Is selective late sodium current inhibition different from class I/B antiarrhythmic action? Comparison of the effects of GS967 to mexiletine in canine ventricular myocardium

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Research, Development and Innovation Office New National Excellence Programme Enhancement of the late Na+ current (INa,late) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS-458967 (GS) is an agent considered to be a selective blocker of INa,late. In the present study, effects of GS967 on INa,late, on L-type calcium current (ICaL), and on action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. These effects of GS were compared to tetrodotoxin (TTX) and to the class I/B antiarrhythmic compound mexiletine. GS (1 μM), mexiletine (40 μM) and TTX (10 μM) dissected largely similarly shaped inward currents under action potential voltage clamp conditions. In case of GS and mexiletine, the amplitude and integral of this inward current was significantly smaller when measured in the presence of 1 μM nisoldipine, while no difference was observed in case of TTX. Under conventional voltage clamp conditions, INa,late was significantly reduced by 1 μM GS and 40 μM mexiletine (about 79% and 63% reduction of current integrals, respectively). The integral of ICa,L was moderately but significantly decreased by both drugs (reduction of 9% and 14%, respectively). These changes were associated with a faster inactivation of ICa,L. Drug effects on early Na+ current (INa,early) were assessed by analyzing the maximal rate of depolarization (V + max) in multicellular preparations. Both GS and mexiletine showed fast onset and offset kinetics: 110 ms and 289 ms offset time constants, respectively, as determined from V + max measurements in right ventricular papillary muscles, while the onset kinetics was characterized by 5.3 AP and 2.6 AP lengths, respectively, at 2.5 Hz. Effects on beat-to-beat variability of AP duration (APD) was studied in isolated myocytes. Short-term variability was significantly decreased by both GS and mexiletine (average reduction of 42% and 24%, respectively) while they caused similar shortening of the APD. The electrophysiological effects of GS are similar to those of mexiletine, but with a somewhat faster offset kinetics of V + max block. However, since GS reduced V+ max and INa,late in the same concentration, the currently accepted view that GS that selectively blocks INa,late has to be questioned and it is suggested that GS should be classified as a class I/B (or I/B + IV) antiarrhythmic agent.