Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model.
OBJECTIVE
We sought to study the role of I(KACh) in atrial fibrillation (AF) and the potential electrophysiologic effects of a specific I(KACh) antagonist.


BACKGROUND
I(KACh) mediates much of the cardiac responses to vagal stimulation. Vagal stimulation predisposes to AF, but the specific role of I(KACh) in the generation of AF and the electrophysiologic effects of specific I(KACh) blockade have not been studied.


METHODS
Adult wild-type (WT) and I(KACh)-deficient knockout (KO) mice were studied in the absence and presence of the muscarinic receptor agonist carbachol. The electrophysiologic features of KO mice were compared with those of WT mice to assess the potential effects of a specific I(KACh) antagonist.


RESULTS
Atrial fibrillation lasting for a mean of 5.7+/-11 min was initiated in 10 of 14 WT mice in the presence of carbachol, but not in the absence of carbachol. Atrial arrhythmia could not be induced in KO mice. Ventricular tachyarrhythmia could not be induced in either type of mouse. Sinus node recovery times after carbachol and sinus cycle lengths were shorter and ventricular effective refractory periods were greater in KO mice than in WT mice. There was no significant difference between KO and WT mice in AV node function.


CONCLUSIONS
Activation of I(KACh) predisposed to AF and lack of I(KACh) prevented AF. It is likely that I(KACh) plays a crucial role in the generation of AF in mice. Specific I(KACh) blockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.
Kovoor
P
P
Department of Cardiology, Westmead Hospital, Sydney, Australia.
Wickman
K
K
Maguire
C T
CT
Pu
W
W
Gehrmann
J
J
Berul
C I
CI
Clapham
D E
DE
D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015221:Potassium Channels / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying
D018679:Cholinergic Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D002217:Carbachol