Inhibitory effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial cells.
It is well known that amiodarone is effective for the treatment of atrial fibrillation. However, effects of amiodarone on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which plays an important role in the repolarization of atrial action potential, have not been evaluated. This study was undertaken to determine whether amiodarone inhibits the acetyl-choline-sensitive muscarinic K+ (KACh) channel by use of the patch-clamp technique. In isolated guinea pig atrial cells, IK.ACh was activated by extracellular application of carbachol (1 microM) or adenosine (10 microM) or by the intracellular loading of GTP gamma S (100 microM). Amiodarone inhibited the IK.ACh activated in these three different ways with similar IC50 values around 2 microM, which indicated that amiodarone directly depresses the function of the KACh channel itself and/or GTP-binding proteins. Single KACh channel current was also recorded by use of a pipette solution containing carbachol (1 microM) or atropine (10 microM) plus theophylline (100 microM) in a cell-attached configuration. Amiodarone at a concentration of 3 microM significantly decreased the open probability of the KACh channel in both conditions. Amiodarone also reversed the carbachol- and adenosine-induced action potential shortening in a concentration-dependent manner. In isolated guinea pig hearts, perfusion of 1 microM carbachol shortened the effective refractory period of the atria and lowered the atrial fibrillation threshold. Addition of 10 microM amiodarone reversed these electrophysiological parameters to the control level. These results suggest that amiodarone inhibits IK.ACh by depressing the function of the KACh channel itself and/or associated GTP-binding proteins. This effect of amiodarone may at least in part be involved in the antiarrhythmic action against atrial fibrillation.
Watanabe
Y
Y
Department of Pharmacology, Chiba University School of Medicine, Japan.
Hara
Y
Y
Tamagawa
M
M
Nakaya
H
H
D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers; D011976:Receptors, Muscarinic / Q000187:drug effects*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D011976:Receptors, Muscarinic; D002217:Carbachol; D000638:Amiodarone