Selective inhibition of physiological late Na⁺ current stabilizes ventricular repolarization

The physiological role of cardiac late Na + current ( I Na ) has not been well described. In this study, we tested the hypothesis that selective inhibition of physiological late I Na 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 Kr ). The effects of GS-458967 (GS967) on the physiological late I Na 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 Na with IC 50 values of 0.5 and 1.9 µM, respectively, and significantly shortened the APD measured at 90% repolarization (APD 90 ). A strong correlation between inhibition of the physiological late I Na and shortening of APD by GS967 or tetrodotoxin ( R 2 of 0.96 and 0.97, respectively) was observed. Pretreatment of isolated myocytes or hearts with GS967 (1 µM) significantly shortened APD 90 and monophasic APD 90 and prevented the prolongation and associated arrhythmias caused by the I Kr inhibitor E4031 (1 µM). In conclusion, selective inhibition of physiological late I Na shortens the APD, stabilizes ventricular repolarization, and decreases the proarrhythmic potential of pharmacological agents that slow ventricular repolarization. Thus, selective inhibition of late I Na 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.