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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 Ca 2+  concentration ([Ca 2+ ] 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 [Ca 2+ ] i  in canine ventricular cells, (2) this [Ca 2+ ] i -dependence of I NaL  is mediated by the Ca 2+ -dependent activation of CaMKII, and (3) I NaL  is augmented by the baseline CaMKII activity.

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