Guanylate cyclase—Cyclic GMP in mouse cerebral cortex and cerebellum: Modification by anticonvulsants

Abstract

Incubated tissue slices from mouse cerebral cortex and cerebellum readily accumulate cyclic GMP in response to a challenge by ouabain, NaN 3, NH 2OH, or KCl. Under similar conditions, l-glutamate, l-aspartate, glycine, γ-aminobutyric acid, kainic acid, and the calcium ionophore, A-23187, were ineffective. Inhibition of the ouabain-induced accumulation of cyclic GMP was evident with valproate, carbamazepine, clonazepam, phenytoin, and phenobarbital. Only phenytoin blocked the action of KCl and cyclic GMP responses to NaN 3 were inhibited by high concentrations of valproate, carbamazepine, phenytoin, or phenobarbital. The effects of NH 2OH were attenuated by high concentrations of carbamazepine, phenobarbital, and clonazepam (cortex only). Guanylate cyclase activity in homogenates of cortex and cerebellum was enhanced in the presence of NaN 3, NH 2OH, or Ca 2+ (in low concentrations of Mn 2+). The enzyme activation induced by Ca + was blocked only by large (1 m m) amounts of carbamazepine. In like manner, large concentrations of carbamazepine, phenytoin (cortex), or clonazepam (cortex) were effective in reducing guanylate cyclase stimulation by NaN 3. No agent affected the NH 2OH responses. The results suggest that anticonvulsant drug actions with regard to central cyclic GMP systems are related to the Na +-induced depolarization of nerve tissue and not to any direct actions on the guanylate cyclase enzyme.