Depression of maximum rate of depolarization of guinea-pig ventricular action potentials by metabolites of encainide.

1. Standard microelectrode methods have been used to record action potentials from guinea-pig ventricular myocardium and dog Purkinje fibres, and to study the effects of the two major metabolites of encainide, O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). 2. In concentrations similar to those found in patients during chronic encainide therapy, neither ODE nor MODE produced significant depression of maximum rate of depolarization (Vmax) of action potentials in unstimulated tissue. Repetitive stimulation, however, was associated with depression of Vmax which increased with increasing driving rates (rate-dependent block, RDB). At the fastest rate studied (interstimulus interval = 300 ms) ODE 1 microM depressed Vmax by 47.5 +/- 5.7% and MODE 1 microM, reduced Vmax by 52.2 +/- 12%. 3. The onset and offset kinetics of this rate-dependent block were very slow. Full development of RDB during a train required over 100 action potentials and the time constants of recovery of Vmax from RDB were 86.4 +/- 37 s for ODE and 100.4 +/- 18 s for MODE. The amount of RDB and its rate of onset increased with drug concentration. The recovery time constants were independent of inter-stimulus interval or drug concentration. Both metabolites also produced rate-dependent depression of conduction velocity in canine Purkinje fibres, but no evidence of selective depression of conduction of interpolated premature potentials was seen. 4. Early afterdepolarizations occurred spontaneously in three preparations in the presence of MODE, 1 microM and one preparation in ODE, 1 microM. 5. It is concluded that these metabolites of encainide may play a role in producing both its antiarrhythmic and its proarrhythmic effects.