Effects of AFD-21, a new class I antiarrhythmic agent, and AFD-19, its active metabolite, on the maximal rate of rise of action potentials in guinea pig papillary muscles: dependence on time, voltage, and action potential duration.

Effects of AFD-21 and AFD-19 (a new class I antiarrhythmic agent and its active metabolite, respectively) on the maximal rate of rise (Vmax) of action potentials (APs) were studied in guinea pig papillary muscles with special reference to their time, voltage, and action potential duration (APD) dependence. Both AFD-21 and AFD-19 (2-10 microM) reduced Vmax in a concentration-dependent manner without affecting the resting potential, APD, and effective refractory period. Both agents (5 microM) shifted the normalized Vmax resting potential curve (examined at 1 Hz) in the hyperpolarizing direction by 4-7 mV (voltage dependence). In addition, both agents (5 microM): a) caused a frequency-dependent reduction of Vmax at 0.25-3 Hz; b) developed a use-dependent (1 Hz) reduction of Vmax with an onset time constant of 1-3 s; and c) slowed the recovery process of Vmax, whose resultant recovery time constant was 2-3 s (time dependence). Nicorandil (1 mM), which shortens APD to about 25% of control, antagonized the AFD-21-induced time-dependent reductions of Vmax but not the AFD-19-induced reductions (APD dependence). These results suggest that the effects of AFD-21 on Vmax are APD dependent but those of AFD-19 are not, and thereby that AFD-21 and AFD-19 preferentially block inactivated and open sodium channels, respectively. The present findings are discussed from the viewpoint of the modulated or the guarded receptor hypothesis.