title: Electrophysiological characterization of BRL-32872 in canine Purkinje fiber and ventricular muscle. Effect on early after-depolarizations and repolarization dispersion.
abstract: Amongst the different pharmacological approaches to the treatment of cardiac arrhythmias, compounds with multiple electrophysiological activities appear to exhibit a reduced adverse effect profile. BRL-32872 (N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride) is a typical example of an antiarrhythmic agent with combined K(+) and Ca(2+) blocking actions. In this study, we investigated the effects of BRL-32872 on early after-depolarizations and on dispersion of repolarization. Action potentials were recorded either in canine cardiac Purkinje fibers alone or in preparations containing both ventricular muscle and the attached Purkinje fibers. In Purkinje fibers, BRL-32872 (0. 3-10 microM) induced a bell-shaped concentration-dependent increase in action potential duration. At 90% of repolarization, the action potential was prolonged at concentrations up to 1 microM and was shortened when the concentration of BRL-32872 was further increased. In all 17 experiments, BRL-32872 did not cause early after-depolarizations in Purkinje fibers. On the contrary, BRL-32872 (3 microM) systematically suppressed early after-depolarizations induced by clofilium (4-chloro-N, N-diethyl-N-heptylbenzenebutanaminium tosylate, 1 microM), a selective inhibitor of the delayed rectifier K(+) current. A similar effect was observed once with 1 microM BRL-32872, a concentration able to prolong Purkinje fiber action potentials. Simultaneous recording of action potentials in ventricular and Purkinje preparations showed that increasing concentrations of BRL-32872 (0. 3-10 microM) induced a limited increase in the difference of repolarization time between the two tissues. The selective K(+) channel inhibitor E-4031 (N-(4-(1-[2-(6-methyl-2-pyridyl) ethyl]-4-piperidyl)-carbonyl] phenyl) methanesulfonamide dihydrochloride dihydrate) exhibited a significant concentration-dependent increase in dispersion of repolarization. We conclude from the present results that the Ca(2+) blocking activity of BRL-32872 (i) prevents the occurrence of early after-depolarizations associated with action potential prolongation and (ii) limits an excessive increase in action potential duration heterogeneity. These electrophysiological features might represent the basis for antiarrhythmic compounds with reduced proarrhythmic profile.
authors.affiliation: SmithKline Beecham Laboratoires Pharmaceutiques, 4 rue du Chesnay Beauregard, BP 58, 35760, Saint-Grégoire, France. jean_francois_faivre@sbphrd.com
authors.forename: J F
authors.initials: JF
authors.lastname: Faivre
authors.forename: M C
authors.initials: MC
authors.lastname: Forest
authors.forename: B
authors.initials: B
authors.lastname: Gout
authors.forename: A
authors.initials: A
authors.lastname: Bril
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D006352:Heart Ventricles / Q000187:drug effects / Q000294:innervation; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011690:Purkinje Fibers / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; C094198:BRL 32872; C063968:E 4031; C022799:clofilium