Shintani F, Kinoshita T, Kanba S, Ishikawa T, Suzuki E, Sasakawa N, Kato R, Asai M, Nakaki T
Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.
J Biol Chem. 1996 Jun 7;271(23):13561-5. doi: 10.1074/jbc.271.23.13561.
Norepinephrine (NE) (von Euler, U. S. (1972) in Catecholamines (Blaschko, H., and Muscholl, E., eds.) pp. 186-230, Springer-Verlag, Berlin) and nitric oxide (NO.) function as neurotransmitters in the nervous system. We have shown that NE levels in the rat hypothalamic paraventricular nucleus (Shintani, F., Kato, R., Kinoshita, N., Kanba, S., Asai, M., and Nakaki, T.(1995) Proceedings of the Satellite Symposium, 4th IBRO World Congress on Neuroscience, Otsu, 1995) diminish in the presence of NO.. This observation prompted us to explore the possibility of an in vivo interaction between NE and NO. or NO.-related molecules. In fact, nitration of NE has been shown to occur in vitro (d'Ischia, M., and Costantini, C. (1995) Bioorg. Med. Chem. 3, 923-927). We now report the identification of 6-nitronorepinephrine in the mammalian brain. Amounts of 6-nitronorepinephrine in the rat brain were attenuated by intraperitoneal administration of an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (L-NAME). This was reversed by coadministration of L-arginine, suggesting that nitric oxide synthase participated in the formation of 6-nitronorepinephrine. Moreover, we found that 6-nitronorepinephrine inhibits the activity of catechol O-methyltransferase, as well as NE transport into rat synaptosomes. A rat brain microdialysis experiment showed that perfusion of 6-nitronorepinephrine into the rat paraventricular nucleus significantly elevated NE while decreasing 3-methoxy-4-hydroxyphenylglycol and that L-NAME administered intraperitoneally decreased NE and increased 3-methoxy-4-hydroxyphenylglycol. These observations suggest that 6-nitronorepinephrine generated in nuclei containing both adrenergic and nitrergic neurons inhibits NE inactivation. We propose that 6-nitronorepinephrine is a potential signal molecule linking the actions of NE and NO..
去甲肾上腺素（NE）（冯·欧勒，美国（1972年），载于《儿茶酚胺》（布拉施科，H.，和穆肖尔，E.，编），第186 - 230页，施普林格出版社，柏林）和一氧化氮（NO.）在神经系统中作为神经递质发挥作用。我们已经表明，在大鼠下丘脑室旁核中，NE水平（新谷，F.，加藤，R.，木下，N.，神波，S.，浅井，M.，和中木，T.（1995年），卫星研讨会论文集，第4届国际脑研究组织世界神经科学大会，大津，1995年）在有NO.存在的情况下会降低。这一观察结果促使我们探索NE与NO.或与NO.相关分子在体内相互作用的可能性。事实上，已经表明NE的硝化作用在体外会发生（迪夏，M.，和科斯坦蒂尼，C.（1995年），《生物有机与药物化学》3，923 - 927）。我们现在报告在哺乳动物大脑中鉴定出6 - 硝基去甲肾上腺素。通过腹腔注射一氧化氮合酶抑制剂NG - 硝基 - L - 精氨酸甲酯（L - NAME），大鼠脑中6 - 硝基去甲肾上腺素的量会减少。同时给予L - 精氨酸可使其逆转，这表明一氧化氮合酶参与了6 - 硝基去甲肾上腺素的形成。此外，我们发现6 - 硝基去甲肾上腺素会抑制儿茶酚 - O - 甲基转移酶的活性，以及NE向大鼠突触体的转运。一项大鼠脑微透析实验表明，向大鼠室旁核灌注6 - 硝基去甲肾上腺素会显著升高NE水平，同时降低3 - 甲氧基 - 4 - 羟基苯乙二醇，而腹腔注射L - NAME会降低NE水平并升高3 - 甲氧基 - 4 - 羟基苯乙二醇。这些观察结果表明，在同时含有肾上腺素能和一氧化氮能神经元的核中产生的6 - 硝基去甲肾上腺素会抑制NE的失活。我们提出6 - 硝基去甲肾上腺素是一种潜在的信号分子，可连接NE和NO.的作用。
