Nitric oxide (NO) has been recently shown to be an endogenous molecule of significant biological importance. It has been shown to play a role in, among other things, the activation of guanylate cyclase and in the cytotoxicity associated with activated macrophages. Thus, the biological significance of NO makes the elucidation of the biosynthetic pathway exceedingly important. For example, inadequate NO biosynthesis can possibly contribute to hypertension, atherosclerosis, male impotence, or immune system deficiency. The research described in this proposal intends to elucidate the mechanism of NO generation from the endogenous precursor, arginine. By utilizing synthetic arginine analogs, the mechanism of oxidation, the binding specificity and the general enzymology will be investigated. As the significance of NO in physiology grows, there will be an increased need for specific and potent compounds to be used to demonstrate NO function. This approach will allow the development of a series of compounds which will be valuable research tools. Also, the knowledge gained from this approach will provide a basis for the development of compounds of potential therapeutic utility.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL046388-02
Application #
3365530
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1992-02-01
Project End
1995-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Fukuto, J M; Chaudhuri, G (1995) Inhibition of constitutive and inducible nitric oxide synthase: potential selective inhibition. Annu Rev Pharmacol Toxicol 35:165-94
Daghigh, F; Fukuto, J M; Ash, D E (1994) Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun 202:174-80
Hobbs, A J; Fukuto, J M; Ignarro, L J (1994) Formation of free nitric oxide from l-arginine by nitric oxide synthase: direct enhancement of generation by superoxide dismutase. Proc Natl Acad Sci U S A 91:10992-6
Fukuto, J M; Gulati, P; Nagasawa, H T (1994) Involvement of nitroxyl (HNO) in the cyanamide-induced vasorelaxation of rabbit aorta. Biochem Pharmacol 47:922-4
Ignarro, L J; Fukuto, J M; Griscavage, J M et al. (1993) Oxidation of nitric oxide in aqueous solution to nitrite but not nitrate: comparison with enzymatically formed nitric oxide from L-arginine. Proc Natl Acad Sci U S A 90:8103-7
Komori, Y; Chiang, K T; Fukuto, J M (1993) The effect of nonionic detergents on the activity and/or stability of rat brain nitric oxide synthase. Arch Biochem Biophys 307:311-5
Fukuto, J M; Stuehr, D J; Feldman, P L et al. (1993) Peracid oxidation of an N-hydroxyguanidine compound: a chemical model for the oxidation of N omega-hydroxyl-L-arginine by nitric oxide synthase. J Med Chem 36:2666-70
Fukuto, J M; Hszieh, R; Gulati, P et al. (1992) N,O-diacylated-N-hydroxyarylsulfonamides: nitroxyl precursors with potent smooth muscle relaxant properties. Biochem Biophys Res Commun 187:1367-73