Korey, Proceedings of the Society of Experimental Biology and Medicine (1951), 472 in a study of the isolated squid giant axon, found that PHT corrected the hyperexcitability induced by the withdrawal of calcium and magnesium from the bathing medium. PHT corrected this excessive firing within two to three minutes. When calcium and magnesium were added back into the medium, it took fifteen minutes for the axon to return to normal.

472. Korey, S. R., Effect of Dilantin and Mesantoin on the giant axon of the squid, Proc. Soc. Exp. Biol. Med., 76: 297-299, 1951.

Pincus and Lee, Archives of Neurology (1973), 1417 found that, when PHT (50-500 µM) was added to rat brain slices, the up-take of calcium was decreased and there was a decrease in the release of norepinephrine from the cells. The authors state that it has been demonstrated that, in the absence of calcium, the electrical stimulation of brain slices does not result in norepinephrine being released from the cell. They note that when calcium concentration is reduced, norepinephrine release from the cells is also reduced. Calcium and PHT were antagonistic with respect to their effect on norepinephrine release induced by potassium depolarization. Tetrodotoxin at high concentration had no effect on norepinephrine release. Thus the authors suggest that the effect of PHT on norepinephrine release was mediated entirely by its reduction of calcium uptake by depolarized brain slices. The authors note that the effects of PHT upon calcium uptake may be relevant to the regulatory action of PHT in other situations, including the secretion of insulin and the contractile mechanisms in skeletal and cardiac muscle.

1417. Pincus, J. H., and Lee, S. H., Diphenylhydantoin and calcium in relation to norepinephrine release from brain slices, Arch. Neurol., 29: 239-244, 1973.

Sohn and Ferrendelli, Neurology (1973), 1567 studied the effect of PHT on calcium uptake by synaptosomes isolated from rat brain. PHT (200 µM or greater) consistently inhibited calcium uptake by potassium depolarized synaptosomes. Non-depolarized synaptosomes required higher concentrations of PHT (400 µM) for an inhibitory effect on calcium uptake. These results support the concept that one pharmacological action of PHT is inhibition of calcium transport into stimulated neuronal tissue. The authors suggest that this may be a mechanism by which PHT inhibits neurotransmitter release and, in turn, suppresses post-tetanic potentiation.

1567. Sohn, R. S. and Ferrendelli, J. A., Inhibition of Ca+ + uptake in rat brain synaptosomes by diphenylhydantoin, Neurology, 23: 444, 1973.

Pento, Glick and Kagan, Endocrinology (1973), 1406 demonstrated the effect of PHT on calcitonin secretion in the pig. Normal basal levels of calcitonin secretion were not significantly changed by PHT. When extra calcitonin secretion was stimulated by means of glucagon or calcium administration, PHT reduced the rise in plasma calcitonin produced by these two stimuli. The authors state that these findings are in accord with other demonstrations that PHT does not alter normal basal secretion of pituitary-adrenal hormones, or insulin; but when unusual stimuli are present, PHT exerts a regulatory influence.

1406. Pento, J. T., Glick, S. M., and Kagan, A., Diphenylhydantoin inhibition of calcitonin secretion in the pig. Endocrinology, 92: 330-333, 1973.

Carnay and Grundfest, Neuropharmacology (1974), 885 studied the effects of PHT and calcium on the electrical properties of the pre- and postsynaptic membranes of frog neuromuscular junction. When muscle fibers were bathed in solutions deficient in calcium, membrane instability and repetitive firing of the muscle fibers occurred. Within five minutes after the addition of PHT (10-20 µg/ml), the abnormal repetitive activity and irritability were abolished, without affecting the threshold or amplitude of the stimulated single action potential or endplate potential. PHT reversed the abnormal membrane receptor desensitization that occurs in calcium-deficient media and, like calcium, corrected the membrane instability induced by germine monoacetate. The authors conclude that PHT has a stabilizing effect similar to that of calcium on abnormal membrane properties.

885. Carnay, L. and Grundfest, S., Excitable membrane stabilization by diphenylhydantoin and calcium, Neuropharmacology, 13: 1097-1108, 1974.

Hasbani, Pincus and Lee, Archives of Neurology (1974), 1136 demonstrated that PHT (200 µM) reduced radioisotopic calcium uptake in rapidly stimulated lobster axons. The PHT metabolite, hydroxy-phenyl-phenylhydantoin (HPPH), had no effect on calcium uptake.

1136. Hasbani, M., Pincus, J. H. and Lee, S. H., Diphenylhydantoin and calcium movement in lobster nerves, Arch. Neurol., 31: 250-254, 1974.

Riddle, Mandel and Goldner, European Journal of Pharmacology (1975), 2046 studied the effects of PHT and calcium simultaneously on solute transport in frog skin. In the presence of external calcium, PHT (15-100 µ/ml) elicited a significant increase in active sodium transport, but in the absence of calcium, PHT had no effect. PHT also increased passive solute permeability, independent of calcium.

2046. Riddle, T. G., Mandel, L. J., Goldner, M. M., Dilantin-calcium interaction and active Na transport in frog skin, Europ. J. Pharmacol., 33: 189-92, 1975.

Watson and Siegel, European Journal of Pharmacology (1976), 2267 demonstrated that PHT inhibited calcium uptake, but not release, by submandibular microsomes. They also found, in in vivo experiments, that PHT decreased secretary response of the submandibular and parotid glands to intra-arterial methacholine. The authors suggest that the reduction in secretary volume related to PHT's regulation of calcium uptake.

2267. Watson, E.L. and Siegel, I.A., Diphenylhydantoin effects on salivary secretion and microsomal calcium accumulation and release, Eur. J. Pharmacol., 37: 207-11, 1976.

Goldberg, Neurology (1977), 1860 states that PHT, which acts on many levels of the nervous system as well as many non-neural sites, must affect some general membrane property, and only when the membrane is unstable. The author found that binding of PHT to phospholipids is related to fatty acid composition in rabbit and human brain fractions. Dipalmitoyl and dioleoyl lecithins, the most abundant lecithins in brain, showed the greatest binding. PHT increased the binding of radioisotopic calcium to phospholipids up to five-fold. The author suggests that this PHT-induced increase in calcium binding may explain PHT's membrane stabilizing action and its effectiveness in treatment of hypocalcemic symptoms. (See also Refs. 1859, 2547.)

1859. Goldberg, M. A., Phenytoin: binding, Antiepileptic Drugs: Mechanisms of Action, 323-37, Glaser, G. H., Penry, J. K. and Woodbury, D. M., Eds., Raven Press, New York, 1980.
1860. Goldberg, M. A., Phenytoin, phospholipids and calcium, Neurology, 27: 827-33, 1977.
2547. Goldberg, M. A., The Pharmacology of Phenytoin, H. Houston Merritt Memorial Volume, Yahr, M.D., Ed., Raven Press, New York, 81-99, 1983.

Pace and Livingston, Diabetes (1979), 2011 studied the effects of PHT on insulin release and metabolism of isolated rat islets of Langerhans. Glucose and veratridine were used to stimulate insulin release by activating the calcium and sodium channels. PHT (100µM) inhibited the glucose-stimulated insulin release (77%) and glycolysis (74%). PHT also inhibited the veratridine-stimulated insulin release (60%) and glycolysis (100%). When extracellular calcium was raised from 2.5 to 5.0 mM, PHT's effects were less. Noting that PHT has been reported to hyperpolarize the beta-cell membrane and to inhibit glucose-induced spike activity, the authors conclude that the inhibitory action of PHT on the pancreatic beta-cell is due to its regulatory effect on sodium and calcium channels.

2011. Pace, C. S. and Livingston, E., Ionic basis of phenytoin sodium inhibition of insulin secretion in pancreatic islets, Diabetes, 28: 1077-82, 1979.

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