GS967, By Blocking the Late Sodium Current (INaL), Has Strong Action Potential–Stabilizing Properties in Isolated Remodeled Ventricular Canine Cells

Abstract

<h3>Background</h3> The chronic atrioventricular (AV) block (CAVB) dog has enhanced susceptibility for drug-induced torsades de pointes arrhythmias. This risk can be estimated using beat-to-beat variability of repolarization, quantified as short term variability (STV) of action potential duration (STV–APD in ms) <i>in vivo</i> or <i>in vitro</i>. Under pathophysiologic conditions, APD prolongation increases STV. Most proarrhythmic drugs increase STV more (up) than APD (rightward), whereas flunarizine, with robust antiarrhythmic properties, has been shown to decrease baseline STV more (down) than APD (leftward) both <i>in vivo</i> and <i>in vitro</i>. The purpose of this study was to assess the stabilizing effect of selective inhibition of late Na⁺ current (I_NaL) by GS-458967 (GS967) and tetrodotoxin (TTX) on the STV–APD relationship. In addition, the effect of ranolazine (RAN), a multiple ion channel blocker, which also inhibits I_NaL, and dofetilide, an I_Kr blocker, were investigated. <h3>Methods</h3> Isolated CAVB myocytes were stimulated at 0.5 Hz and exposed to RAN (15 μM), GS967 (0.1, 0.3, 1 μM), TTX (5 μM), and dofetilide (1 μM). <h3>Results</h3> As expected, dofetilide appeared more up and rightward on the STV-APD (Figure) and caused early afterdepolarizations (4/6). The results of GS967 and TTX showed the opposite effect (down and leftward). This effect was greater than that of flunarizine, whereas RAN had minimal effect. <h3>Conclusions</h3> The appearance of GS967 and TTX, by blocking I_NaL, indicates strong AP-stabilizing properties.