LATE SODIUM-CHANNEL OPENINGS UNDERLYING EPILEPTIFORM ACTIVITY ARE PREFERENTIALLY DIMINISHED BY THE ANTICONVULSANT PHENYTOIN

Late openings of sodium channels were observed in outside-out patch re cordings from hippocampal neurons in culture. In previous studies of s uch neurons, a persistent sodium current appeared to underlie the icta l epileptiform activity. All the channel currents were blocked by tetr odotoxin. In addition to the transient openings of sodium channels mak ing up the peak sodium current, there were two types of late channel o penings: brief late and burst openings. These late channel openings oc curred throughout voltage pulses that lasted 750 ms, producing a persi stent sodium current. At -30 mV, this current was 0.4% of the peak cur rent. The late channel openings occurred throughout the physiological range of trans-membrane voltages. The anticonvulsant phenytoin reduced the late channel openings more than the peak currents. The effect on the persistent current was greatest at more depolarized voltages, wher eas the effect on peak currents was not substantially voltage dependen t. In the presence of 60 mu M phenytoin, peak sodium currents at -30 m V were 40-41% of control, as calculated using different methods of ana lysis. Late currents were 22-24% of control. Phenytoin primarily decre ased the number of channel openings, with less effect on the duration of channel openings and no effect on open channel current. This set of findings is consistent with models in which phenytoin binds to the in activated state of the channel. The preferential effect of phenytoin o n the persistent sodium current suggests that an important pharmacolog ical mechanism for a sodium channel anticonvulsant is to reduce late o penings of sodium channels, rather than reducing all sodium channel op enings. We hypothesize that pharmacological interventions that are mos t selective in reducing late openings of sodium channels, while leavin g early channel openings relatively intact, will be those that produce an anticonvulsant effect while interfering minimally with normal func tion.