New proarrhythmia model based on reduced repolarization reserve in isolated guinea pig hearts
█ Original article
Papp Henriett1, Sarusi Annamária1, Farkas Attila2, Polyák Alexandra2, Papp Gyula1, Varró András1, Farkas András2
1Szegedi Tudományegyetem, Általános Orvostudományi Kar, Farmakológiai és Farmakoterápiai Intézet, Szeged
2SZTE, Általános Orvostudományi Kar, II. sz. Belgyógyászati Klinika és Kardiológiai Központ, Szeged
Aims: Specific and sensitive experimental models are needed for testing the proarrhythmic liability of newly developed drugs. Recently, we found that reduced repolarization reserve sensitized isolated, Langendorff perfused rabbit hearts to development of drug-induced torsades de pointes type ventricular tachycardia (TdP). Ion channel constitution of the guinea pig heart may make it more suitable for proarrhythmia development than the rabbit heart. Thus, aim of the present study was to investigate if reduced repolarisation reserve can sensitize guinea pig heart to development of drug-induced torsades de pointes.
Methods: The proarrhythmic activity of the selective IKr K+ current inhibitor dofetilide was tested in Langendorff perfused, isolated guinea pig hearts. Repolarization reserve was reduced by the selective IKs K+ current inhibitor HMR 1556. Three groups of hearts were tested: (1) Control (n=7 hearts), (2) hearts perfused with HMR 1556 (n=6 hearts), (3) hearts perfused with dofetilide+HMR 1556 (n=7 hearts). The incidences of arrhythmias were determined as primary endpoints. Also, the rate corrected QT (QTc) interval was measured.
Results: No TdP developed in any of the groups. Dofetilide+HMR 1556 perfusion did not influence significantly the incidence of ventricular tachycardias, but it significantly increased the incidence of conduction blocks as an indication of development of extreme repolarization prolongation. (Control: 0%, HMR 1556: 0%, dofetilide+HMR 1556: 100%). Reduction of repolarization reserve synergistically increased the QTc prolonging effect of dofetilide (QTc prolongation: HMR 1556: 14%, dofetilide: 20%, dofetilide+HMR 1556: 95%)
Conclusions: Reduced repolarisation reserve did not sensitize guinea pig heart to development of drug-induced torsades de pointes. However, drug-induced QTc prolongation can be tested as a sensitive proarrhythmia endpoint in the model, as reduced repolarization reserve synergistically increases the QTc prolonging effect of the test drug.