Electrophysiological effects of AN-132, a new antiarrhythmic compound, in guinea pig papillary muscles

We used electrophysiological techniques to examine the effects of AN-132, a new antiarrhythmic agent, on transmembrane action potentials of isolated papillary muscles of guinea pigs. AN-132 (1-90 microM) produced a dose-dependent decrease in the maximum upstroke velocity of the action potential (Vmax). The resting potential and the amplitude, overshoot, and the duration of the action potential were not affected, even at the highest concentration of the drug used (90 microM). In the presence of AN-132, trains of stimuli at a rate of 0.5, 1, 2, and 4 Hz led to an exponential decline in the Vmax, reaching a new steady state (use-dependent block, UDB). The UDB was augmented by higher stimulation frequencies or lower membrane potentials. In the presence of the drug (60 microM), the time constant and the rate of onset of UDB of Vmax were 13.4-4.5 s and 0.141-0.053 AP-1 at stimulation frequencies of 0.5-4.0 Hz, respectively. The time constant for the recovery of Vmax from the UDB was 81.2 +/- 17.2 s. AN-132 (60 microM) only slightly depressed the Vmax of the first action potential elicited after an 8-min quiescent period (tonic block, TB). In papillary muscles depolarized with 8.4 and 10.4 mM [K+]0, both UDB and TB were augmented, but the augmentation was greater with the former. None of the parameters of the slow response elicited in the presence of 27 mM [K+]0 and 0.2 mM Ba2+ were affected by the drug (30-90 microM).(ABSTRACT TRUNCATED AT 250 WORDS)