Enhancement of 7-nitro indazole-induced inhibition of brain nitric oxide synthase by norharmane.
7-Nitro indazole (7-NI) has been used as a selective inhibitor of neuronal nitric oxide synthase (NOS) in vivo. This agent has a short duration of action which may be due to its metabolism. The structure of 7-NI resembles that of tryptophan which can be metabolized by the enzyme indolamine 2,3-dioxygenase (IDO). If 7-NI is also metabolized by this enzyme, then inhibition of IDO should augment the action of 7-NI on brain NOS activity. This possibility was examined by investigating the potential of norharmane, an IDO inhibitor, on the inhibitory effect of 7-NI on NOS catalytic activity (3, 4.5 and 7.5 h post-injection of 7-NI) in five brain regions. Norharmane, which alone did not alter NOS activity, enhanced the action of 7-NI on NOS activity in the cortex (4.5 and 7.5 h), hippocampus (3 h) and substantia nigra (3, 4.5 and 7.5 h) but not in the cerebellum or striatum. This suggests that IDO activity may, at least in part, be responsible for the relatively short duration of 7-NI action.
Connop
B P
BP
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Kalisch
B E
BE
Boegman
R J
RJ
Jhamandas
K
K
Beninger
R J
RJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002243:Carbolines; D002531:Cerebellum / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D006247:Harmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002243:Carbolines; D007191:Indazoles; D006247:Harmine; C010262:norharman; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases