Selective inhibition of physiological late Na⁺ current stabilizes ventricular repolarization

Abstract

The physiological role of cardiac late Na current ( I) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late I abbreviates the normal action potential (AP) duration (APD) and counteracts the prolongation of APD and arrhythmic activities caused by inhibition of the delayed rectifier K current ( I). The effects of GS-458967 (GS967) on the physiological late I and APs in rabbit isolated ventricular myocytes and on the monophasic APs and arrhythmias in rabbit isolated perfused hearts were determined. In ventricular myocytes, GS967 and, for comparison, tetrodotoxin concentration dependently decreased the physiological late I with IC values of 0.5 and 1.9 µM, respectively, and significantly shortened the APD measured at 90% repolarization (APD). A strong correlation between inhibition of the physiological late I and shortening of APD by GS967 or tetrodotoxin ( R of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 µM) significantly shortened APD and monophasic APD and prevented the prolongation and associated arrhythmias caused by the I inhibitor E4031 (1 µM). In conclusion, selective inhibition of physiological late I shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late I may constitute a generalizable approach to stabilize ventricular repolarization and suppress arrhythmogenicity associated with conditions whereby AP or QT intervals are prolonged. NEW & NOTEWORTHY The contribution of physiological late Na current in action potential duration (APD) of rabbit cardiac myocytes was estimated. The inhibition of this current prevented the prolongation of APD in rabbit cardiac myocytes, the prolongation of monophasic APD, and generation of arrhythmias in rabbit isolated hearts caused by delayed rectifier K current inhibition.

β-adrenergic regulation of late Na+ current during cardiac action potential is mediated by both PKA and CaMKII

“…However, TTX-sensitive Na+ channels (Na v 1.1–1.4, Na v 1.6– 1.7) are less likely to contribute to I NaL here. This agrees with the reported IC 50 values of 1–2 ^M for TTX I NaL inhibition in rabbit [51], guinea-pig [33, 52] and human [1] ventricular myocytes, although TTX- sensitive Na+ channel isoforms have been reported to contribute to I NaL in heart failure [53]. Moreover, TTX-resistant Na v 1.8 channels have also been suggested to be expressed and contribute to I NaL in mouse, rabbit [54] and failing human [55] ventricular myocytes.…”

Is Selective Late Na+ Current Inhibition Different From Class I/B Antiarrhythmic Action? Comparison of The Effects of GS967 to Mexiletine in Canine Ventricular Myocardium

“…Similarly to our results, V + max was reduced by 0.3 µM GS967 in murine myocytes [49] , while the same concentration of the drug failed to modify V + max in canine Purkinje strands [50] . On the other hand, GS967 shortened APD in a variety of preparations, including rat [51,52] , murine [49] , rabbit [16,53] and human [54] ventricular cells within a wide concentration range (0.1-1 µM)similarly to the present observations in isolated canine ventricular cells. In our multicellular preparations, however, a signi cant APD shortening effect appeared only at cycle lengths longer than 1.5 s. This can be explained by the well-known higher drug-sensitivity of single cells comparing to multicellular preparations.…”

“…Taken together the present results and the literature, it is likely that a compound having kinetic properties similar to GS967 would be a very promising new antiarrhythmic agent, since several in vitro [16][17][18][19][49][50][51][52][53][54] and in vivo [51,55] studies support the potent antiarrhythmic activity of GS967. Its kinetic properties are better than those of mexiletine, as shown in this study, and also than those of ranolazine [9] , agents known to suppress I NaL .…”

Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart

“…To investigate a possible role for late INa in cardiac action potential, we measured the effect of the selective late INa inhibitor GS-967 49 , 51 . In current clamp recording of action potentials induced by current injection in isolated adult human ventricular cardiomyocytes, we found that the application of 0.1 µM GS-967 decreased the action potential duration and reduced the temporal variability in action potential duration at 90% repolarization (APD90) between consecutive beats, a biomarker for pro-arrhythmia 52 , quantified as short-term variability in APD90 (STV(APD90)) (Fig.…”