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 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.