BIOACTIVE 6-NITRONOREPINEPHRINE IDENTIFIED IN MAMMALIAN BRAIN

Norepinephrine (NE) (von Euler, U.S. (1972) in Catecholamines (Blaschk o, H., and Muscholl, E., eds.) pp. 186-230, Springer-Verlag, Berlin) a nd nitric oxide (NO.) function as neurotransmitters in the nervous sys tem. We have shown that NE levels in the rat hypothalamic paraventricu lar nucleus (Shintani, F., Kato, R., Kinoshita, N., Kanba, S., Asai, M ., and Nakaki, T. (1995) Proceedings of the Satellite Symposium, 4th I BRO World Congress on Neuroscience, Otsu, 1995) diminish in the presen ce 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 Constantini, C. (1995) Bioorg. Med. Chem. 3, 923-927). We now rep ort 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 syntha se, N-G-nitro-L-arginine methyl ester (L-NAME). This was reversed by c oadministration of L-arginine, suggesting that nitric oxide synthase p articipated in the formation of 6-nitronorepinephrine. Moreover, we fo und that 6-nitronorepinephrine inhibits the activity of catechol O-met hyltransferase, as well as NE transport into rat synaptosomes. A rat b rain microdialysis experiment showed that perfusion of 6-nitronorepine phrine into the rat paraventricular nucleus significantly elevated NE while decreasing 3-methoxy-4-hydroxyphenylglycol and that L-NAME admin istered intraperitoneally decreased NE and increased 3-methoxy-4-hydro xyphenylglycol. These observations suggest that 6-nitronorepinephrine generated in nuclei containing both adrenergic and nitrergic neurons i nhibits NE inactivation. We propose that 6-nitronorepinephrine is a po tential signal molecule linking the actions of NE and NO..