Langendorff perfusion ; Methods ; Proarrhythmia ; Rate corrected QT interval ; Repolarization reserve ; Safety screening ; Synergism ; Torsades de pointes
• 刊名：Journal of Pharmacological and Toxicological Methods
• 出版年：2016
• 出版时间：July-August 2016
• 年：2016
• 卷：80
• 期：Complete
• 页码：26-34
• 全文大小：1006 K

文摘

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.