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(Circulation. 1995;91:2834-2843.)
© 1995 American Heart Association, Inc.

Articles

Anticholinergic Effects of Class III Antiarrhythmic Drugs in Guinea Pig Atrial Cells

Different Molecular Mechanisms

Katsumi Mori, MD; Yukio Hara, PhD; Toshihiro Saito, MD, PhD; Yoshiaki Masuda, MD, PhD; Haruaki Nakaya, MD, PhD

From the Department of Pharmacology and the Third Department of Internal Medicine, School of Medicine, Chiba University, Chiba, Japan.

Correspondence to Haruaki Nakaya, MD, PhD, Department of Pharmacology, School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260, Japan.

Background It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor–mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor–operated K⁺ current (I_K.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.

Methods and Results Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 µmol/L)–induced action potential shortening and outward K⁺ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 µmol/L), E-4031 (3 µmol/L), and MS-551 (30 µmol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, I_K.ACh was activated by extracellular application of carbachol (1 µmol/L) or adenosine (10 µmol/L) or by intracellular loading of GTPS (100 µmol/L). Sotalol (3 to 1000 µmol/L), E-4031 (1 to 100 µmol/L), and MS-551 (1 to 100 µmol/L) inhibited the carbachol-induced I_K.ACh in a concentration-dependent manner, and their IC₅₀ (half-maximal inhibition) values were 35.5, 7.8, and 11.4 µmol/L, respectively. However, the GTPS-induced and adenosine-induced I_K.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.

Conclusions Sotalol may inhibit I_K.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K⁺ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on I_K.ACh.

Key Words: potassium • antiarrhythmia agents • receptors, muscarinic • atrium

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