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)