Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts.
OBJECTIVE
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.


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 1 micromol x l(-1)norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256 +/- 25 pF (n = 26) and action potential duration (APD90) during control conditions was 620 +/- 45 ms at 1 Hz (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 0 mV.


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.
Veldkamp
M W
MW
Experimental and Molecular Cardiology Group, Cardiovascular Research Institute Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.
Verkerk
A O
AO
van Ginneken
A C
AC
Baartscheer
A
A
Schumacher
C
C
de Jonge
N
N
de Bakker
J M
JM
Opthof
T
T
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects; D003692:Delayed-Action Preparations; D006333:Heart Failure / Q000097:blood*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D009206:Myocardium / Q000166:cytology*; D009638:Norepinephrine
D000316:Adrenergic alpha-Agonists; D015220:Calcium Channels; D003692:Delayed-Action Preparations; D007473:Ion Channels; D009638:Norepinephrine