Inhibition by Lamotrigine of the Generation of Nitric Oxide in Rat Forebrain Slices-猫眼课题宝

拉莫三嗪抑制大鼠前脑切片中一氧化氮的产生

DOI：

发表时间：

1995

期刊：

Journal of Neurochemistry

影响因子：

4.7

通讯作者：

中科院分区：

医学2区

文献类型：

作者：

I. Lizasoaín;Richard Graham Knowles;S. Moncada

摘要：去极化成年大鼠前脑片与藜芦碱诱导兴奋性氨基酸（谷氨酸和天冬氨酸）的释放，一氧化氮（NO）的合成，并增加环GMP（cGMP）。NO合成酶抑制剂Nω-单甲基-L-精氨酸和Nω-硝基-L-精氨酸甲酯可降低NO的释放和cGMP水平，但不影响兴奋性氨基酸的释放。与此相反，抗癫痫药物拉莫三嗪抑制兴奋性氨基酸和NO的释放，并降低cGMP的水平，而不引起显着的直接抑制NO合成酶。此外，N-甲基-d-天冬氨酸（NMDA）受体拮抗剂MK-801可部分阻断藜芦碱诱导的NO合成和cGMP升高，但非NMDA受体拮抗剂6-硝基-7-磺氨苯并（f）喹喔啉-2，3-二酮不能阻断。这两种化合物都不能直接抑制NO合酶或兴奋性氨基酸的释放。因此，这三种类型的化合物作为电压敏感性钠通道的抑制剂（拉莫三嗪），作为受体拮抗剂（MK-801），或作为NO合酶的直接抑制剂，以阻断藜芦碱去极化后导致cGMP增加的途径。这三种类型的化合物所共有的一些药理学和治疗作用可能至少部分是抑制NO合成的结果。

Abstract: 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 Nω‐monomethyl‐l‐arginine and Nω‐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.