Antifibrillatory Actions of Cisatracurium: An Atrial Specific M2 Receptor Antagonist

• Published in: Journal of cardiovascular electrophysiology 2008-08, Vol.19 (8), p.861-868
• Main Authors: PATTERSON, EUGENE, SCHERLAG, BENJAMIN J., ZHOU, JING, JACKMAN, WARREN M., LAZZARA, RALPH, COSCIA, DANIEL, PO, SUNNY
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - administration & dosage; arrhythmia; Atracurium - administration & dosage; Atracurium - analogs & derivatives; atrial fibrillation; Atrial Fibrillation - physiopathology; Atrial Fibrillation - prevention & control; cardiac electrophysiology; Dogs; Dose-Response Relationship, Drug; Heart Atria - drug effects; Heart Atria - physiopathology; Heart Rate - drug effects; Injections, Intravenous; Male; Neuromuscular Blocking Agents - administration & dosage; parasympathetic nervous system; pulmonary veins; Receptor, Muscarinic M2 - antagonists & inhibitors
• ISSN: 1045-3873; 1540-8167
• DOI: 10.1111/j.1540-8167.2008.01123.x

Introduction: Muscarinic receptor antagonists are proposed to prevent atrial fibrillation (AF), but also facilitate AV conduction, limiting clinical usefulness. Methods: Cisatracurium, a neuromuscular blocker, was administered to anesthetized dogs (0.05–0.8 mg/kg IV) and was administered to superfused pulmonary vein (PV) tissues in vitro. Results: Dose‐dependent suppression of AF induced by premature atrial stimuli was observed under control conditions (n = 3), right vagus nerve stimulation (n = 7), and anterior right ganglionated plexus stimulation (n = 3). AF was prevented (P < 0.0001) concurrent with suppression of the decreased atrial MAP duration/ERP accompanying vagus nerve stimulation without altering AH intervals or sinus cycle length. Although atropine (0.001–0.016 mg/kg, n = 4) suppressed AF (P < 0.04) in association with suppression of atrial MAP shortening induced by vagus nerve stimulation, atropine also prevented sinus cycle length and AH interval prolongation with vagus nerve stimulation, and decreased AV effective and functional refractory periods. In vitro, both cisatracurium and atropine prevented (1) action potential shortening produced by acetylcholine administration and (2) action potential shortening and arrhythmia triggering within PV sleeves produced by local autonomic nerve stimulation, atropine producing competitive inhibition, and cisatracurium producing noncompetitive M2 muscarinic receptor blockade. Conclusions: Cisatracurium demonstrates a dose‐dependent (1) suppression of AF and atrial action potential shortening accompanying vagus nerve stimulation without facilitating sinus or atrioventricular nodal function and (2) noncompetitive blockade of action potential shortening and triggered firing induced in isolated PVs by local autonomic nerve stimulation. The data are consistent with allosteric binding of cisatracurium to the M2 muscarinic receptor in canine atrium.