title: Antifibrillatory effects of BRL-32872 in anesthetized Yucatan minipigs with regional myocardial ischemia.
abstract: The antifibrillatory potential of BRL-32872, a novel antiarrhythmic compound with K+ and Ca2+ channel blocking activities, was examined in a minipig model of ischemia-induced arrhythmia. The effects of intravenous (i.v.) BRL-32872 (0.3 and 1.0 mg/kg, n = 8), dofetilide (0.3 mg/kg, n = 8), and flecainide (2.0 mg/kg, n = 8), were investigated on the incidence of ventricular fibrillation (VF) during a 20-min occlusion of the left anterior descending coronary artery (LAD). Ischemia-induced VF occurred in 6 of 9 vehicle-treated pigs. BRL-32872 reduced the incidence of ischemic VF to 13% at 0.3 mg/kg (p < 0.05) and to 0% at 1.0 mg/kg (p < 0.01). Dofetilide also prevented the occurrence of VF (0%, p < 0.01) In contrast, flecainide did not reduce the incidence of VF (63%). Indeed, flecainide shortened the time to onset of VF from 17 +/- 1 min in the vehicle group to 10 +/- 1 min (p < 0.001). The antifibrillatory effects of BRL-32872 and dofetilide were associated with a prolongation of QT interval on ECG. Flecainide did not prolong repolarization, but slowed the ventricular conduction velocity, as shown by significant increases in PR and QRS intervals. During early reperfusion, 1 of 8 surviving pigs in each group treated with BRL-32872 and 4 of 8 in the dofetilide group developed VF. This study demonstrated an antifibrillatory effect of BRL-32872 associated with prolonged ventricular repolarization and showed enhanced efficacy over dofetilide on reperfusion arrhythmias which is most likely a consequence of its Ca2+ blocking activity.
authors.affiliation: SmithKline Beecham Laboratoires Pharmaceutiques, Unité de Recherche, Saint-Grégoire, France.
authors.forename: B
authors.initials: B
authors.lastname: Gout
authors.forename: A J
authors.initials: AJ
authors.lastname: Nichols
authors.forename: G Z
authors.initials: GZ
authors.lastname: Feuerstein
authors.forename: A
authors.initials: A
authors.lastname: Bril
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005424:Flecainide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007275:Injections, Intravenous; D017202:Myocardial Ischemia / Q000150:complications* / Q000188:drug therapy; D015428:Myocardial Reperfusion Injury / Q000150:complications; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D013556:Swine, Miniature; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000209:etiology
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D010627:Phenethylamines; D013449:Sulfonamides; C094198:BRL 32872; D005424:Flecainide; C063533:dofetilide