Rundfeldt C, Koch R, Richter A, Mevissen M, Gerecke U, Löscher W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Eur J Pharmacol. 1995 Feb 14;274(1-3):73-81. doi: 10.1016/0014-2999(94)00711-f.
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)
在中枢神经系统中，一氧化氮（NO）越来越被视为一种跨突触逆行信使，例如参与对NMDA亚型谷氨酸受体刺激的细胞反应。因此，能够改变NO生成的化合物，如NO合酶抑制剂，可能提供一种改变NMDA受体功能的方法。然而，NO合酶抑制的功能后果很复杂，因为NO不仅作为一种信使来激活鸟苷酸环化酶，从而在NMDA受体受到刺激时提高靶细胞中的环磷酸鸟苷（cGMP），而且还通过受体复合物上的氧化还原调节位点诱导对NMDA受体的反馈抑制。这可能解释了先前在缺血和癫痫动物模型中使用NO合酶抑制剂所得到的相互矛盾的结果。在本研究中，我们试图通过在一种新型皮质癫痫阈值模型中研究不同剂量的此类药物，来解决关于NO合酶抑制剂在癫痫模型中作用的报道差异。在这个模型中，通过直接向大脑皮层施加斜坡形电脉冲序列，在短时间间隔内确定大鼠癫痫发作的阈值，从而能够确定个体大鼠中抗惊厥或促惊厥药物作用的时间进程。将两种NO合酶抑制剂，即N G -硝基-L-精氨酸和N G -硝基-L-精氨酸甲酯，与一种临床有效的抗癫痫药物丙戊酸盐进行了比较。（摘要截选至250字）
