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

Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofet...

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Bibliographic Details
Published in:European journal of pharmacology 2022-10, Vol.932, p.175218-175218, Article 175218
Main Authors: van Bavel, Joanne J.A., Beekman, Henriëtte D.M., van Weperen, Valerie Y.H., van der Linde, Henk J., van der Heyden, Marcel A.G., Vos, Marc A.
Format: Article
Language:English
Subjects:
CAVB Dog model
Contractility
IKs
JNJ303
QT interval
Ventricular arrhythmia
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Summary:Impaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P 
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2022.175218