Inhibition of NO synthase increases the severity of kainic acid-induced seizures in rodents.
The nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (NNA) and the putative brain-selective NO synthase inhibitor 7-nitroindazole (7-NI) were used to determine the role of endogenous NO on seizures induced by kainic acid (KA) in rats and KA, pilocarpine, bicuculline, picrotoxin and pentylenetetrazole (PTZ) in mice. Rats given a subconvulsant dose of KA (6 mg/kg, i.p.) had seizures after they had been pretreated with NNA (50 mg/kg, i.p.). With a higher dose of KA (12 mg/kg, i.p.), NNA caused an increase in wild running seizures and mortality. Unlike NNA, 7-NI had no effect on KA-induced seizures. Similarly, NNA but not 7-NI caused a worsening of seizures in mice measured as a shortening of seizure latency and an increase in wild running and mortality. The effect of NNA on seizure latency was completely reversed by the competitive substrate for NO synthase, L-arginine. NNA had no effect on seizure latency following any of the other convulsants and increased mortality following pilocarpine and picrotoxin alone. Our results indicate that NNA may enhance the severity of KA-induced seizures through suppression of NO synthase activity in the vascular endothelium. The resulting impairment of cerebrovascular autoregulation may cause a mismatch between metabolic demand and blood flow during seizures leading to facilitation of spread. The absence of a comparable effect of NNA on other seizure models may indicate differences in the degree to which seizure activity in different models is influenced by the metabolic impairment secondary to decreased blood flow.
Penix
L P
LP
Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Davis
W
W
Subramaniam
S
S
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D007191:Indazoles; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D007608:Kainic Acid; C080122:7-nitroindazole; D010433:Pentylenetetrazole; D001640:Bicuculline