I_Ks Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected I_Ks is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target I_Ks as antiarrhythmics. We examined the antiarrhythmic effect of I_Ks channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). I_Ks channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.