title: Selective inhibitors of nitric oxide synthase (NOS) implicate a constitutive isoform of NOS in the regulation of interleukin-1-induced ACTH secretion in rats.
abstract: Nitric oxide synthase (NOS) exists in at least three distinct isoforms: an inducible NOS (NOS II), and two forms which are constitutively expressed-brain NOS (NOS I) and endothelial NOS (NOS III). We have previously shown that the NOS inhibitor, N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), markedly potentiates and prolongs the increase in plasma adrenocorticotropin (ACTH) concentrations produced by the intravenous injection of interleukin-1β (IL-1β) in the rat. However, the mechanism of action of L-NAME is unknown. The purpose of the present study was to determine the effects on IL-1β-induced ACTH secretion in the rat, of several NOS inhibitors, whose selectivity for the different NOS isoforms has been well characterized, and which lack the muscarinic receptor antagonist properties that have been reported for L-NAME. Subcutaneous (sc) pretreatment with L-NAME (50-300 μmol/kg) produced the expected pronounced exacerbation of the ACTH response to IL-1β. This effect was mimicked by N(G)-nitro-L-arginine, which preferentially inhibits constitutive forms of NOS. In contrast, aminoguanidine, a selective inducible NOS inhibitor at doses up to 3×1.8 mmol/kg, was without effect, suggesting that it is a constitutive form of NOS that regulates the ACTH response to IL-1β. Selective inhibition of brain NOS using either 7-nitro-indazole (administered intraperitoneally) or L-NAME (administered intracerebroventricularly) did not significantly alter ACTH concentrations after IL-1β. Collectively, these data indicate that NO restrains the ACTH response to IL-1β, and that the NO responsible for this effect is generated by a constitutive, most probably endothelial, isoform of NOS.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 North Torrey Pines Road, 92037, La Jolla, CA.
authors.forename: A V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: C
authors.initials: C
authors.lastname: Rivier