Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes

Background-Alterations in K+ channel expression and gating are thought to b e the major cause of action potential remodeling in heart failure (HF). We previously reported the existence of a late Na+ current (I-NaL) in cardiomy ocytes of dogs with chronic HF, which suggested the importance of the Na+ c hannel in this remodeling process. The present study examined whether this I-NaL exists in cardiomyocytes isolated from normal and failing human heart s. Methods and Results-A whole-cell patch-clamp technique was used to measure ion currents in cardiomyocytes isolated from the left ventricle of explante d hearts from 10 patients with end-stage HF and from 3 normal hearts. We fo und I-NaL was activated at a membrane potential of -60 mV with maximum dens ity (0.34+/-0.05 pA/pF) at -30 mV in cardiomyocytes of both normal and fail ing hearts. The steady-state availability was sigmoidal, with an averaged m idpoint potential of -94+/-2 mV and a slope factor of 6.9+/-0.1 mV, The cur rent was reversibly blocked by the Na+ channel blockers tetrodotoxin (IC50= 1.5 mu mol/L) and saxitoxin (IC50=98 nmol/L) in a dose-dependent manner. Bo th inactivation and reactivation of I-NaL had an ultraslow time course (tau approximate to 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 ina ctivation and reactivation.