IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog

Bavel, Joanne J. A. van; Beekman, Henriette D.M.; Weperen, Valerie Y. H. van; Linde, Henk J. van der; Heyden, Marcel A.G. van der; Vos, Marc A.

doi:10.1016/j.ejphar.2022.175218

Cited by 1 publication

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“…This explains the ML277-induced delay in repolarization prolongation upon dofetilide in the CAVB dog, and a lack of ML277-induced QTc modulation in sinus rhythm dogs. I Ks blocking by JNJ303 prolonged the QT interval in the CAVB model, and in combination with a trigger as enhanced inotropy, ventricular tachycardia and TdP arrhythmias were induced [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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Long QT syndrome type 1 with affected IKs 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 IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs 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). IKs 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.

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Section: Discussionmentioning

confidence: 99%