Background—:
The acetylcholine-activated K
+
current (
IK,ACh
) is a novel candidate for atrial-specific antiarrhythmic therapy. The present study investigates the involvement of
IK,ACh
in atrial fibrillation (AF) using NTC-801, a novel potent and selective
IK,ACh
blocker.
Methods and Results—:
The effects of NTC-801, substituted 4-(aralkylamino)-2,2-dimethyl-3,4-dihydro-
2H
-benzopyran-3-ol, on
IK,ACh
and other cardiac ionic currents (
INa
,
ICaL
,
Ito
,
IKur
,
IKr
,
IKs
,
IKl
,
IKATP
, and
If
) and on atrial and ventricular action potentials were examined in vitro. NTC-801 potently inhibited carbachol-induced
IK,ACh
in guinea pig atrial cells and the GIRK1/4 current in
Xenopus
oocytes with IC
50
values of 5.7 and 0.70 nmol/L, respectively. NTC-801 selectively inhibited
IK,ACh
>1000-fold over other cardiac ionic currents. NTC-801 (10 to 100 nmol/L) reversed the action potential duration (APD
90
) shortened by carbachol or adenosine in atrial cells, whereas it did not affect APD
90
at 100 nmol/L in ventricular cells. Antiarrhythmic effects of NTC-801 were evaluated in 3 AF models in vivo. NTC-801 significantly prolonged atrial effective refractory period without affecting ventricular effective refractory period under vagal nerve stimulation. NTC-801 dose-dependently converted AF to normal sinus rhythm in both vagal nerve stimulation–induced (0.3 to 3 μg · kg
−1
· min
−1
IV) and aconitine-induced (0.01 to 0.1 mg/kg IV) models. In a rapid atrial pacing model, NTC-801 (3 μg · kg
−1
· min
−1
IV) significantly decreased AF inducibility with a prolonged atrial effective refractory period that was frequency-independent.
Conclusions—:
A selective
IK,ACh
blockade induced by NTC-801 exerted anti-AF effects mediated by atrial-selective effective refractory period prolongation. These findings suggest that
IK,ACh
may be important in the development and maintenance of AF.