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Calcium Continued

Yaari, Pincus and Argov, Brain Research (1979), 2130 showed a biphasic effect of PHT at the frog neuromuscular junction. PHT (200 µM) increased quantal content of acetylcholine in media containing low calcium concentrations, but decreased quantal content in normal calcium. The authors suggest that PHT not only reduced calcium entry into axon terminals, but also reduced the activity of the intracellular calcium sequestration-extrusion system. 

2130. Yaari, Y., Pincus, J. H., Argov, Z., Phenytoin and transmitter release at the neuromuscular junction of the frog, Brain Res., 160: 479-87, 1979.

Quandt and Narahashi, Neuroscience Abstracts (1980), 2884 studied the effects of PHT (20-50 µM) on sodium and calcium voltage-dependent currents in neuroblastoma cells in culture. Peak inward calcium current was reduced 25%, whereas peak sodium-dependent current was reduced only 10%. The suggestion is that, at least in these cells, PHT's inhibition of calcium flux is more important than its effect on sodium.

2884. Quandt, F. N., Narahashi, T., Internal perfusion of neuroblastoma cells and the effects of diphenylhydantoin on voltage-dependent currents, Neurosci. Abstr., 6: 97, 1980.

Study, Journal of Pharmacology and Experimental Therapeutics (1980), 2093 reported that PHT inhibited the calcium-dependent increases in cyclic GMP induced by high-potassium depolarization and muscarinic receptor activation in N1E-115 neuroblastoma cells. PHT's inhibition of the cyclic GMP response to depolarization was half-maximal at 40 µM. Inhibition of the muscarinic receptor response by PHT could be overcome by increasing extracellular calcium. The author suggests that reduction of calcium influx is the means by which PHT blocks cyclic GMP responses in these cells.

2093. Study, R. E., Phenytoin inhibition of cyclic guanosine 3’:5’-monophosphate (cGMP) accumulation in neuroblastoma cells by calcium channel blockade, J. Pharmacol. Exp. Ther., 215(3): 575-81, 1980.

Herchuelz, Lebrun, Sener and Malaisse, European Journal of Pharmacology (1981), 2589 investigated the mechanism by which PHT inhibits glucose-stimulated insulin release by studying its effects on calcium and rubidium fluxes in isolated pancreatic islets. PHT inhibited both basal and glucose-stimulated calcium uptake by islet cells and markedly reduced the secondary rise in calcium efflux normally provoked by glucose. PHT also decreased the calcium exchange evoked by an increase in extracellular calcium concentration. Rubidium uptake was not affected, indicating that PHT's effects on insulin release were not attributable to activation of sodium-potassium-ATPase. The authors conclude that PHT inhibits glucose-induced insulin release by limiting calcium entry into islet cells.

2589. Herchuelz, A., Lebrun, P., Sener, A., Malaisse, W. J., Ionic mechanism of diphenylhydantoin action on glucose-induced insulin release, Eur. J. Pharmacol., 73 (2-3): 189-97, 1981.

Pincus and Hsiao, Experimental Neurology (1981), 2241 demonstrated that PHT (200 µM) inhibits both depolarization-coupled synaptosomal calcium uptake and calcium efflux in rat brain. The authors specifically related PHT's effect on calcium efflux to modulation of calcium-sodium exchange. (See also Ref. 2240.)

2241. Pincus, J. H. and Hsiao, K., Phenytoin inhibits both synaptosomal 45Ca uptake and efflux, Exp. Neurol., 74: 293-8, 1981.
2240. Pincus, J. H. and Hsiao, K., Calcium uptake mechanisms affected by some convulsant anticonvulsant drugs, Brain Res, 217: 119-27, 1981.

Ferendelli and Daniels-McQueen, Journal of Pharmacology and Experimental Therapeutics (1982), 2490 studied the actions of PHT on veratridine-stimulated (sodium-dependent) and on potassium-stimulated (sodium-independent) calcium uptake in synaptosomes from rat cerebral cortex. PHT (15-300 µg/ml) inhibited both veratridine-and potassium-induced calcium uptake, but was more effective against veratridine. Inhibition of veratridine-stimulated calcium uptake by PHT appeared to be competitive, whereas the interaction between potassium and PHT was noncompetitive. The authors conclude that PHT inhibits sodium and calcium conductances in nervous tissue by different mechanisms.

2490. Ferrendelli, J. A., Daniels-McQueen, S., Comparative actions of phenytoin and other anticonvulsant drugs on potassium- and veratridine-stimulated calcium uptake in synaptosomes, J. Pharm. Exp. Ther., 220(1): 29-34, 1982.

Siegel, Janjic and Wollheim, Diabetes (1982), 2952 studied the inhibition of insulin release by PHT in rat pancreatic islet culture. PHT (80 µM), added during the second phase of glucose-induced biphasic insulin release, resulted in marked and rapid inhibition. PHT also significantly reduced glucose-induced calcium uptake of islet cells. The authors suggest that PHT inhibits glucose-stimulated insulin release by regulating calcium uptake via voltage-dependent calcium channels.

2952. Seigel, E. C., Janjic, D., Wollheim, C. B., Phenytoin inhibition of insulin release: studies on the involvement of Ca+ fluxes in rat pancreatic islets, Diabetes, 31: 265-9, 1982.

DeLorenzo, Annals of Neurology (1984), 2441 reviewed his own work and that of others on calmodulin systems in neuronal excitability. PHT has been found to inhibit calcium-calmodulin-regulated protein phosphorylation and neurotransmitter release by synaptic vesicles. The author suggests that this action of PHT is important in its ability to regulate abnormal neuronal excitability. (See also Refs. 2438, 2439, 2440.)

2441. De Lorenzo, B. J., Calmodulin systems in neuronal excitability: a molecular approach to epilepsy, Ann. Neural., 16: S 104-S 114, 1984.
2438. De Lorenzo, R. J., Antagonistic action of diphenylhydantoin and calcium on the endogenous phosphorylation of specific brain proteins, Neurology, 26: 386, 1976.
2439. De Lorenzo, R. J., Calmodulin in neurotransmitter release and synaptic function, Fed. Proc., 41(7): 2265-72, 1982.
2440. De Lorenzo, R. J., Calcium calmodulin protein phosphorylation in neuronal transmission: A molecular approach to neuronal excitability and anticonvulsant drug action, Advances in Neurology. Status Epilepticus, Delgado-Escueta, A. V., et al., Eds., Raven Press, New York, 325-38, 1983.

Greenberg, Cooper and Carpenter, Annals of Neurology (1984), 2555 report that PHT (30-300 µM) inhibited binding of the calcium antagonist [3H]-nitrendipine to voltage-dependent calcium channels in brain membranes. Phenobarbital, carbamazepine, valproic acid, and clonazepam failed to do so, or did so only at concentrations much higher than used clinically.

2555. Greenberg, D. A., Cooper, E. C., Carpenter, C. L., Phenytoin interacts with calcium channels in brain membranes, Ann. Neurol., 16: 616-17, 1984.

Gurevich and Razumovskaya, Farmakologii i Toksikologii (1984), 2563 in a review of the world laboratory literature, conclude that most of PHT's membrane stabilizing effects are related to its modulation of trans-membrane calcium flux. The authors suggest that PHT's inhibition of sodium entry into the cell may actually be secondary to its effects on calcium. In addition, they point out that PHT's effects on cyclic nucleotides, synaptic protein phosphorylation, transmitter release, and microtubule polymerization are calcium-dependent.

2563. Gurevich, V. S., Razumovskaya, N. I., Molecular mechanisms of the interaction of diphenylhydantoin with biological membranes, Farmakol. Toksiko., 47(l): 114-19, 1984.

Harris, Biophysical Journal (1984), 2575 studied the effects of membrane perturbants on voltage-activated sodium and calcium channels and calcium-dependent potassium channels in mouse synaptosomes. PHT (200 µM) decreased synaptosomal uptake of sodium and calcium, while decreasing calcium-stimulated potassium efflux. The author concludes that PHT's inhibition of sodium influx may be due to perturbation of membrane lipids, but that this effect is not sufficient to explain all of its effects on calcium and potassium channels.

2575. Harris, R. A., Differential effects of membrane perturbants on voltage-activated sodium and calcium-dependent potassium channels, Biophys. J., 45: 132-4, 1984.

Pincus and Weinfeld, Brain Research (1984), 2870 evaluated the effects of PHT on the release of acetylcholine (ACh) from rat brain synaptosomes. PHT (200 µM) reduced depolarization-linked ACh release in calcium-containing (1.0 mM) media. In non-depolarized synaptosomes, PHT increased basal ACh release irrespective of the external calcium concentration. The first effect, the authors suggest, is due to PHT's reduction of calcium influx, whereas the latter is due to an inhibition of intracellular calcium sequestration-extrusion mechanisms.

2870. Pincus, J. H., Weinfeld, H. M., Acetylcholine release from synaptosomes and phenytoin action, Brain Res., 296: 313-17, 1984.

Sugaya, Matsuo, Takagi, Kajiwara and Kidokoro, IRCS Medical Science (1984), 2990 reported that PHT (10 µM) inhibits the hyperexcitability of frog sciatic nerve induced by low extracellular calcium. The authors suggest that PHT inhibits abnormal intra-cellular calcium release induced by the low-calcium medium.

2990. Sugaya, E., Matsuo, T., Takagi, T., Kajiwara, K., Kidokoro, Y., Phenytoin inhibition of hyperexcitability induced by low calcium in frog nerves, IRCS Med. Sci., 12: 1109-10, 1984.

Sugaya, Onozuka, Furuichi, Kishii, Imao and Sugaya, Brain Research (1985), 2991 studied the effects of PHT on intracellular calcium and protein changes during pentylenetetrazol (PTZ)-induced bursting activity in snail neurons. They utilized computer-controlled electron probe x-ray microanalysis. PHT inhibited the intracellular calcium shift induced by PTZ, as well as the calcium binding state change near the cell membrane. PHT also inhibited the intracellular protein changes. These intracellular changes were produced without any effect on sodium, calcium, or potassium trans-membrane ionic currents.The authors suggest that PHT's actions on intracellular calcium movement and intracellular proteins are important to its ability to regulate abnormal excitability.

2991. Sugaya, E., Onozuka, M., Furuichi, H. A., Kishii, K., Imai, S., Sugaya, A., Effect of phenytoin on intracellular calcium and intracellular protein changes during pentylenetetrazole-induced bursting activity in snail neurons, Brain Res., 327(1985) 161-8, 1985.

Messing, Carpenter and Greenberg, Journal of Pharmacology and Experimental Therapeutics (1985), 2790 evaluated the effects of PHT on potassium-stimulated calcium uptake and [3H]-nitrendipine binding in PCI2 pheochromocytoma cells and compared these effects to those of a group of classical calcium channel antagonists including nimodipine, diltiazem, verapamil and flunarizine.PHT inhibited calcium uptake at clinically relevant concentrations and this effect was not significantly modified by sodium or potassium channel blockage. PHT also inhibited binding of [3H]-nitrendipine to PCI2 membranes. The authors suggest that PHT and the above calcium channel antagonists inhibit voltage-gated calcium flux by distinct, but functionally linked, mechanisms.

2790. Messing, B. O., Carpenter, C. L., Greenberg, D. A., Mechanism of calcium channel inhibition by phenytoin: comparison with classical calcium channel antagonists, J. Pharmacol. Exp. Ther., 235(2): 407-1 1, 1985.

Twombly and Narahashi, Society for Neuroscience Abstracts (1986), 3036 in voltage-clamp studies of N1E-115 neuroblastoma cells, found that PHT (above 10 µM) interfered with type I calcium currents by favoring the inactivated state of the calcium channel. PHT shifted the voltage dependence of this steady-state inactivation in the hyperpolarizing direction, allowing fewer calcium channels to open during test pulses. PHT's effects were both use- and frequency-dependent.

3036. Twombly, D. A., Narahashi, T., Phenytoin block of low threshold calcium channels is voltage and frequency-dependent, Soc. Neurosci. Abstr., 12 (Pt 2): 1193, 1986.

Yatani, Hamilton and Brown, Circulation Research (1986), 3094 using whole-cell patch-clamp techniques, studied the effects of PHT on calcium currents in single isolated guinea pig ventricular cells after suppression of sodium and potassium currents. PHT produced a voltage-and concentration-dependent decrease in calcium currents without significant change in current-voltage relations. At low frequencies (0.1 Hz) and negative holding potentials (-50 mV), PHT's half-blocking effect occurred at 200 µM. PHT prolonged the recovery of calcium currents from inactivation, bound selectively to the inactivated calcium channel state, and competitively blocked [3H]-nitrendipine binding to ventricular membrane preparations. Noting that PHT's effects on sodium and calcium channels are similar, the authors suggest that binding sites for PHT exist on both channels. (See Ref. 2922.)

3094. Yatani, A., Hamilton, S. L., Brown, A. M., Diphenylhydantoin blocks cardiac calcium channels and binds to the dihydropyridine receptor, Circ. Res., 59: 356-61, 1986.
2922. Sanchez-Chapula, J., Josephson, 1. R., Effect of phenytoin on the sodium current in isolated rat ventricular cells, J. Mol. Cell Cordial., 58(8): 515-22, 1983.

Yi, Seitz and Cooper, Federation Proceedings (1987), 3095 using a radioimmunoassay, found that PHT (100 µM) inhibited the release of calcitonin induced by high extracellular calcium (2.5 mM) in rat thyro-parathyroid complexes in vitro. Release of calcitonin in normal (1 mM) calcium was unaffected. The calcium channel blocker, nitrendipine, also inhibited calcium-stimulated calcitonin release. A calcium channel activator (BAY-K-8644) reversed the inhibitory effects of both nitrendipine and PHT. The authors suggest that PHT inhibits stimulated calcitonin secretion by interacting with calcium channels in thyroid parafollicular cells.

3095. Yi, S. J., Seitz, P. K., Cooper, C. W., Inhibition of in vitro secretion of rat calcitonin by phenytoin, Fed. Proc, 46(3): 393, 1987.

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