@article {Ferrendelli787, author = {J A Ferrendelli and D A Kinscherf}, title = {Similar effects of phenytoin and tetrodotoxin on cyclic nucleotid regulation in depolarized brain tissue.}, volume = {207}, number = {3}, pages = {787--793}, year = {1978}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Veratridine, ouabain, glutamate and high concentrations of K+, agents which cause depolarization of excitable cells, markedly elevate levels of adenosine 3{\textquoteright}:5{\textquoteright}-monophosphate (cyclic AMP) and guanosine 3{\textquoteright}:5{\textquoteright}-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.}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/207/3/787}, eprint = {https://jpet.aspetjournals.org/content/207/3/787.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }