Abstract 506: Non-Competitive Inhibition of M2 (Muscarinic) Receptors in Atrial Myocardium - A New Antiarrhythmic Mechanism
Cisatracurium (CA) and mivacurium (MIV), competitive inhibitors of acetylcholine (Ach) at the neuromuscular junction, were evaluated as atrial antiarrhythmic agents and compared to the competitive muscarinic antagonist, atropine (ATR). CA (0.05– 0.8 mg/Kg)(N=13), MIV (0.05–0.8 mg/Kg)(N=10), and ATR (0.001– 0.016 mg/Kg)(N=6) produced dose-dependent suppression of atrial fibrillation (AF) induced in anesthetized dogs by premature atrial stimuli under control conditions and during right vagus nerve stimulation. At dosages completely suppressing AF induction (CA, MIV=0.8 mg/Kg; ATR=0.008 mg/Kg), CA and MIV acted as inverse agonists, prolonging the atrial monophasic action potential at 90% of repolarization (MAP90). Sinus cycle length (SCL), AH interval, and AH functional refractory period were prolonged. CA and MIV prevented only vagal-induced MAP90 shortening, and did not alter vagal-induced SCL and AH prolongation. Although ATR prevented AF, ATR shortened SCL, AH interval, and AH functional refractory period under control conditions while preventing vagal-induced shortening of SCL, AH interval, and MAP90. In superfused canine pulmonary veins, CA produced non-competitive blockade of action potential shortening by Ach and suppressed triggered firing induced by local autonomic nerve stimulation. ATR suppressed triggered firing and action potential shortening by Ach in the same in vitro preparation via competitive blockade. The data demonstrate selective non-competitive blockade of Ach at atrial myocardial M2 receptors by CA and MIV without blocking M2 receptors in SA and AV nodes. CA and MIV may bind to an allosteric site on the M2 receptor, acting as an inverse agonist under control conditions and a non-competitive antagonist during vagus nerve stimulation, preventing triggered firing and reentrant AF without facilitating AV conduction or producing sinus tachycardia. CA and MIV may represent a new class of atrial-specific antiarrhythmic agents.