Inhibition by lamotrigine of the generation of nitric oxide in rat forebrain slices.
Depolarization of adult rat forebrain slices with veratrine induced the release of excitatory amino acids (glutamate and aspartate), the synthesis of nitric oxide (NO), and increases in cyclic GMP (cGMP). The NO synthase inhibitors N omega-monomethyl-L-arginine and N omega-nitro-L-arginine methyl ester decreased the release of NO and the levels of cGMP without affecting the release of excitatory amino acids. In contrast, the antiepileptic drug lamotrigine inhibited the release of excitatory amino acids and of NO, and decreased the levels of cGMP without causing a significant direct inhibition of the NO synthase. Furthermore, the synthesis of NO and the increases in cGMP induced by veratrine were partially blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 but not by 6-nitro-7-sulphamobenzo (f) quinoxaline-2,3-dione, a non-NMDA receptor antagonist. Neither of these compounds inhibited directly the NO synthase or the release of excitatory amino acids. Thus, these three types of compound act as an inhibitor of voltage-sensitive sodium channels (lamotrigine), as a receptor antagonist (MK-801), or as direct inhibitors of the NO synthase, to block the pathway leading to increased cGMP after veratrine depolarization. It is likely that some of the pharmacological and therapeutic actions shared by these three types of compound are, at least in part, a consequence of inhibition of the synthesis of NO.
Lizasoain
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Wellcome Research Laboratories, Kent, England, UK.
Knowles
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RG
Moncada
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D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D066298:In Vitro Techniques; D000077213:Lamotrigine; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014227:Triazines / Q000494:pharmacology*; D014702:Veratrine / Q000494:pharmacology
D000596:Amino Acids; D014227:Triazines; D009569:Nitric Oxide; D014702:Veratrine; D006152:Cyclic GMP; D000077213:Lamotrigine