Abstract
Effects of azimilide, a class III antiarrhythmic drug, on the acetylcholine (ACh) receptor-operated K+ current (IK.ACh) and the delayed rectifier K+ current (IK) were examined in guinea-pig atrial cells using patch-clamp techniques. Effects of azimilide on experimental atrial fibrillation (AF) were also examined in isolated guinea-pig hearts. In single atrial myocytes, azimilide inhibited both the rapid (IKr) and slow component of IK (IKs). Azimilide inhibited the IK.ACh induced by carbachol (CCh, 1 μM), adenosine (10 μM), and intracellular loading of GTPγS (100 μM) in a concentration-dependent manner. The IC50 values of azimilide for inhibiting the CCh-, adenosine-, and GTPγS-induced IK.ACh were 1.25, 29.1, and 20.9 μM, respectively, suggesting that azimilide inhibits IK.ACh mainly by blocking the muscarinic receptors. Azimilide concentration-dependently (0.3 – 10 μM) prolonged the action potential duration (APD) in the absence and presence of muscarinic stimulation. In isolated hearts, perfusion of CCh shortened the duration of the monophasic action potential (MAP) and effective refractory period (ERP) of the left atrium and lowered the atrial fibrillation threshold (AFT). Addition of azimilide inhibited the induction of AF by prolonging the duration of MAP and ERP. The IK.ACh inhibition by azimilide may at least in part contribute to the effectiveness to prevent parasympathetic-type AF.
