Antiarrhythmic effects of the highly selective late sodium channel current blocker GS-458967

Abstract

Previous studies have shown that late sodium channel current (INa) blockers such as ranolazine can exert antiarrhythmic effects by suppressing early and delayed afterdepolarization (EAD and DAD)-induced triggered activity. To evaluate the electrophysiological properties of GS-458967 (GS967), a potent and highly selective late INa blocker, in canine Purkinje fibers (PFs) and pulmonary vein (PV) and superior vena cava (SVC) sleeve preparations. Transmembrane action potentials were recorded from canine PFs and PV and SVC sleeve preparations by using standard microelectrode techniques. The rapidly activating delayed rectifier potassium channel current blocker E-4031 (2.5-5 µM) and the late INa agonist ATX-II (10 nM) were used to induce EADs in PFs. Isoproterenol (1 µM), high calcium ([Ca(2+)]o = 5.4 mM), or their combination was used to induce DADs and triggered activity. In PFs, GS967 (10-300 nM) caused a significant concentration-dependent reduction in action potential duration without altering the maximum rate of rise of the action potential upstroke, action potential amplitude, or resting membrane potential at any rate studied (basic cycle lengths of 1000, 500, and 300 ms) or concentration evaluated (n = 5; P < .05). GS967 (30-100 nM) abolished EADs and EAD-induced triggered activity elicited in PFs by exposure to E-4031 (n = 4) or ATX-II (n = 4). In addition, GS967 reduced or abolished DADs and suppressed DAD-induced triggered activity elicited in PFs (n = 4) and PV (n = 4) and SVC (n = 3) sleeve preparations by exposure to isoproterenol, high calcium, or their combination. Our data suggest that the selective inhibition of late INa with GS967 can exert antiarrhythmic effects by suppressing EAD- and DAD-mediated extrasystolic activity in PFs and PV and SVC sleeve preparations.