Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity.
OBJECTIVE
The K(+) channel encoded by the human ether-a-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (I(Kr)) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart.


RESULTS
ECG recordings at baseline showed no obvious difference between transgenic and wild-type (WT) mice with the exception of the T wave, which was more negative in transgenic mice than in WT mice. E4031 (20 mg/kg) prolonged the QTc interval and flattened the T wave in transgenic mice, but not in WT mice. Injection of BaCl(2) (25 mg/kg) induced short runs of ventricular tachycardia in 9/10 WT mice, but not in transgenic animals. Atrial pacing reproducibly induced atrial tachyarrhythmias in 11/15 WT mice. In contrast, atrial arrhythmia was inducible in only 2/11 transgenic mice. When pretreated with dofetilide (10 mg/kg), transgenic mice were as sensitive to experimental arrhythmias as WT mice. Microelectrode studies showed that atrial action potentials have a steeper slope of duration-rate adaptation in WT than in transgenic mice. Transgenic mice were also characterized by a post-repolarization refractoriness, which could result from the substantial amount of I(Kr) subsisting after repolarization as assessed with action potential-clamp experiments and simulations with a model of the transgenic mouse action potential.


CONCLUSIONS
HERG expression in the mouse heart can protect against experimental induction of arrhythmias. This is the first report of such a protective effect of HERG in vivo.
Royer
Anne
A
INSERM U533, Institut du Thorax, Faculté de Médecine, 1 rue G. Veil, 44035 Nantes cedex, France.
Demolombe
Sophie
S
El Harchi
Aziza
A
Le Quang
Khaï
K
Piron
Julien
J
Toumaniantz
Gilles
G
Mazurais
David
D
Bellocq
Chloé
C
Lande
Gilles
G
Terrenoire
Cécile
C
Motoike
Howard K
HK
Chevallier
Jean-Christophe
JC
Loussouarn
Gildas
G
Clancy
Colleen E
CE
Escande
Denis
D
Charpentier
Flavien
F
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D015153:Blotting, Western / Q000379:methods; D002304:Cardiac Pacing, Artificial; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D003198:Computer Simulation; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D005818:Genetic Engineering; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008839:Microelectrodes; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010880:Piperidines; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; C063968:E 4031