Phenytoin: effects on calcium flux and cyclic nucleotides

Previous studies have demonstrated that phenytoin alters calcium conductance in isolated presynaptic nerve endings (synaptosomes) from rat or rabbit brain. Drug concentrations of 0.08 mM (20 microgram/ml) or higher inhibit stimulated calcium influx into synaptosomes depolarized by high concentrations of potassium (69 mM) by 7-58%. Calcium transport into undepolarized synaptosomes is only inhibited by 0.4 mM or greater concentrations of phenytoin. Recent investigations show that in mouse brain slices, phenytoin inhibited elevations of cyclic GMP and cyclic AMP produced by ouabain or veratridine. In contrast, elevations of the two cyclic nucleotides produced by high concentrations of potassium were not inhibited by phenytoin, suggesting that the anticonvulsant suppresses depolarization-induced elevation of cyclic nucleotide levels in brain slices by inhibiting influx of sodium into cells. These data indicate that phenytoin inhibits both sodium and calcium influx into cells during cellular depolarization and alters regulation of brain cyclic nucleotide levels. Both of these actions may be important for the antiepileptic effect of phenytoin.