PT  - JOURNAL ARTICLE
AU  - Luiz Belardinelli
AU  - Gongxin Liu
AU  - Cathy Smith-Maxwell
AU  - Wei-Qun Wang
AU  - Nesrine El-Bizri
AU  - Ryoko Hirakawa
AU  - Serge Karpinski
AU  - Cindy Hong Li
AU  - Lufei Hu
AU  - Xiao-Jun Li
AU  - William Crumb
AU  - Lin Wu
AU  - Dmitry Koltun
AU  - Jeff Zablocki
AU  - Lina Yao
AU  - Arvinder K. Dhalla
AU  - Sridharan Rajamani
AU  - John C. Shryock
TI  - A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias
AID  - 10.1124/jpet.112.198887
DP  - 2013 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 23--32
VI  - 344
IP  - 1
4099  - http://jpet.aspetjournals.org/content/344/1/23.short
4100  - http://jpet.aspetjournals.org/content/344/1/23.full
SO  - J Pharmacol Exp Ther2013 Jan 01; 344
AB  - Inhibition of cardiac late sodium current (late INa) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late INa are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late INa, and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)–induced late INa in ventricular myocytes and isolated hearts with IC50 values of 0.13 and 0.21 µM, respectively. Reduction of peak INa by GS967 was minimal at a holding potential of −120 mV but increased at −80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late INa enhancer ATX-II and the IKr inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late INa and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late INa. In summary, GS967 selectively suppressed late INa and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts.