Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats.
In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate.(ABSTRACT TRUNCATED AT 250 WORDS)
Rundfeldt
C
C
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Koch
R
R
Richter
A
A
Mevissen
M
M
Gerecke
U
U
Löscher
W
W
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D009569:Nitric Oxide; D014635:Valproic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester