title: Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: experimental profile of BRL-32872.
abstract: In the search for novel antiarrhythmic agents, compounds with a diversity of electrophysiological actions have been suggested to result in treatments with potentially improved efficacy but with reduced proarrhythmic risk. To test this hypothesis, the antiarrhythmic versus proarrhythmic profile of BRL-32872, a novel agent with combined potassium and calcium channel blocking activity, was assessed in two different in vivo models of ventricular arrhythmia. Furthermore, the effects of potassium and calcium channel antagonists given either alone or in combination were assessed in the same models. Dogs with myocardial infarction received intravenously either vehicle, BRL-32872, the class III antiarrhythmic agent, E-4031, verapamil or a combination of E-4031 with verapamil (n = 8 per group). Ventricular tachyarrhythmias were induced by programmed electrical stimulation (PES). BRL-32872 (0.1, 0.3, 1.0 mg/kg) significantly increased QTc interval (from 387 +/- 10 to 462 +/- 19 msec.sec-1/2 at 1.0 mg/kg, P < .01). Ventricular effective refractory periods were increased in normal and infarcted areas (P < .01). Similar effects were observed with E-4031 (0.1, 0.3, 1.0 mg/kg). Verapamil (0.03, 0.1, 0.3 mg/kg) reduced heart rate, mean arterial pressure and, to a lesser extent, (+)dP/dtmax. Verapamil did not change QTc interval and ventricular effective refractory periods, but increased PR interval (P < .001). PES-induced tachyarrhythmias were not changed by vehicle or increasing doses of verapamil. E-4031 reduced the severity of arrhythmias from sustained ventricular tachycardia (VT) to nonsustained VT (7 dogs at 1.0 mg/kg, P = .013 vs. vehicle). BRL-32872 (0.1 and 0.3 mg/kg) suppressed the induction of sustained VT in six dogs (P = .02 vs. vehicle). In the presence of BRL-32872, 1.0 mg/kg, five dogs became noninducible to PES (P = .013 vs. vehicle). Combination of E-4031 (0.1 mg/kg) with verapamil provided a degree of protection that was similar to that observed with BRL-32872. In a second model, the proarrhythmic potential of BRL-32872 was assessed in anesthetized rabbits sensitized to develop torsades de pointes (TdP). BRL-32872 was compared with the class III antiarrhythmic agents, E-4031, dofetilide, clofilium and RP-58866. The pure class III antiarrhythmic agents induced TdP in 50 to 90% of the rabbits, and prolonged QT interval by 20 to 50%. BRL-32872 (10 micrograms/kg/min) increased QT interval by 35 +/- 5%, but did not promote TdP. In additional experiments, verapamil reduced the incidence of TdP induced by E-4031. These results show that BRL-32872 is a potent antiarrhythmic compound in a model of PES-induced arrhythmias and induces fewer proarrhythmic events than typical class III antiarrhythmic agents. The effects observed with BRL-32872 suggest that a compound with a combination of potassium (class III) and calcium (class IV) channel antagonistic properties might constitute a novel antiarrhythmic agent with reduced proarrhythmic risk.
authors.affiliation: SmithKline Beecham Laboratories Pharmaceutiques, Saint-Grégoire, France.
authors.forename: A
authors.initials: A
authors.lastname: Bril
authors.forename: B
authors.initials: B
authors.lastname: Gout
authors.forename: M
authors.initials: M
authors.lastname: Bonhomme
authors.forename: L
authors.initials: L
authors.lastname: Landais
authors.forename: J F
authors.initials: JF
authors.lastname: Faivre
authors.forename: P
authors.initials: P
authors.lastname: Linee
authors.forename: R H
authors.initials: RH
authors.lastname: Poyser
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004285:Dogs; D004558:Electric Stimulation; D004569:Electroencephalography; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology; D026902:Potassium Channel Blockers; D011817:Rabbits; D016171:Torsades de Pointes / Q000188:drug therapy
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; C094198:BRL 32872