FACTORS DETERMINING PROCONVULSANT AND ANTICONVULSANT EFFECTS OF INHIBITORS OF NITRIC-OXIDE SYNTHASE IN RODENTS

Although a majority of studies suggest that inhibitors of nitric oxide synthase (NOS) are proconvulsant, a substantial minority indicate the opposite (i.e. that inhibitors of NOS are anticonvulsant). As a conse quence, the role of endogenous nitric oxide (NO) in the expression of seizures is unclear. In the present series of experiments, we therefor e assessed factors governing pro- and anticonvulsant effects of inhibi tors of NOS. In mice receiving systemic injections of kainate or picro toxin, we confirmed the hypothesis that the effects of inhibitors of N OS vary with the model of seizure: Whereas 7-nitroindazole (7-NI) redu ced the latency and increased the severity of kainate-induced convulsi ons (Expt. 1), both 7-NI and N-omega-nitro-L-arginine methyl ester (L- NAME) slightly delayed clonus following the systemic administration of picrotoxin at doses greater than or equal to 3.5 mg/kg but not at dos es less than or equal to 3.0 mg/kg (Expts. 2-5). Paradoxically, L-NAME but not 7-NI significantly reduced the CD50 of picrotoxin, which was approximately 2 mg/kg in control mice (Expt. 4), revealing inhibitor-s pecific interactions with the dose of the convulsant. Finally, we dete rmined in rats that the effects of L-NAME on kainate-induced seizures vary as a function of genetic factors: L-NAME significantly potentiate d kainate-induced convulsions in Sprague-Dawley rats but not in Wistar rats (Expt. 6).