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Sodium and Potassium Continued

Perry, McKinney and DeWeer, Nature (1978), 2021 demonstrated that PHT (100 µM) does not affect active sodium transport, but regulates resting and excitable sodium channels in isolated squid giant axons.By limiting sodium influx, in addition to limiting calcium influx through the sodium channel, PHT raises the firing threshold, stabilizes excitable membranes and counteracts post-tetanic potentiation.

2021. Perry, J. G., McKinney, L. and DeWeer, P., The cellular mode of action of the anti-epileptic drug 5, 5-diphenylhydantoin. Nature, 272: 271-3, 1978.

Nosek, Epilepsia (1981), 2233 studying the crayfish giant axon, found that PHT (110 µM) decreased both sodium and potassium conductances, but had no effect on chloride conductance or active transport of sodium and potassium. The author suggests that PHT's ability to reduce potassium efflux from the neuron may be important in its selective effects on hyperexcitability.

2233. Nosek, T.M., How valproate and phenytoin affect the ionic conductances and active transport characteristics of the crayfish giant axon, Epilepsia, 22: 651-65, 1981.

Yeh, Quandt and Kirsch, Federation Proceedings (1981), 2133 noting that PHT is used clinically in cardiac, nervous system and muscle disorders, sought to demonstrate common mechanisms of action of PHT in a variety of excitable membranes: perfused squid axons, single fibers of frog skeletal muscle and cultured neuroblastoma cells. In all three preparations, PHT (20-100 µM) decreased slow sodium currents. PHT also reduced calcium currents in neuroblastoma cells. The more the depolarization of the membrane, the greater PHT's effect.

2133. Yeh, J. Z., Quandt, F. N. and Kirsch, G. E., Comparative studies of phenytoin action on ionic channels in excitable membranes, Fed. Proc., 40(3): 240, 1981.

Grenader, Pnomareva, Zurabishvili and Vasiev, Biofizika (1982), 2557 report that PHT (2-8 µg/ml) causes a decrease in the fast inward sodium current in rabbit heart atrium and ventricular tissue. This leads to increased refractoriness and is one of the mechanisms by which PHT achieves its antiarrhythmic effects.

2557. Grenader, A. K., Ponomareva, V. M., Zurabisbvili, G. C., Vasiev, B. N., Changes in the refractoriness of cardiac tissue as a result of a decrease in the fast inward sodium current. Comparison of the atrium and ventricle, Biofizika, 27(5): 911-14,1982.

Courtney and Etter, European Journal of Pharmacology (1983), 2412 studying single myelinated sciatic nerve fibers with voltage clamp techniques, showed that PHT, carbamazepine and phenobarbital selectively bind to the inactive state of the sodium channel. These agents also showed increased effects when the membrane was depolarized, indicating selectivity for the hyperactive state.

2412. Courtney, K. R., Etter, E. F., Modulated anticonvulsant block of sodium channels in nerve and muscle, Eur. J. Clin. Pharmacol., 88; 1-9, 1983.

McLean and MacDonald, The Journal of Pharmacology and Experimental Therapeutics (1983), 2783 studied the concentration dependence of several actions of PHT in mouse spinal cord neurons in culture using intracellular microelectrode techniques. At 1-2 µg/ml (equivalent to therapeutic cerebrospinal fluid concentrations), PHT reduced high-frequency repetitive firing during long depolarizing current pulses. There was a progressive reduction of the maximal rate of rise of the action potential (Vmax) during the train until firing failed. While PHT did not affect Vmax of single action potentials, recovery of Vmax after repetitive firing was prolonged.PHT concentrations above 3 µg/ml reduced Vmax and spontaneous neuronal firing, reduced calcium-dependent action potential amplitude, eradicated convulsant-induced paroxysmal bursting, and augmented postsynaptic responses to iontophoretically applied gamma-aminobutyric acid. The authors conclude that, at therapeutic levels, PHT prolongs sodium channel recovery from inactivation, an effect which is critical to its ability to limit sustained high-frequency repetitive firing. (See also Refs. 2745, 2746, 2747, 2748, 2782.)

2783. McLean, M. J., Macdonald, R. L., Multiple actions of phenytoin on mouse spinal cord neurons in cell culture, Pharmacol. Exp. Ther., 227(3): 779-89, 1983.
2745. Macdonald, R. L., Barbiturate and hydantoin anticonvulsant mechanisms of action, Basic Mechanisms of Neuronal Hyperexcitability, Jasper, H. H. and Van Gelder, N. M., Eds., Alan R. Liss, Inc., New York, 361-87, 1983.
2746. Macdonald, B. L., Anticonvulsant and convulsant drug actions on vertebrate neurones in primary dissociated cell culture, Electrophysiology of Epilepsy, Schwartzkroin, P.A. and Wheal, H. V., Eds., Academic Press, London, 353-87, 1984.
2747. Macdonald, R. L., McLean, M. J., Skerritt, J. H., Anticonvulsant drug mechanisms of action, Fed. Proc., 44: 2634-9, 1985.
2748. Macdonald, R. L., Skerritt, J. H., McLean, M. J., Anticonvulsant drug cations on GABA responses and sustained repetitive firing neurons in cell culture, Neuropharmacology, 23(7): 843-4, 1984.
2782. McLean, M., Carbamazepine and phenytoin limit rapid firing of action potentials of dorsal root ganglion neurons in cell culture, Soc. Neurosci. Abstr., 12 (Pt 2): 1015, 1986.

Matsuki, Quandt, Ten Eick and Yeh, Journal of Pharmacology and Experimental Therapeutics (1984),2770 studied the interaction of PHT with membrane ionic channels of cultured mouse neuroblastoma cells, using voltage clamp and intracellular perfusion techniques. PHT (20-100 µM) inhibited inward sodium current in a dose-dependent manner, and slowed recovery from voltage-dependent inactivation of sodium current during conditioned block. Recovery was faster when the membrane was hyperpolarized. When the membrane was depolarized or stimulated at higher frequencies, PHT's inhibitory effects increased. The authors conclude that PHT regulates membrane function both by increasing the fraction of sodium channels in an inactivated state and by delaying the transition from inactivated to closed but available channels.

2770. Matsuki, N., Quandt, F. N., Ten Eich, R. E., Yeh, J. Z., Characterization of the block of sodium channels by phenytoin in mouse neuroblastoma cells, J. Pharmacol. Exp. Ther., 22,8(2): 523-30, 1984.

Norris and Saez, IRCS Medical Science (1984), 2832 compared the effects of PHT and carbamazepine on the electrical properties of isolated toad skin. Both agents increased sodium transport across the skin, but the stimulatory effect of carbamazepine was less than that of PHT. In some cases, carbamazepine had inhibitory effects in the same dosage range within which PHT was stimulatory.

2832. Norris, B., Saez, C., Comparison of the effects of carbamazepine and of diphenylhydantoin on the electrical properties of isolated toad skin, IRCS Med. Sci., 12: 164-5, 1984. 

Willow, Kuenzel and Catterall, Molecular Pharmacology (1984), 2268 and Willow, Gonoi and Catterall, Molecular Pharmacology (1985), 3073 studied the effects of PHT on voltage-sensitive sodium channels in cultured neuroblastoma cells and rat brain synaptosomes using voltage clamp techniques and 22Na+. In the neuroblastoma cells, PHT reduced sodium currents without effect on the voltage dependence of sodium-channel activation. Half-maximal inhibition was seen at 30 µM. Depolarization and repetitive stimulation increased PHT's inhibition of sodium current. Hyperpolarization decreased the effect. In other experiments, PHT competitively inhibited batrachotoxin-activated 22Na+ influx in both the neuroblastoma cells and the synaptosomes. The authors suggest that PHT regulates electrical activity by binding to receptor sites associated with activation of voltage-sensitive sodium channels. (See also Refs. 2379, 3072.)

2268. Willow, M., Kuenzel, E. A., Catterall, W. A., Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine, Mol. Pharmacol., 25 (2): 228.35, 1984.
3073. Willow, M., Gonoi, T., Catterall, W. A., Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells, Mol. Pharmacol., 27(5): 549-58, 1985.
2379. Catterall, W. A., Inhibition of voltage-senisitive sodium channels in neuroblastoma cells by antiarrhythmic drugs. Mol. Pharmacol., 20: 356-62, 1981.
3072. Willow, M., Pharmacology of diphenylhydantoin and carbamazepine action on voltage-sensitive sodium channels, Trends in Neurosciences, 147-9, 1986.

Caldwell and Harris, European Journal of Pharmacology (1985), 2374 evaluated the effects of anesthetics and anticonvulsants on the calcium-dependent efflux of potassium in human erythrocytes. PHT (30-100 µM) and phenobarbital were the only agents that inhibited the efflux process in a concentration-dependent manner.

2374. Caldwell, K. K., Harris, R. A., Effects of anesthetic and anticonvulsant drugs on calcium dependent efflux of potassium from human erythrocytes, Eur. J. Pharmacol., 107(2): 119-25, 1985.

David, Selzer and Yaari, Brain Research (1985), 2429 reported that PHT (100-300 µM) is able to block aminopyridine-induced afterdischarges at presynaptic nerve terminals. The authors suggest that this is due to PHT's ability to reduce sodium conductance at the synaptic terminal.

2429. David, G., Selzer, M. E., Yaari, Y., Suppression by phenytoin of convulsant-induced after-discharges at presynaptic nerve terminals, Brain Res., 330(1): 57-66, 1985.

Wada, Izumi, Yanagihara and Kobayashi, Archives of Pharmacology (1985), 3053 showed that PHT (10-100 µM) reduced veratridine-induced influx of sodium and calcium, and secretion of catecholamines in cultured bovine adrenal medullary cells. PHT also abolished ouabain's potentiation of the veratridine-induced effects. The authors conclude that PHT modulates the intracellular accumulation of sodium which, in turn, regulates calcium influx and secretion of medullary catecholamines.

3053. Wada, A., Izumi, F., Yanagihara, N., Kobayashi, H., Modulation by ouabain and diphenylhydantoin of veratridine-induced 22 Na influx and its relation to 46 Ca influx and the secretion of catecholamines in cultured bovine adrenal medullary cells, Arch. Pharmacol., 328(3): 273-8, 1985.

White, Chen, Kemp and Woodbury, Epilepsia (1985), 3069 studied the effects of acute and chronic PHT on various parameters of anion and cation transport in the cerebral cortex of neonatal and adult rats. Acute administration of PHT (20 mg/kg) inhibited sodium-potassium-ATPase activity in both neonates and adult rats. Chronic treatment (20 mg/kg b.i.d. or q.i.d. for seven days) in adult rats slightly decreased neuronal sodium-potassium-ATPase activity, while markedly increasing its activity in glia. Chronic PHT treatment also increased both DNA content and the activity of the glial enzyme carbonic anhydrase and the mitochondrial enzyme HCO3-ATPase. Both of these enzymes are involved in ionic regulation and are related to brain excitability. The authors suggest that PHT's stimulation of glial uptake of extracellular potassium may be important in its regulatory effects on hyperexcitability. (See also Refs. 3084, 3085.)

3069. White, H. S., Chen, C. F., Kemp, J. W., Woodbury, D. M., Effects of acute and chronic phenytoin on the electrolyte content and the activities of NA+, K+-, Ca2+, Mg2+-, and HCO3- - ATPases and carbonic anhydrase of neonatal and adult rat cerebral cortex, Epilepsia, 26(l): 43-57, 1985.
3084. Woodbury, D. M., Engstrom, F. L., White, H. S., Chen, C. F., Kemp, J. W., Chow, S. Y., Ionic and acid-base regulation of neurons and glia during seizures, Ann. Neurol., 16:sl35-sl44, 1984.
3085. Woodbury, D. M., Kemp, J. W., Chow, S. Y., Mechanism of action of antiepileptic drugs, Epilepsy, Ward, A. A., et al., Eds., Raven Press, New York, 179-223, 1983.

White, Yen-Chow, Chow, Kemp and Woodbury, Epilepsia (1985), 3070 studied the effects of PHT in primary rat glial cell cultures. PHT (1-100 µM) increased glial cell control of elevated extracellular potassium. The efficiency of glial sodium-potassium-ATPase was substantially enhanced by PHT over a wide range of extracellular potassium concentrations. Significant membrane hyperpolarization accompanied the marked increase in intracellular potassium which resulted from the PHT-induced increase in enzyme activity.

3070. White, H. S., Yen-Chow, Y. C., Chow, S. Y., Kemp, W., Woodbury, D. M., Effects of phenytoin on primary glial cell cultures, Epilepsia, 26(l): 58-68, 1985.

Quandt and Yeh, Society for Neuroscience Abstracts (1986), 2885 found that PHT enhanced the slow inactivation of single sodium channels in excised patches of membrane from cultured N1E-115 neuroblastoma cells. PHT (100 µM) reduced the time to onset of slow inactivation. Under conditions of sustained depolarization, PHT reduced the duration of bursts of sodium channel opening; lengthened interval between bursts; and reduced the probability of a channel being open and the mean open-channel time. The authors suggest that these actions could account for PHT's selective effects on repetitive neuronal firing.

2885. Quandt, F. N., Yeh, J. Z., Slow inactivation of single Na channels induced by diphenylhydantoin, Soc. Neurosci. Abstr., 12 (Pt 1): 45, 1986.

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