In vivo and in vitro antiarrhythmic effects of SSR149744C in animal models of atrial fibrillation and ventricular arrhythmias.
SSR149744C (2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate isopropyl fumarate) is a new noniodinated benzofuran derivative structurally related to amiodarone and dronedarone that is currently undergoing clinical trials as an antiarrhythmic agent. As SSR149744C exhibits electrophysiological and hemodynamic properties of class I, II, III, and IV antiarrhythmic agents, the aim of this study was to evaluate its acute intravenous (IV) or oral (PO) antiarrhythmic activities in in vitro and in vivo animal models of atrial and ventricular arrhythmias. In vagally induced atrial fibrillation (AF) in anesthetized dogs, SSR149744C (3 and 10 mg/kg IV) terminated AF in all 7 dogs and prevented reinduction in 4 out of 7 dogs; effective refractory periods of right atrium were dose-dependently and frequency-independently lengthened. In low-K+ medium-induced AF models, SSR149744C (0.1 to 1 microM) prevented AF in isolated guinea pig hearts in a concentration-dependent manner. At the ventricular level, SSR149744C (0.1 to 10 mg/kg IV and 3 to 90 mg/kg PO) prevented reperfusion-induced arrhythmias in anesthetized rats with a dose-effect relationship, and, at doses of 30 to 90 mg/kg PO, it reduced early (0-24 hours) mortality following permanent left coronary artery ligature in conscious rats. The present results show that SSR149744C is an effective antiarrhythmic agent in atrial fibrillation and in ventricular arrhythmias. Like amiodarone and dronedarone, its efficiency in these animal models of arrhythmias is likely be related to its multifactorial mechanism of action.
Gautier
Patrick
P
Cardiovascular-Thrombosis Department, Sanofi-Synthelabo Recherche, Montpellier, France. patrick.gautier@sanofi-aventis.com
Serre
Martine
M
Cosnier-Pucheu
Sylvie
S
Djandjighian
Laurent
L
Roccon
Alain
A
Herbert
Jean-Marc
JM
Nisato
Dino
D
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology*; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D011188:Potassium / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014630:Vagus Nerve / Q000502:physiology; D018754:Ventricular Dysfunction / Q000188:drug therapy* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; C499879:celivarone; D011188:Potassium