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

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Abstract
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 GTPγS (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 IC 50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 μmol/L, respectively. However, the GTPγS-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 .

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