Copyright © 2001 by the European Society of Cardiology.
Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts
a Experimental and Molecular Cardiology Group, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, the Netherlands
b Department of Physiology, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, the Netherlands
c Department of Cardiac Transplantation, University Medical Center Utrecht, the Netherlands
d Department of Medical Physiology, University Medical Center Utrecht, the Netherlands
e Interuniversity Cardiovascular Institute, the Netherlands
revised October 10, 2000; accepted October 11, 2000
Abstract
Aims Congestive heart failure is characterized by high levels of norepinephrine which is considered to be arrhythmogenic. It is unclear whether increased norepinephrine is only a marker of the severity of heart failure or whether it directly triggers ventricular arrhythmias.
Methods and Results Ventricular myocytes were isolated from eight explanted hearts of patients with end-stage heart failure (ischaemic or dilated cardiomyopathy). With the whole-cell configuration of the patch–clamp technique the effect of 1µmol.l–1norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256±25pF (n=26) and action potential duration (APD90) during control conditions was 620±45ms at 1Hz (n=14). Norepinephrine induced action potential prolongation in all cells and early afterdepolarizations in 50% of them. Norepinephrine significantly increased the calcium current but had no effect on the delayed rectifier current, the inward rectifier current or the transient outward current. Norepinephrine also significantly increased the steady-state calcium window-current measured between –40 and 0mV.
Conclusions In contrast to many animal species, norepinephrine induces action potential prolongation in ventricular myocytes from human failing hearts, as well as early afterdepolarization, by an increase in both the calcium peak current and window current. Thus norepinephrine seems to be an important arrhythmogenic factor in congestive heart failure.
Key Words: Heart failure, norepinephrine, myocytes, arrhythmias, action potential duration
f1 Correspondence: Tobias Opthof, Department of Medical Physiology, University Medical Center Utrecht, PO Box 85060, 3508 AB Utrecht, The Netherlands.
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