Y. Watanabe et al., INHIBITORY EFFECT OF AMIODARONE ON THE MUSCARINIC ACETYLCHOLINE RECEPTOR-OPERATED POTASSIUM CURRENT IN GUINEA-PIG ATRIAL CELLS, The Journal of pharmacology and experimental therapeutics, 279(2), 1996, pp. 617-624
It is well known that amiodarone is effective for the treatment of atr
ial fibrillation. However, effects of amiodarone on the muscarinic ace
tylcholine receptor-operated K+ current (I-K.ACh), which plays an impo
rtant role in the repolarization of atrial action potential, have not
been evaluated. This study was undertaken to determine whether amiodar
one inhibits the acetylcholine-sensitive muscarinic K+ (K-ACh) channel
by use of the patch-clamp technique. In isolated guinea pig atrial ce
lls, I-K.ACh was activated by extracellular application of carbachol (
1 mu M) or adenosine (10 mu M) or by the intracellular loading of GTP
gamma S (100 mu M). Amiodarone inhibited the I-K.ACh activated in thes
e three different ways with similar IC50 values around 2 mu M, which i
ndicated that amiodarone directly depresses the function of the K-ACh
channel itself and/or GTP-binding proteins. Single K-ACh channel curre
nt was also recorded by use of a pipette solution containing carbachol
(1 mu M) or atropine (10 mu M) plus theophylline (100 mu M) in a cell
-attached configuration. Amiodarone at a concentration of 3 mu M signi
ficantly decreased the open probability of the K-ACh channel in both c
onditions. Amiodarone also reversed the carbachol- and adenosine-induc
ed action potential shortening in a concentration-dependent manner, In
isolated guinea pig hearts, perfusion of 1 mu M carbachol shortened t
he effective refractory period of the atria and lowered the atrial fib
rillation threshold. Addition of 10 mu M amiodarone reversed these ele
ctrophysiological parameters to the control level. These results sugge
st that amiodarone inhibits I-K.ACh by depressing the function of the
K-ACh channel itself and/or associated GTP-binding proteins. This effe
ct of amiodarone may at least in part be involved in the antiarrhythmi
c action against atrial fibrillation.