Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium
- 1 May 2001
- journal article
- Published by Elsevier BV in Journal of Molecular and Cellular Cardiology
- Vol. 33 (5), 923-932
- https://doi.org/10.1006/jmcc.2001.1355
Abstract
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 (I(NaL)) in ventricular cardiomyocytes (VC) isolated from both normal and failing human hearts. Both in failing human and canine VC, partial block of I(NaL)normalized 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 I(NaL)to be a new therapeutic target. The present study tested a hypothesis that I(naL)could 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. I(NaL)was effectively blocked by AMIO in therapeutic concentrations, with IC(50)being 6.7+/-1.1 microM (mean+/-S.E.M., n=16 cells). At the same time, AMIO (5 microM ) produced almost no effect on the transient Na(+)current (IC(50)=87+/-28 microM, n=8). AMIO significantly shifted the steady-state inactivation (SSI) curve of I(NaL)towards more negative potentials and accelerated decay time course in a dose-dependent manner. At 5 microM, 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).Keywords
This publication has 28 references indexed in Scilit:
- Sensitivity of the slow component of the delayed rectifier potassium current (IKs) to potassium channel blockers: Implications for clinical reverse use-dependent effectsJournal of Biomedical Science, 1999
- Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure.Circulation Research, 1993
- Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs.JCI Insight, 1992
- Kinetics of interaction of the lidocaine metabolite glycylxylidide with the cardiac sodium channel. Additive blockade with lidocaine.Circulation Research, 1992
- Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells.Circulation Research, 1991
- Events in the cardiac arrhythmia suppression trial (CAST): Mortality in the entire population enrolledJournal of the American College of Cardiology, 1991
- Block of single cardiac Na+ channels by antiarrhythmic drugs: The effect of amiodarone, propafenone and diprafenoneThe Journal of Membrane Biology, 1988
- Side effects and complications of amiodarone therapyAmerican Heart Journal, 1985
- Side effects and possible contraindications of amiodarone useAmerican Heart Journal, 1983
- Lidocaine block of cardiac sodium channels.The Journal of general physiology, 1983