ANTICONVULSANT EFFECTS OF 7-NITROINDAZOLE IN RODENTS WITH REFLEX EPILEPSY MAY RESULT FROM L-ARGININE ACCUMULATION OR A REDUCTION IN NITRIC-OXIDE OR L-CITRULLINE FORMATION

1 To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound-ind uced seizures in DBA/2 mice and in genetically epilepsy-prone (GEP) ra ts. 2 The neuronal selective nitric oxide synthase inhibitor, 7-nitroi ndazole (7-NI) is anticonvulsant in these models with ED(50) values ag ainst clonic seizures in mg kg(-1) i.p. (times following injection) of : 74 (+0.25 h), 120 (+1 h) in DBA/2 mice, and 56 (+0.25 h), 42 (+0.5 h ), 36 (+1 h), 28 (+2 h), 38 (+4 h), 93 (+8 h) in GEP rats. 3 Therapeut ic indices (locomotor deficit ED(50)/anticonvulsant ED(50)) for 7-NI a re low, ranging from 0.6 to 1.1 at +0.25 h to +1 h after administratio n in GEP rats, but are more favourable at later times (1.6 at +2 h and 2.9 at +4 h). 4 The substrate for nitric oxide synthase, L-arginine ( 500-5000 mg kg(-1), i.p. or 100-300 mu g, i.c.v.) but not D-arginine ( 300 mu g i.c.v.) is anticonvulsant in DBA/2 mice. L-Arginine (500-5000 mg kg(-1), i.p. or 1800-6000 mu g, i.c.v.) is a more potent anticonvu lsant than D-arginine (1500-2500 mg kg(-1), i.p. or 6000 mu g, i.c.v.) in GEP rats. 5 In DBA/2 mice, L-arginine (30 mu g i.c.v.) reverses th e anticonvulsant effect of 7-NI (50 mg kg(-1), i.p.). 6 In GEP rats, l ow dose L-arginine (25-50 mg kg(-1), i.p.) but not D-arginine (50 mg k g(-1), i.p.) reverses the anticonvulsant effect of low dose 7-NI (25 m g kg(-1), i.p.). A higher dose of L-arginine (500 mg kg(-1), i.p.) or 7-NI (50 mg kg(-1), i.p.) produces summation of anticonvulsant effect. 7 The product for nitric oxide synthase, L-citrulline (250-831 mu g i .c.v.), is convulsant in DBA/2 mice. 8 The anticonvulsant effect of th e neuronal selective nitric oxide synthase inhibitor, 7-nitroindazole, may therefore be mediated by L-arginine accumulation, as well as by a reduction in nitric oxide and L-citrulline formation in rodent models of reflex epilepsy.