Ruan Lei, Quan Xiaoqing, Li Liandong, Bai Rong, Ni Mingke, Xu Rende, Zhang Cuntai
Department of Gerontology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, P.R. China.
Exp Ther Med. 2014 May;7(5):1279-1284. doi: 10.3892/etm.2014.1601. Epub 2014 Mar 4.
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.
药物诱发的尖端扭转型室性心动过速（TdP）在Ⅲ类抗心律失常药物中很常见。复极跨壁离散度（TDR）增加是TdP发生的重要原因。缝隙连接在长QT综合征中维持TDR起重要作用。本研究检测了缝隙连接增强剂抗心律失常肽10（AAP10）对伊布利特诱发TdP的影响。采用冠状动脉灌注兔心室楔形标本评估AAP10对伊布利特诱发心律失常的作用。同时记录跨壁心电图和动作电位。观察早期后除极（EADs）、R波落在T波上的室性早搏、TdP以及T峰末间期（Tp-e）和Tp-e/QT比值的变化。通过免疫印迹法检测非磷酸化连接蛋白43（Cx43）水平的变化。与对照组相比，在低钾血症和低镁血症条件下，灌注伊布利特的心室楔形标本中，QT间期、Tp-e/QT以及EAD和TdP的发生率随着去磷酸化增加而升高。在AAP10存在的情况下，EAD和TdP的发生率降低，Tp-e/QT比值下降，同时非磷酸化Cx43水平也相应降低。结果表明，AAP10在低钾血症和低镁血症条件下通过降低TDR抑制伊布利特诱发的TdP。AAP10可能通过阻止Cx43的去磷酸化从而增加心肌细胞缝隙连接耦联来降低TDR。
