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: B Gout, A J Nichols, G Z Feuerstein, A Bril
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 26 Issue 4 Pg. 636-44 (Oct 1995) ISSN: 0160-2446 [Print] United States
• PMID: 8569227 (Publication Type: Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Benzamides
• Phenethylamines
• Sulfonamides
• BRL 32872
• Flecainide
• dofetilide

Topics

• Analysis of Variance
• Animals
• Anti-Arrhythmia Agents (administration & dosage, pharmacology, therapeutic use)
• Benzamides (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Flecainide (administration & dosage, pharmacology, therapeutic use)
• Injections, Intravenous
• Myocardial Ischemia (complications, drug therapy)
• Myocardial Reperfusion Injury (complications)
• Phenethylamines (administration & dosage, pharmacology, therapeutic use)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)
• Swine
• Swine, Miniature
• Ventricular Fibrillation (drug therapy, etiology)