GS967 significantly suppressed the late sodium current by 80.4% and depressed the maximum velocity of action potential upstroke, demonstrating class I/B antiarrhythmic properties similar to mexiletine.
GS967 depresses both peak and late sodium currents in canine ventricular myocardium, suggesting it should be classified as a class I/B antiarrhythmic rather than a selective late sodium current blocker.
Absolute Event Rate: 80.4% vs 59.1%
p-value: p=<0.05
Abstract Enhancement of the late Na + current (I NaL ) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of I NaL . In the present study, effects of GS967 on I NaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, I NaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of I NaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of I NaL towards negative potentials. GS967 and mexiletine dissected inward I NaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of −0.37 ± 0.07 and −0.28 ± 0.03 A/F, and current integrals of −56.7 ± 9.1 and −46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na + current (I NaP ) were assessed by recording the maximum velocity of AP upstroke (V + max ) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V + max block. However, since GS967 depressed V + max and I NaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block I NaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.
Hézső et al. (2021) studied Normal canine ventricular myocardium. GS967 vs. Mexiletine (40 µM) was evaluated on Reduction in late Na+ current (INaL) density measured at 50 ms of depolarization (p=<0.05). GS967 significantly suppressed the late sodium current by 80.4% and depressed the maximum velocity of action potential upstroke, demonstrating class I/B antiarrhythmic properties similar to mexiletine.