NITRIC-OXIDE, A NOVEL BIOLOGIC MESSENGER
NITRIC-OXIDE, A NOVEL BIOLOGIC MESSENGER
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DOI：
10.1016/0092-8674(92)90301-r
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发表时间：
1992-09-04
期刊：
影响因子：
64.5
通讯作者：
SNYDER, SH
中科院分区：
文献类型：
--
作者：
LOWENSTEIN, CJ;SNYDER, SH
NO首先在哺乳动物生理学中被认为是巨噬细胞作用的中介（Nathan and Hibbs, 1991）。巨噬细胞产生来源于一氧化氮的硝酸盐，一氧化氮的前体是精氨酸。精氨酸衍生物阻断NO的形成，从培养培养基中去除精氨酸也是如此。这两种治疗方法都阻断了巨噬细胞的杀肿瘤和杀菌作用，使NO成为巨噬细胞功能的重要介质（图1）。NO在血管中的作用源于发现乙酰胆碱和其他药物放松平滑肌从而扩张血管的能力依赖于完整内皮的存在，内皮释放扩散因子（Ignarro, 1990; Moncada et al., 1991）。这种内皮来源的松弛因子似乎非常不稳定，半衰期为5 s。平行研究证实NO是介导硝酸甘油和其他抗心绞痛有机硝酸盐的平滑肌松弛作用的活性代谢物，从而促进了NO的鉴定。一氧化氮作为内皮来源的松弛因子的鉴定导致实验表明脑组织可以产生一氧化氮（Garthwaite, 1991）。随后的证据表明NO在大脑中的功能来自于NO在血管中的作用。NO通过与关酰环化酶活性位点血红素中的铁结合，激活酶生成cGMP， cGMP刺激cGMP依赖性蛋白激酶，导致肌肉松弛（图1）。在大脑中，cGMP的最高密度发生在小脑，在小脑中，兴奋性神经递质谷氨酸通过n -甲基-对天冬氨酸（NMDA）亚型受体提高cGMP水平。谷氨酸或NMDA三重NO合成酶活性（Bredt和Snyder， 1992）。添加NO合成酶抑制剂，如n -甲基精氨酸或ng -硝基精氨酸阻断剂，均可提高NO合成酶活性和cGMP水平，从而确定NO在谷氨酸神经递质作用中的作用（Bredt和Snyder, 1992; Garthwaite, 1991）。没有合酶
NO was first appreciated in mammalian physiology as a mediator of macrophage actions (Nathan and Hibbs, 1991). Macrophages produce nitrates that derive from NO, whose precursor is arginine. Arginine derivatives block the formation of NO, as does removal of arginine from the incubation medium. Both these treatments block the tumoricidal and bactericidal actions of macrophages, establishing NO as a crucial mediator of macrophage function (Figure 1).A role for NO in blood vessels stemmed from the discovery that the ability of acetylcholine and other agents to relax smooth muscle and hence dilate blood vessels is dependent on the presence of an intact endothelium, which releases a diffusible factor (Ignarro, 1990; Moncada et al., 1991). This endothelial-derived relaxing factor appeared to be extremely labile with a half-life of-5 s. Its identification as NO was facilitated by parallel studies that established NO as the active metabolite mediating the smooth muscle relaxant effects of nitroglycerin and other anti-angina1 organic nitrates. The identification of NO as endothelial-derived relaxing factor led to experiments showing that brain tissue can generate NO (Garthwaite, 1991). Subsequent evidence for NO functions in brain derived from knowledge of how NO acts in blood vessels. By binding to iron in the heme at the active site of guanylyl cyclase, NO activates the enzyme to generate cGMP, which stimulates cGMP-dependent protein kinase, resulting in muscle relaxation (Figure 1). In the brain, the highest densities of cGMP occur in the cerebellum, where the excitatory neurotransmitter glutamate elevates cGMP levels via the N-methyl-p-aspartate (NMDA) subtype of receptors. Glutamate or NMDA triple NO synthase activity (Bredt and Snyder, 1992). Addition of NO synthase inhibitors such as N-methyl-arginine or NG-nitro-arginine block both increased NO synthase activity and elevation of cGMP levels, establishing a role for NO in the neurotransmitter actionsof glutamate (Bredt and Snyder, 1992; Garthwaite, 1991). NO Synthase