Increasing gap junction coupling reduces transmural dispersion of repolarization and prevents torsade de pointes in rabbit LQT3 model.
BACKGROUND
Increased transmural dispersion of repolarization (TDR) contributes importantly to the development of torsades de pointes (TdP) in long QT syndrome (LQTS). Intercellular electrical coupling via gap junctions plays an important role in maintaining TDR in both normal and diseased hearts. This study examined the effects of antiarrhythmic peptide AAP10, a gap junction enhancer, on TDR and induction of TdP in a rabbit LQT3 model.


RESULTS
An arterially perfused rabbit left ventricular preparation and sea anemone toxin II (ATX-II, 20 nM) were used to establish a LQT3 model. Transmural ECG as well as action potentials from both endocardium and epicardium were simultaneously recorded. Changes in nonphosphorylated connexin43 (Cx43) were measured by immunoblotting. Compared with the control group, the QT interval, TDR, early afterdepolariztion (EAD), R-on-T extrasystole, and TdP increased sharply with augmented nonphosphorylated Cx43 in the LQT3 group (P < 0.001 for both). Interestingly, compared with the LQT3 group, 500 nM AAP10 reduced QT interval, TDR (P < 0.001 for both), and prevented EAD, R-on-T extrasystole, and TdP (P = 0.003, P = 0.001, P = 0.02) with a parallel decrease in nonphosphorylated Cx43 in the presence of ATX-II (P < 0.001).


CONCLUSIONS
Gap junction enhancer AAP10 is capable of abbreviating the QT interval, reducing TDR, and suppressing TdP in a rabbit LQT3 model probably via its effect by preventing dephosphorylation of Cx43. These data suggest that increasing intercellular coupling may reduce TDR and, therefore, prevent TdP in LQTS.
Quan
Xiao-Qing
XQ
Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Bai
Rong
R
Liu
Nian
N
Chen
Bo-Di
BD
Zhang
Cun-Tai
CT
D000818:Animals; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D008133:Long QT Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D009842:Oligopeptides / Q000627:therapeutic use*; D010766:Phosphorylation; D011817:Rabbits; D016171:Torsades de Pointes / Q000209:etiology / Q000517:prevention & control*
C090806:AAP 10; D018031:Connexin 43; D009842:Oligopeptides