Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells

Abstract

The actions of diphenylhydantoin (DPH) and carbamazepine (CBZ) on sodium channels in mouse neuroblastoma cells (clone N18) were analyzed using the patch voltage clamp procedure in the whole cell configuration. DPH and CBZ reduced sodium currents without effect on the voltage dependence of sodium channel activation. Half-maximal inhibition was observed with approximately 30 microM of each drug. Depolarization increased and hyperpolarization reversed channel block by these two drugs in the voltage range from -90 to -45 mV. Repetitive stimulation at 2 Hz or greater enhanced inhibition of sodium channels. The half-time for recovery from voltage-dependent inhibition was greater for DPH (1.36 sec) than for CBZ (0.38 sec). A combination of prolonged depolarizing pulses of 15 mV with superimposed brief maximal depolarizations designed to mimic the electrical activity in an epileptic focus gave additive effects of voltage-dependent and frequency-dependent inhibition. The results support the previous proposal that DPH and CBZ are sodium channel-selective anticonvulsants and provide a potential basis for specific inhibition of neurons in epileptic foci. The mechanism of DPH and CBZ action is considered in terms of an allosteric or modulated receptor model of drug binding and action.