Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium

V. A. Maltsev, H. N. Sabbah and A. I. Undrovinas. Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium. Journal of Molecular and Cellular Cardiology (2001) 33, 923–932. The authors recently reported the existence of a novel late Na+current (INaL) in ventricular cardiomyocytes (VC) isolated from both normal and failing human hearts. Both in failing human and canine VC, partial block of INaLnormalized action potential (AP) duration and abolished early after depolarizations (EADs). The most recent computer simulation studies indicate a significant contribution of the persistent Na+current into the ion current balance on the plateau of VC AP as well as its important role in the dispersion of AP duration across the ventricular wall. The data thus indicate a possibility for INaLto be a new therapeutic target. The present study tested a hypothesis that InaLcould be a novel target for amiodarone (AMIO). Midmyocardial VC isolated from left ventricle of explanted failing human hearts were measured by a whole-cell clamp. INaLwas effectively blocked by AMIO in therapeutic concentrations, with IC50being 6.7±1.1 μ M(mean±S.E.M., n=16 cells). At the same time, AMIO (5 μ M) produced almost no effect on the transient Na+current (IC50=87±28 μ M, n=8). AMIO significantly shifted the steady-state inactivation (SSI) curve of INaLtowards more negative potentials and accelerated decay time course in a dose-dependent manner. At 5 μ M, AMIO shifted SSI by 21±3 mV (n=7) and decreased the decay time constant from 0.67±0.05 s to 0.37±0.04 s (n=5, P<0.004). Evaluation of AMIO binding to different Na+channel (NaCh) states by means of mathematical models describing dose-dependent SSI shift and decay acceleration was consistent with an action that AMIO blocks NaCh preferentially in inactivated and activated states rather than in resting state. The authors conclude that the late Na+current is effectively blocked by AMIO and represents a new target for the drug in patients with chronic heart failure (HF).