Late sodium current is a novel target for amiodarone: Studies in failing human myocardium

The authors recently reported the existence of a novel late Na+ current (I- Nal) in ventricular cardiomyocytes (VC) isolated from both normal and faili ng human hearts. Both in failing human and canine VC, partial block of I-Na l normalized action potential (AP) duration and abolished early after depol arizations (EADs). The most recent computer simulation studies indicate a s ignificant contribution of the persistent Na+ current into the ion current balance on the plateau of VC Ar as well as its important rt,le in the dispe rsion of Ar duration across the ventricular wall. The data thus indicate a possibility for I-Nal to be a new therapeutic target. The present study tes ted a hypothesis that I-Nal could be a novel target fur amiodarone (AR;IIO) . Midmyocardial VC isolated from left ventricle of explanted failing human hearts were measured by a whole-cell clamp. I-Nal was effectively blocked b y AMIO in therapeutic concentrations. with IC50 being 6.7 +/- 1.1 muM (mean +/- S.E.M., n = 16 cells). At the same time. AMIO (5 muM) produced almost no effect on the transient Na+ current (IC50 = 87 +/- 28 muM, n = 8). AMIO significantly. shifted the steady-state inactivation (SSI) curl e of I-Nal towards more negative potentials and accelerated decay time course in a dos e-dependent manner. At 5 muM AMIO shifted SSI by 21 +/- 3 mV (n = 7) and de creased 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) stales by means of mathematical models describing dose-dependent SSI shift and decay acceleration was consistent with all 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 blocke d by AMIO and represents a new target for the drug in patients with chronic heart failure (HF). (C) 2001 Academic Press.