Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus.
Nitric oxide mediates norepinephrine-induced prostaglandin E2 release from the hypothalamus.
复制标题
一氧化氮介导去甲肾上腺素诱导的下丘脑前列腺素 E2 释放。
DOI：
10.1073/pnas.89.23.11543
复制
发表时间：
1992
影响因子：
11.1
通讯作者：
McCann,SM
中科院分区：
文献类型：
--
作者：
Rettori,V;Gimeno,M;Lyson,K;McCann,SM
一氧化氮(NO)由精氨酸转化为瓜氨酸，NO由一氧化氮合酶(NO)合酶生成，介导血管平滑肌的松弛。免疫细胞化学方法显示，包括下丘脑在内的中枢神经系统不同部位的神经元均未发现合酶。后者的发现提示，NO可能在控制下丘脑多肽的释放中起作用。我们先前已经证明去甲肾上腺素介导促黄体激素释放激素(LHRH)从正中隆起的LHRH终末释放到垂体门静脉，后者将LHRH输送到脑下垂体前叶，从而触发促性腺激素释放。从这些终末释放LHRH需要增加前列腺素E2(PGE2)的释放。PGE2激活腺苷环化酶生成cAMP，cAMP诱导LHRH分泌颗粒胞吐。鉴于上述证据，以及关于NO在中枢神经系统中的重要性的越来越多的证据，我们想到NO可能参与了这一过程。因此，我们评估了NO在下丘脑内侧基底节PGE2释放中的作用。正如先前报道的那样，去甲肾上腺素(10微米)增加了下丘脑碎片中PGE2的释放。NO合成酶抑制剂NG-单甲基-L-精氨酸(NMMA，300微米)可阻断去甲肾上腺素诱导的前列腺素E_2释放，但对前列腺素E_2的基础释放无影响。释放NO的硝普钠(100微米)也增加了下丘脑碎片中PGE2的释放。这一升高不受NMMA的影响，可能是因为NMMA阻止了NO的酶促生成，但不改变硝普钠释放的NO。当硝普钠释放的NO被血红蛋白(2微克/毫升)灭活时，硝普钠对PGE2释放的影响被完全抑制。NMMA和Hb均不改变PGE2的基础释放，这表明NO不是PGE2基础释放的原因。添加一氧化氮合酶底物L-精氨酸(10微米至1 mM)对基础前列腺素E_2产量无影响。这些结果表明，在体外未受刺激的下丘脑碎片中，一氧化氮合酶不被激活。结果表明，去甲肾上腺素激活了NO合成酶，导致了NO的产生，进而激活了环氧合酶，导致了PGE2的产生。然后PGE2激活腺苷环化酶，导致cAMP增加，从而诱导LHRH分泌颗粒和PGE2释放的其他神经肽的胞吐。NO在去甲肾上腺素诱导的下丘脑PGE2释放过程中是必不可少的，这一迹象为LHRH释放的机制提供了洞察力，这一结果开启了NO对神经功能的重要性可能在神经系统中广泛存在的可能性。
Nitric oxide (NO), formed by conversion of arginine to citrulline and NO by NO synthase, mediates relaxation of vascular smooth muscle. NO synthase has been demonstrated by immunocytochemical methods in neurons in various parts of the central nervous system including the hypothalamus. The latter finding suggested to us that NO might play a role in controlling the release of hypothalamic peptides. We have previously shown that norepinephrine mediates the release of luteinizing hormone-releasing hormone (LHRH) from LHRH terminals in the median eminence into the hypophyseal portal veins, which transport LHRH to the anterior pituitary gland to trigger release of luteinizing hormone from gonadotrophs. LHRH release from these terminals requires increased release of prostaglandin E2 (PGE2). PGE2 activates adenylate cyclase to produce cAMP, and then cAMP induces the exocytosis of LHRH secretory granules. In view of the evidence above and because of the developing evidence for the importance of NO in the central nervous system, it occurred to us that NO might be involved in this process. Consequently, we evaluated the role of NO in the release of PGE2 from medial basal hypothalamic fragments. As previously reported, norepinephrine (10 microM) increased PGE2 release from the hypothalamic fragments. The inhibitor of NO synthase NG-monomethyl-L-arginine (NMMA, 300 microM) blocked the stimulation of PGE2 release induced by norepinephrine but had no effect on the basal release of PGE2. Sodium nitroprusside (100 microM), which liberates NO, also elevated PGE2 release from the hypothalamic fragments. This elevation was not affected by NMMA, presumably because NMMA blocks enzymatic generation of NO but does not alter NO liberated by nitroprusside. When the NO liberated by nitroprusside was inactivated by hemoglobin (2 micrograms/ml), the effect of nitroprusside on PGE2 release was completely inhibited. Neither NMMA nor hemoglobin altered the basal release of PGE2, which indicates that NO is not responsible for basal PGE2 release. Addition of L-arginine (10 microM to 1 mM), the substrate for NO synthase, had no effect on basal PGE2 production. These results indicate that NO synthase is not activated in unstimulated hypothalamic fragments in vitro. The results suggest that norepinephrine activates NO synthase leading to the production of NO, which subsequently activates cyclooxygenase and results in the production of PGE2. PGE2 then activates adenylate cyclase leading to generation of increased cAMP, which induces exocytosis of secretory granules of LHRH and other neuropeptides released by PGE2. The indication that NO is essential to norepinephrine-induced release of PGE2 from hypothalamic fragments provides insight into the mechanism of LHRH release and the results open the possibility that the importance of NO to neuronal functions may be widespread in the nervous system.