Late Na⁺ Current Is [Ca²⁺]_i-Dependent in Canine Ventricular Myocytes

Enhancement of the late sodium current (I_NaL) increases arrhythmia propensity in the heart, whereas suppression of the current is antiarrhythmic. In the present study, we investigated I_NaL in canine ventricular cardiomyocytes under action potential voltage-clamp conditions using the selective Na⁺ channel inhibitors GS967 and tetrodotoxin. Both 1 µM GS967 and 10 µM tetrodotoxin dissected largely similar inward currents. The amplitude and integral of the GS967-sensitive current was significantly smaller after the reduction of intracellular Ca²⁺ concentration ([Ca²⁺]_i) either by superfusion of the cells with 1 µM nisoldipine or by intracellular application of 10 mM BAPTA. Inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII) by KN-93 or the autocamtide-2-related inhibitor peptide similarly reduced the amplitude and integral of I_NaL. Action potential duration was shortened in a reverse rate-dependent manner and the plateau potential was depressed by GS967. This GS967-induced depression of plateau was reduced by pretreatment of the cells with BAPTA-AM. We conclude that (1) I_NaL depends on the magnitude of [Ca²⁺]_i in canine ventricular cells, (2) this [Ca²⁺]_i-dependence of I_NaL is mediated by the Ca²⁺-dependent activation of CaMKII, and (3) I_NaL is augmented by the baseline CaMKII activity.