Novel, Ultraslow Inactivating Sodium Current in Human Ventricular Cardiomyocytes

Abstract

Background —Alterations in K + channel expression and gating are thought to be the major cause of action potential remodeling in heart failure (HF). We previously reported the existence of a late Na + current (I NaL ) in cardiomyocytes of dogs with chronic HF, which suggested the importance of the Na + channel in this remodeling process. The present study examined whether this I NaL exists in cardiomyocytes isolated from normal and failing human hearts. Methods and Results —A whole-cell patch-clamp technique was used to measure ion currents in cardiomyocytes isolated from the left ventricle of explanted hearts from 10 patients with end-stage HF and from 3 normal hearts. We found I NaL was activated at a membrane potential of −60 mV with maximum density (0.34±0.05 pA/pF) at −30 mV in cardiomyocytes of both normal and failing hearts. The steady-state availability was sigmoidal, with an averaged midpoint potential of −94±2 mV and a slope factor of 6.9±0.1 mV. The current was reversibly blocked by the Na + channel blockers tetrodotoxin (IC 50 =1.5 μmol/L) and saxitoxin (IC 50 =98 nmol/L) in a dose-dependent manner. Both inactivation and reactivation of I NaL had an ultraslow time course (τ≈0.6 seconds) and were independent of voltage. The amplitude of I NaL was independent of the peak transient Na + current. Conclusions —Cardiomyocytes isolated from normal and explanted failing human hearts express I NaL characterized by an ultraslow voltage-independent inactivation and reactivation.