Diphenylhydantoin: Excitability reducing action in single myelinated nerve fibres

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Current and voltage clamp experiments on single myelinated nerve fibres from Xenopus laevis were carried out in Ringer solutions with 0–800 μM diphenylhydantoin (DPH). In preliminary experiments, 80 μM DPH reduced the conduction velocity of Aα-fibres from the sciatic nerve to 86% of control. Application of 80 μM DPH hyperpolarized the resting membrane potential by about 5 mV, raised the threshold potential by 7.5 mV, and reduced the peak of the action potential to about 90% of control. The peak of the sodium current was reduced to 55% and the steep part of its current-voltage relation was reversibly shifted in a depolarizing direction; the steady-state potassium current reached 84% of control after treatment with 80 μM DPH. The leakage current remained unchanged. The reduction of the sodium current could be partly eliminated by long-lasting hyperpolarizing prepulses, the half-time of this process being 0.27 sec. In 80 μM DPH, the inactivation curve of the sodium system as tested with 5 sec prepulses was shifted in a hyperpolazing direction by about 20 mV. The dose-response relation of the DPH effect on the peak sodium current could be fitted by assuming a one-to-one reaction between DPH molecules and sites at the sodium channel with an equilibrium constant K = 157 μM (pH 9). At pH 7, the curve was shifted to lower concentrations. Onset and ending of the blocking effect of a 80 μM DPH Ringer solution on the peak sodium current had a half-time of 3.8 and 7.5 sec respectively. The voltage-clamp data suggest that the excitability-reducing action is mainly due to a potential dependent blockage of the sodium channel by the amphoteric DPH molecule.