Sodium and Potassium

Woodbury, Journal of Pharmacology and Experimental Therapeutics (1955), 387 demonstrated that in normal rats, PHT decreased both the total and the intracellular concentration of brain sodium and increased the rate of movement of radio-sodium into and out of brain cells. The net result was that the ratio of extracellular to intracellular brain sodium was increased. PHT also decreased intracellular sodium concentrations in skeletal and cardiac muscle, but to a lesser extent than in brain. Acutely induced low sodium in blood was associated with an increase in intracellular brain sodium and a decrease in intracellular brain potassium. These changes from normal were largely prevented by treatment with PHT.

387. Woodbury, D. M., Effect of diphenylhydantoin on electrolytes and radiosodium turnover in brain and other tissues of normal, hyponatremic and postictal rats, J. Pharm. Exp. Ther., 115: 74-95, 1955.

Koch, Higgins, Sande, Tierney and Tulin, Physiologist (1962), 1225 studied the effect of PHT on the reabsorption of ions by kidney in dogs. PHT enhanced active sodium transport in the kidney.

1225. Koch, A., Higgins, R., Sande, M., Tierney, J., and Tulin, R., Enhancement of renal Na+ transport by Dilantin, Physiologist, 5: 168, 1962.

Festoff and Appel, Journal of Clinical Investigation (1968), 94 studied the effects of PHT on sodium-potassium-ATPase in rat brain synaptosomes. With a ratio of 5-10 to 1 of sodium-to-potassium, PHT had no effect. When the ratio of sodium-to-potassium was raised to 50 to 1 or higher, PHT exerted an increasingly greater effect on enzyme activity, causing stimulation of synaptosome ATPase. Thus the authors observed a selectivity of action of PHT on ATPase, depending on whether the ratio of sodium-to-potassium is in the normal or abnormal range.

94. Festoff, B. W. and Appel, S. H., Effect of diphenylhydantoin on synaptosome sodium-potassium-ATPase, J. Clin. Invest., 47: 2752-2758, 1968.

Helfant, Ricciutti, Scherlag and Damato, American Journal of Physiology (1968), 157 demonstrated that PHT prevented the efflux of potassium from cardiac tissue pretreated with toxic doses of digitalis and reversed digitalis-induced ventricular arrhythmias.

157. Helfant, R. H., Ricciutti, M. A., Scherlag, B. J., and Damato, A. N., Effect of diphenylhydantoin sodium (Dilantin) an myocardial A-V potassium difference, Amer. J. Physiol., 214: 880-884, 1968.

Van Rees, Woodbury and Noach, Archives Internationales de Pharmacodynamie et de Therapie (1969), 1642 found that in loops of intestine of intact rats, PHT increased the rate of absorption of both sodium and water from the lumen of the intestine.

1642. Van Rees, H., Woodbury, D. M. and Noach, E. L., Effects of ouabain and diphenylhydantoin on electrolyte and water shifts during intestinal absorption in the rat, Arch. Int. Pharmacodyn., 182: 437, 1969.

Pincus, Grove, Marino and Glaser, Archives of Neurology (1970), 699 indicate that PHT (100 µM) does not affect intracellular sodium in normally functioning, oxygenated nerves, but that it tends to reduce the abnormal accumulation of intracellular sodium in hypoxic nerves. PHT was also found to limit the rise in intracellular sodium in nerves in which the sodium extrusion mechanism has been destroyed by ouabain, cyanide or both. The authors state: “Phenytoin has been shown to have a stabilizing influence on virtually all excitable membranes. These effects have been seen in a wide variety of vertebrate and invertebrate species.” (See also Refs. 285, 293.)

699. Pincus, J. H., Grove, I., Marino, B. B., and Glaser, G. E., Studies on the mechanism of action of diphenylhydantoin, Arch. Neurol., 22: 566-571, 1970.

285. Pincus, J. H. and Giarman, N. J., The effect of diphenylhydantoin on sodium-, potassium-, magnesium-stimulated adenosine triphosphatase activity of rat brain, Biochem. Pharmacol., 16: 600-603, 1967.
293. Rawson, M. D. and Pincus, J. H., The effect of diphenylhydantoin on sodium, potassium, magnesium-activated adenosine triphosphatase in rnicrosomal fractions of rat and guinea pig brain and on whole homogenates of human brain, Biochem. Pharmacol., 17: 573-579, 1968.

Crane and Swanson, Neurology (1970), 728 showed that PHT (100-500 µM) prevents the loss of potassium and the gain in sodium by brain slices during repeated high-frequency electrical stimulation. Repeated depolarization of neuronal membranes makes it increasingly likely that the resting intra- and extracellular balance of ions will not be restored. These "downhill movements" of sodium and potassium ions represent the failure of active transport to restore the resting balance of ions between intracellular and extracellular compartments. PHT, by pre-venting and reversing these shifts, tends to restore the balance toward the normal resting state.

728. Crane, P. and Swanson, P. D., Diphenylhydantoin and the cations and phosphates of electrically stimulated brain slices, Neurology, 20: 1119-1123, 1970.

Fertziger, Liuzzi and Dunham, Brain Research (1971), 1025 studied the effect of PHT on potassium transport in lobster axons using radioisotopic potassium. The authors observed that PHT (100 µM) stimulated potassium influx. They postulated that this regulatory effect on potassium transport, in addition to the well-established regulation of intracellular sodium content of nerve, might relate to the stabilizing effect of PHT on hyperactive neurons.

1025. Fertziger, A. P., Liuzzi, S. E., and Dunham, P. B., Diphenylhydantoin (Dilantin): stimulation of potassium influx in lobster axons, Brain Res., 33: 592-596, 1971.

Den Hertog, European Journal of Pharmacology (1972), 955 studied the basis for PHT's ability to inhibit post-tetanic potentiation and repetitive after discharge. The author found that PHT (20 µg/ml) did not alter the electrogenic component of the sodium pump or change normal membrane threshold or post-tetanic hyperpolarization in repetitively stimulated, non-myelinated axons of desheathed rat vagus nerve.

955. Den Hertog, A., The effect of diphenylhydantoin on the electronic component of the sodium pump in mammalian non-myelinated nerve fibers, Europ. J. Pharmacol., 19: 94-97, 1972.

Escueta and Appel, Archives of Internal Medicine (1972), 1012 studied the effect of PHT (100 µM) on sodium and potassium levels in isolated brain synaptosomes. Rat brain rendered hyperexcitable by electrical stimulation resulting in seizure states was found to contain a decreased level of potassium and an increased level of sodium within the synaptic terminals. The authors note that these changes reflected the "downhill movement" of ions in synaptic terminals. PHT corrected these changes through its effect on membrane function.

1012. Escueta, A. V. and Appel, S. H., Brain synapses-an in vitro model for the study of seizures, Arch. Intern. Med., 129: 333-344, 1972.

Lipicky, Gilbert and Stillman, Proceedings of the National Academy of Sciences (1972), 1291 studied the effect of PHT (5-50µM) on the voltage-dependent currents of the squid giant axon. PHT did not change the resting membrane potential, but decreased the early transient sodium currents by 50%, with little or no effect on potassium currents. The authors suggest that this observation may be relevant to PHT’s antiarrhythmic action in heart and its stabilizing effects in peripheral nerve.

1291. Lipicky, R. J., Gilbert, D. L., and Stillman, I. M., Diphenylhydantoin inhibition of sodium conductance in squid giant axon, Proc. Nat. Acad. Sci., 69: 1758-1760, 1972.

Nasello, Montini and Astrada, Pharmacology (1972), 1379 studied the effect of PHT on electrically stimulated rat dorsal hippocampus. When the hippocampus was constantly stimulated, potassium release was observed. PHT counteracted this release.

1379. Nasello, A. G., Montini, E. E., and Astrada, C. A., Effect of veratrine, tetraethylammonium and diphenyihydantoin on potassium release by rat hippocampus, Pharmacology, 7: 89-95, 1972.

Pincus, Archives of Neurology (1972), 1418 found that PHT (100 µM) reduced sodium influx by 40% in stimulated lobster nerves. Sodium influx was not found to be affected in the resting nerve. PHT did not affect the rate of stimulated or resting sodium efflux. The author concludes that PHT acts primarily by limiting the increase in sodium permeability which occurs during stimulation. PHT appears to counteract "downhill" sodium movements in stimulated nerves without affecting normal sodium movements.

1418. Pincus, J. H., Diphenylhydantoin and ion flux in lobster nerve, Arch. Neurol., 26: 4-10, 1972. 

Watson and Woodbury, Chemical Modulation of Brain Function (1973), 1664 studied the effect of PHT on sodium transport and membrane permeability of the epithelium of frog skin and toad urinary bladder preparations. PHT increased net sodium transport in both cases by increasing the permeability of the outer membrane to sodium. The authors suggest that these findings are consistent with PHT's action in stimulating sodium-potassium-ATPase, when the sodium-potassium ratio is high (25 to 1).

1664. Watson, E. L. and Woodbury, D. M., Effects of diphenylhydantoin on electrolyte transport in various tissues, Chemical Modulation of Brain Function, 187-198, Sabelli, H. C., Ed., Raven Press, New York, 1973.

Noach, Van Rees and De Wolff, Archives Internationales de Pharmacodynamie et de Therapie (1973), 1385 found that when sodium is lacking from the intestinal lumen, PHT causes the sodium to increase in the lumen by active extrusion of sodium from the gut wall.

1385. Noach, E. L., VanRees, H. and DeWolff, F. A., Effects of Diphenylhydantoin (DPH) on absorptive processes in the rat jejunum, Archives Internationales de Pharmacodynamie et de Therapie, 206: 392-393, 1973.

Loh, Federation Proceedings (1974), 2224 in studies of isolated frog atrial trabeculae, found that PHT reversed digitalis-induced potassium loss. The net gain of tissue potassium and the reduction of potassium efflux led the author to conclude that these changes might account for PHT's effects on transmembrane potentials and its stabilization of membranes.

2224. Loh, C.K., Effects of diphenylhydantoin (DPH) on potassium exchange kinetics and transmembrane potentials in amphibian atrium, Fed. Proc., 33: 445, 1974.

Johnston and Ayala, Science (1975), 1917 demonstrated that PHT (20-200 µM) decreases the bursting pacemaker activity in certain Aplysia neurons. The sodium-dependent negative resistance characteristic, which is essential for bursting behavior, is reduced in the presence of PHT. The authors believe these findings may be applicable to PHT's inhibition of the downhill flux of sodium ions and paroxysmal depolarizing shifts in mammalian neurons.

1917. Johnston, D. and Ayala, G. F., Diphenylhydantoin: action of a common anticonvulsant on bursting pacemaker cells in aplysia, Science, 189: 1009-11, 1975.

O’Donnell, Kovacs and Szabo, Pflugers Archives (1975), 2006 noting that PHT is considered to exert a stabilizing effect on all excitable cell membranes, studied the influence of PHT on potassium and sodium movements in isolated frog skeletal muscle. They conclude that in this system PHT acts in a normal ionic environment to reduce the resting passive component of potassium exchange across the muscle fiber membrane, and that this might account for the membrane stabilizing action of PHT.

2006. O’Donnell, J. M., Kovacs, T. and Szabo, B., Influence of the membrane stabilizer diphenylhydantoin on potassium and sodium movements in skeletal muscle, Pflugers Arch, 358: 275-88, 1975.

Ehring and Hondeghem, Proceedings of the Western Pharmacological Society (1978),1815 studied the effects of PHT on isolated guinea pig heart papillary muscle. PHT (60-100 µM) decreased action potential Vmax only when stimulus frequency was high or when the cells were depolarized. PHT's effects were less when the cells were hyperpolarized. Based on this evidence, the authors suggest that PHT achieves its antiarrhythmic effects by binding to open sodium channels, thus regulating sodium influx.

1815. Ehring, G. R. and Hondeghem, L. M., Rate, rhythm and voltage dependent effects of phenytoin: a test of a model of the mechanisms of action of antiarrhythmic drugs, Proc. West. Pharmacol. Soc., 21: 63-5, 1978.

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