Molecular Bases of the Acute Coronary Syndromes

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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 In 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-KACh), 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 mu mol/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 mu mol/L), E-4031 (3 mu mol/L), and MS-551 (30 mu mol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, I-KACh was activated by extracellular application of carbachol (1 mu mol/L) or adenosine (10 mu mol/L) or by intracellular loading of GTP gamma S (100 mu mol/L). Sotalol (3 to 1000 mu mol/L), E-4031 (1 to 100 mu mol/L), and MS-551 (1 to 100 mu mol/L) inhibited the carbachol-induced I-KACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8; and 11.4 mu mol/L, respectively. However, the GTP gamma S-induced and adenosine-induced I-KACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol. Conclusions Sotalol may inhibit I-KACh 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-KACh.

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Muscle, Smooth, Vascular Coronary Vessels Extracellular Matrix Humans Angina, Unstable Myocardial Infarction Collagen Metalloendopeptidases Glycoproteins Proteins