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 mu M GS967 and 10 mu M 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 mu M 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.

Automated summary

The study found that in canine ventricular cardiomyocytes, the late sodium current (I-NaL) depends on the magnitude of intracellular calcium concentration ([Ca2+]i) and this dependence is mediated by the Ca2+-dependent activation of CaMKII. Additionally, the augmentation of I-NaL is influenced by the baseline activity of CaMKII.