title: Increasing gap junction coupling suppresses ibutilide-induced torsades de pointes.
abstract: Drug-induced torsades de pointes (TdP) is common with class III antiarrhythmic drugs. Increased transmural dispersion of repolarization (TDR) contributes significantly to the development of TdP. Gap junctions play an important role in maintaining TDR in long QT syndrome. The present study examined the effect of a gap junction enhancer, antiarrhythmic peptide 10 (AAP10), on ibutilide-induced TdP. Coronary-perfused rabbit ventricular wedge preparations were used to evaluate the effect of AAP10 on ibutilide-induced arrhythmia. Transmural electrocardiograms and action potentials were recorded simultaneously. Early afterdepolarizations (EADs), R-on-T extrasystole, TdP and changes in Tpeak-end (Tp-e) and the Tp-e/QT ratio were observed. Changes in the levels of non-phosphorylated connexin 43 (Cx43) were measured by immunoblotting. Compared with those in the control group, the QT interval, Tp-e/QT and incidence rates of EAD and TdP increased with augmented dephosphorylation in the ventricular wedge preparations perfused with ibutilide under conditions of hypokalemia and hypomagnesemia. In the presence of AAP10, the incidence rates of EAD and TdP were reduced and the Tp-e/QT ratio decreased, with a parallel reduction in the level of non-phosphorylated Cx43. The results indicate that AAP10 suppressed ibutilide-induced TdP under conditions of hypokalemia and hypomagnesemia by decreasing TDR. AAP10 reduced TDR, possibly by preventing the dephosphorylation of Cx43 and thereby increasing myocardial cell gap junction coupling.
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ruan
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Quan
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Liandong
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Mingke
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Rende
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
authors.forename: Cuntai
authors.initials: C
authors.lastname: Zhang
keywords: ion channel; long QT syndrome; torsades de pointes; wedge