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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. 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. Click here for more on Sodium and Potassium. | |||
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