Key result
GS967 reduced late Na+ current by 79.0% but also inhibited peak Na+ and L-type Ca2+ currents, indicating it acts as a class I/B antiarrhythmic similar to mexiletine rather than a selective inhibitor.
Why the study?
GS967 is considered a selective blocker of late sodium current, but whether its electrophysiological effects differ from class I/B antiarrhythmics like mexiletine required clarification.
Absolute Event Rate: 79% vs 63.3%
p-value: p=<0.05
GS967 exhibits class I/B antiarrhythmic properties similar to mexiletine, challenging the concept that it is a purely selective late Na+ current inhibitor.
GS967's multi-channel inhibition in animal models challenges assumed late Na+ selectivity; hypothesis-generating versus mexiletine.
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 , on L-type calcium current (I Ca ), 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 GS967 were compared to tetrodotoxin (TTX) and to the class I/B antiarrhythmic compound mexiletine. 1 µM GS967, 40 µM mexiletine, and 10 µM TTX dissected largely similarly shaped inward currents under action potential voltage clamp conditions. In case of GS967 and mexiletine, the amplitude and integral of this 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, I NaL was significantly decreased by 1 µM GS967 and 40 µM mexiletine (79.0±3.0% and 63.3±2.7% reduction of current integrals, respectively). The integral of I Ca was moderately but significantly diminished by both drugs (reduction of 9.3±3.3% and 14.1±1.5%, respectively). These changes were associated with acceleration of inactivation of I Ca . Drug effects on peak Na + current (I NaP ) were also assessed by recording AP upstroke in multicellular preparations. Both GS967 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, respectively, at 2.5 Hz. Effects on beat-to-beat variability of AP duration (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 questiond and it is suggested that GS967 should be classified as a class I/B (or I/B + IV) antiarrhythmic agent.
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Hézső et al. (2021) studied Normal canine ventricular myocardium. GS967 vs. Mexiletine (40 µM) was evaluated on Reduction of late Na+ current (INaL) integral (p=<0.05). GS967 reduced late Na+ current by 79.0% but also inhibited peak Na+ and L-type Ca2+ currents, indicating it acts as a class I/B antiarrhythmic similar to mexiletine rather than a selective inhibitor.
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