Late Sodium Current Is an Intrinsic Regulator of Cardiac Repolarization—A Quantitative Assessment

Abstract

Background Although enhancement of late Na + current (I NaL ) may cause prolongation of action potential duration (APD) in myocytes, the contribution of endogenous I NaL to APD is thought to be small. To test this assumption, we quantified the relationship between endogenous I NaL and APD using GS967, a novel and highly selective inhibitor of I NaL , and for comparison, the Na + channel blocker tetrodotoxin (TTX). Methods The amplitude of I NaL and the APD of guinea pig ventricular myocytes were measured at 36°C using the whole-cell patch-clamp technique. I NaL was activated by either a step or a ramp voltage-clamp pulse. Results The amplitude of I NaL and the APD at 50% repolarization in myocytes paced at 0.17 Hz were –30 ± 2 pA (n = 46) and 229 ± 6 ms (n = 43), respectively. GS967 (0.01–1 μmol/L) concentration-dependently reduced the amplitude of I NaL by 18 ± 3 to 82 ± 4% ( P 2 = 0.958) between the percent inhibition of INaL and the percent shortening of APD caused by either GS967 or TTX (Figure), indicating that endogenous INaL significantly contributes to APD. Conclusions The amplitude of endogenous INaL was linearly related to the duration of AP in ventricular myocytes, and the effect of inhibition of this current on APD was greater than expected. The effect of physiologic INaL on repolarization in the intact heart may be more important than is currently appreciated.