title: Electrophysiological effect of BRL-32872, a novel antiarrhythmic agent with potassium and calcium channel blocking properties, in guinea pig cardiac isolated preparations.
abstract: The effects of N-(3,4-dimethoxyphenyl)-N-[3[[2-(3,4-dimethoxyphenyl) ethyl] propyl]-4-nitrobenzamide hydrochloride (BRL-32872), a novel antiarrhythmic agent, were studied in guinea pig cardiac preparations using standard microelectrode and patch-clamp techniques. In papillary muscle, BRL-32872 did not change resting membrane potential and maximum rate of depolarization but prolonged action potential duration (APD) by 24% +/- 2% at 1.0 microM. When the concentration was increased to 3.0 and 10.0 microM, the effect on APD was not further enhanced, and a bell-shaped dose-response curve resulted. Patch-clamp experiments in isolated myocytes showed that BRL-32872 inhibited the rapidly activating component of the delayed rectifier potassium current (EC50 = 0.028 microM) and the L-type calcium current (EC50 = 2.8 microM) but had a limited effect on the inward rectifier potassium current. In papillary muscles stimulated at 300, 500, 1000 and 2000 msec, the effect of BRL-32872 in prolonging APD did not vary (P = .717). By contrast, N-(4-(1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl)- carbonyl]phenyl)methanesulfonamide dihydrochloride dihydrate (E-4031), a pure class III antiarrhythmic agent, increased APD more at slower than at faster stimulation rates (P = .001), which illustrated the reverse frequency-dependence of this agent. Among the 35 experiments performed with BRL-32872, only one fiber showed early afterdepolarizations (EADs), and these, which occurred at 1.0 microM, were suppressed at higher concentration (3.0 microM). Moreover, EADs induced by E-4031 were suppressed by BRL-32872 (3.0 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: SmithKline Beecham Laboratories Pharmaceutiques, Saint-Grégoire, France.
authors.forename: A
authors.initials: A
authors.lastname: Bril
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: Cheval
authors.forename: B
authors.initials: B
authors.lastname: Gout
authors.forename: P
authors.initials: P
authors.lastname: Linée
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
authors.forename: R H
authors.initials: RH
authors.lastname: Poyser
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008839:Microelectrodes; D026902:Potassium Channel Blockers
chemical_list: D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D002121:Calcium Channel Blockers; D026902:Potassium Channel Blockers; C094198:BRL 32872