Similar effects of phenytoin and tetrodotoxin on cyclic nucleotid regulation in depolarized brain tissue.
Veratridine, ouabain, glutamate and high concentrations of K+, agents which cause depolarization of excitable cells, markedly elevate levels of adenosine 3':5'-monophosphate (cyclic AMP) and guanosine 3':5'-monophosphate (cyclic GMP) in brain tissue, in vitro. Phenytoin inhibits veratridine (5 micron)- and ouabain (100 micron)-induced accumulations of both cyclic nucleotides in slices of mouse cerebral cortex. As little as 10 to 30 micron phenytoin produces a statistically significant depression, and 100 to 400 micron inhibits more than 90%. In contrast, at concentrations up to 400 micron, the drug has little or no effect on elevations of cyclic AMP or cyclic GMP caused by glutamate (10 mM) or K+ (64 mM). The inhibitory action of phenytoin on ouabain-induced elevations of cyclic nucleotides appears to be noncompetitive; inhibition of the veratridine effects probably is also noncompetitive. Tetrodotoxin also inhibits ouabain- and veratridine-induced elevations of cyclic nucleotides in brain slices, but it is 3 orders of magnitude more potent than phenytoin. Like phenytoin, tetrodotoxin does not inhibit the effects of glutamate or K+ on cyclic nucleotide regulation. These data suggest that, similar to tetrodotoxin phenytoin blocks sodium channels in excitable membranes. Possibly this mechanism is responsible for the antiepileptic action of phenytoin.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D005971:Glutamates / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010672:Phenytoin / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology*; D014701:Veratridine / Q000494:pharmacology
D005971:Glutamates; D009712:Nucleotides, Cyclic; D013779:Tetrodotoxin; D010042:Ouabain; D010672:Phenytoin; D014701:Veratridine; D011188:Potassium