Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine.
The aim of this study was to characterize the role of the late Na+ current (I(Na,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, I(Na,L). In sixteen hearts studied, exposure to 1-10nM 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 after depolarisations, delayed after depolarisations 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 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,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.
Centre for Ion Channel Research and Department of Cardiovascular Diseases, Xiehe Hospital, Huazhong University of Sciences and Technology, Wuhan, China.
Jingjing
J
Wu
Longxian
L
Cheng
Wim J
WJ
Lammers
Lin
L
Wu
Xin
X
Wang
John C
JC
Shryock
Luiz
L
Belardinelli
Ming
M
Lei
D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D003064:Cnidarian Venoms / Q000633:toxicity; D004195:Disease Models, Animal; D004562:Electrocardiography; D055724:Electrophysiological Phenomena; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D012804:Sick Sinus Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D012849:Sinoatrial Node / Q000187:drug effects / Q000503:physiopathology
D000083:Acetanilides; D003064:Cnidarian Venoms; D010879:Piperazines; C028800:toxin II (Anemonia sulcata); D000069458:Ranolazine