Ionic Basis of Phenytoin Sodium Inhibition of Insulin Secretion in Pancreatic Islets

The possibility that phenytoin sodium has a dual role in blocking Ca and Na channels in the pancreatic β-cell membrane was studied to clarify the mechanism of action of the drug in inhibiting insulin release. Glucose and veratridine were used to activate the Ca and Na channels, respectively. The increase in insulin release induced by 16.7 mM glucose or 200 μM veratridine was inhibited 77% and 60%, respectively, by 100 μM phenytoin, whereas the increase in the rate of glycolysis was inhibited 74% and 100%, respectively. An increase in extracellular Ca from 2.5 to 5.0 mM attenuated the inhibitory effect of phenytoin oh both the metabolic and secretory responses to glucose and veratridine. This Ca-dependent reversal was greater for glucose than for veratridine. Furthermore, 1,0 mM ouabain partially reversed the inhibitory effect of phenytoin on the secretory responses to both stimulants. This may be attributed to the indirect effect of ouabain in increasing intracellular Ca. However, ouabain together with phenytoin almost completely blocked glycolytic flux measured in the presence of either glucose or veratridine. These results suggest that phenytoin may block the stimulation of passive Na and/or Ca transport in the β-cell membrane.