(Circulation. 1998;98:2545-2552.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Novel, Ultraslow Inactivating Sodium Current in Human Ventricular Cardiomyocytes
From the Department of Medicine, Division of Cardiovascular Medicine (V.A.M., H.N.S., M.L., A.I.U.) and Department of Surgery, Division of Cardiac and Thoracic Surgery (R.S.D.H., N.S.), Henry Ford Heart and Vascular Institute, Detroit, Mich.
Correspondence to Albertas I. Undrovinas, PhD, Henry Ford Hospital, Cardiovascular Research, 2799 W Grand Blvd, Detroit, MI 48202-2689.
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 (INaL) 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 INaL 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 INaL 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
(IC50=1.5 µmol/L) and saxitoxin (IC50=98
nmol/L) in a dose-dependent manner. Both inactivation and reactivation
of INaL had an ultraslow time course (
0.6 seconds)
and were independent of voltage. The amplitude of INaL was
independent of the peak transient Na+ current.
Conclusions—Cardiomyocytes isolated from normal and explanted failing human hearts express INaL characterized by an ultraslow voltage-independent inactivation and reactivation.
Key Words: heart failure • myocytes • action potentials • saxitoxin • tetrodotoxin
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