TY - JOUR
T1 - Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine
AU - Wu, Jingjing
AU - Cheng, Longxian
AU - Lammers, Wim J.
AU - Wu, Lin
AU - Wang, Xin
AU - Shryock, John C.
AU - Belardinelli, Luiz
AU - Lei, Ming
N1 - Funding Information:
The work was supported by the Chinese Nature Science Foundation (Project No, 30470634, ML), Chinese Scholar Research Council (JW, LC), The Wellcome Trust (ML), The British Heart Foundation (ML) and a CVT Research Grant (ML).
PY - 2008/10
Y1 - 2008/10
N2 - The aim of this study was to characterize the role of the late Na+ current (INa,L) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, INa,L. In sixteen hearts studied, exposure to 1-10 nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early afterdepolarisations, delayed afterdepolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n = 5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 μM ranolazine in intact hearts (n = 11) and isolated sino-atrial preparations (n = 5). In conclusion, the INa,L enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the INa,L blocker, ranolazine (10 μM). The results suggest that INa,L blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.
AB - The aim of this study was to characterize the role of the late Na+ current (INa,L) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, INa,L. In sixteen hearts studied, exposure to 1-10 nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early afterdepolarisations, delayed afterdepolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n = 5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 μM ranolazine in intact hearts (n = 11) and isolated sino-atrial preparations (n = 5). In conclusion, the INa,L enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the INa,L blocker, ranolazine (10 μM). The results suggest that INa,L blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.
KW - ATX-II
KW - I
KW - LQT3
KW - Late Na current
KW - SCN5A
KW - Sinus node dysfunction
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U2 - 10.1016/j.pbiomolbio.2009.01.003
DO - 10.1016/j.pbiomolbio.2009.01.003
M3 - Article
C2 - 19351514
AN - SCOPUS:61849102371
SN - 0079-6107
VL - 98
SP - 198
EP - 207
JO - Progress in Biophysics and Molecular Biology
JF - Progress in Biophysics and Molecular Biology
IS - 2-3
ER -