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A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

Sep 19, 2012 • By Luiz Belardinelli, Gongxin Liu, Cathy Smith-Maxwell, Wei-Qun Wang, Nesrine El-Bizri, Ryoko Hirakawa, Serge Karpinski, Cindy Hong Li, Lufei Hu, Xiao-Jun Li, William Crumb, Lin Wu, Dmitry Koltun, Jeff Zablocki, Lina Yao, Arvinder K. Dhalla, Sridharan Rajamani, John C. Shryock

Abstract

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 mM, respectively. Reduction of peak INa by GS967 was minimal at a holding potential of2120 mV but increased at280 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 methoxamine1clofilium and suppressed ischemiainduced 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.

Introduction

Sodium (Na1) channel opening and influx of Na1 are responsible for the upstroke of the cardiac action potential (AP). When Na1 channels in myocytes fail to inactivate after opening, Na1 influx continues throughout the AP plateau. The resulting Na1 current (INa) is referred to as late INa to distinguish it from the larger and transient peak INa. Late INa in the normal heart is small, but its magnitude is increased in many pathologic conditions, such as in the failing and/or ischemic heart, in the heart exposed to oxidative stress, and in hearts of patients with congenital long QT3 syndromes (Ver Donck et al., 1993; Le Grand et al., 1995; Bennett et al., 1995; Wang et al., 1995; Ju et al., 1996; Maltsev et al., 1998; Maltsev and Undrovinas, 2006; Song et al., 2006; Sossalla et al., 2010).

Regardless of cause, an enhanced cardiac late INa is proarrhythmic (Boutjdir and El-Sherif, 1991; Sicouri et al., 1997; Undrovinas and Maltsev, 2008; Zaza et al., 2008). Late INa during the plateau of the AP reduces repolarization reserve (i.e., net outward current) and may prolong AP duration (APD). Prolongation of APD can result in early afterdepolarizations as a result of L-type Ca21 channel reopening (Ca21 window current) (January and Riddle, 1989). Enhancement of late INa has been shown to elicit after-depolarizations, triggered arrhythmic activity, and torsades de pointes (TdP) tachycardia in studies of Purkinje fibers, isolated atrial and ventricular myocytes, isolated wedges of cardiac tissue, and intact hearts (Boutjdir and El-Sherif, 1991; Sicouri et al., 1997; Song et al., 2004, 2008). Conversely, drug-induced reduction of late INa has been associated with improvement of electrical function in myocytes isolated from failing hearts and in hearts made ischemic or that have been exposed to cardiac glycosides, hydrogen peroxide, enhancers of late INa, or drugs that block the rapidly activating delayed-rectifier K1 current (IKr) and reduce repolarization reserve (Ver Donck et al., 1993; Haigney et al., 1994; Le Grand et al., 1995; Sicouri et al., 1997; Song et al., 2004, 2006, 2008; Sossalla et al., 2010; Undrovinas and Maltsev 2008; Wu et al., 2011).

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