Atria are More Sensitive Than Ventricles to GS-458967-Induced Inhibition of Late Sodium Current

Abstract

Introduction: The differential response of atrial and ventricular cells to late sodium channel current (late INa) inhibition has not been thoroughly investigated. The aim of the present study was to compare the atrioventricular differences in electrophysiological actions of GS-458967, a potent late INa blocker. Methods and Materials: Canine coronary-perfused atrial and ventricular preparations and isolated ventricular myocytes were used. Transmembrane action potentials were recorded using standard microelectrode recording techniques. Results: In coronary-perfused preparations paced at a cycle length (CL) of 500 ms, GS-458967 (100-300 nmol/L) significantly abbreviated action potential duration at 50% to 90% (APD50-90) in atria but not in the ventricles. GS-458967 (≥100 nmol/L) prolonged the effective refractory period (ERP) in atria due to the development of postrepolarization refractoriness (PRR) but did not alter ERP in the ventricles. The maximum rate of rise in the action potential upstroke (Vmax) was significantly reduced at concentrations ≥100 nmol/L in atria but not in the ventricles (CL = 300 ms). At slower pacing rates (CL = 2000 ms) and higher concentrations, GS-458967 (100-1000 nmol/L) still failed to abbreviate ventricular APD. However, when APD was prolonged by the rapidly activating delayed rectifier potassium channel blocker E-4031 (1 µmol/L), addition of 1 μmol/L GS-458967 abbreviated APD in the ventricles at slow rates. In contrast, GS-458967 (300 nmol/L) consistently abbreviated APD in untreated isolated ventricular myocytes. Conclusion: In canine coronary-perfused preparations, GS-458967 abbreviates APD, induces PRR, and reduces Vmax in atria but has no significant effect on these parameters in the ventricles, indicating an atrial-selective effect of GS-458967 on both peak and late INa-mediated parameters. In multicellular preparations, GS-458967 abbreviated ventricular APD only under long QT conditions, suggesting a pathology-specific action of GS-458967 in canine ventricular myocardium.