title: Potent inhibition of human neuronal nitric oxide synthase by N(G)-nitro-L-arginine methyl ester results from contaminating N(G)-nitro-L-arginine.
abstract: N(G)-Nitro-L-arginine methyl ester (L-NAME), inhibits the three isozymes of nitric oxide synthase (NOS) in vitro and in vivo. The mechanism of NOS inhibition by L-NAME is uncertain. L-NAME was a time-dependent inhibitor of neuronal NOS (nNOS). Concommitantly, L-NAME was hydrolyzed, non-enzymatically, to N(G)-Nitro-L-arginine (L-NA) during the enzyme assay. The time-dependent inhibition of nNOS by L-NAME was the result of this time-dependent formation of L-NA. Furthermore, N(G)-Nitro-L-arginine methyl amide, which is an isosteric analogue of L-NAME that is much less susceptible to hydrolysis, was a rapidly reversible weak inhibitor of NOS. These data suggested that L-NAME itself was a weak and rapidly reversible inhibitor of nNOS. Most of the inhibition of nNOS by a solution of L-NAME is the result of the formation of L-NA. L-NAME was a substrate for porcine liver esterase.
authors.affiliation: Glaxo Wellcome Research Institute, Department of Molecular Biochemistry, Research Triangle Park, NC 27709, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Furfine
authors.forename: K
authors.initials: K
authors.lastname: Carbine
authors.forename: S
authors.initials: S
authors.lastname: Bunker
authors.forename: G
authors.initials: G
authors.lastname: Tanoury
authors.forename: M
authors.initials: M
authors.lastname: Harmon
authors.forename: V
authors.initials: V
authors.lastname: Laubach
authors.forename: P
authors.initials: P
authors.lastname: Sherman
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000201:enzymology; D002417:Cattle; D006224:Cricetinae; D004340:Drug Contamination; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D011817:Rabbits; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester