Abstract

Nitric oxide synthase catalyzes the conversion of arginine to citrulline and NO. NO activates soluble guanylyl cyclase, and thereby increases cellular cGMP content. Since cGMP is a vasorelaxant, NO generation has profound physiologic and pathophysiologic function in maintaining normal blood pressure. The hypotension resulting from shock and other conditions may be attributed to overproduction of NO. Since NO is generated by three isoforms of NOS which may be differentially activated, the applicant proposes to develop mechanism-based, isoform- specific inhibitors of NOS. Four interactive but independent aims are presented.
Aim 1 concerns a better understanding of the chemistry of arginine conversion to OH-arginine.
Aim 2 will investigate the arginine/citrulline binding site(s) in the three NOS isoforms.
Aim 3 will be to design and synthesise heme-binding arginine and citrulline derivatives.
Aim 4 will develop covalently reactive, non-metabolizable inhibitory arginine and citrulline derivatives. The overall rationale for developing isoform specific inhibitors is to provide experimental as well as therapeutic tools which may alleviate hypotensive complications which accompany cytokine-induced and endotoxemic shock.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048423-03
Application #
2391487
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Linder, Barbara
Project Start
1995-06-01
Project End
2000-03-31
Budget Start
1997-04-15
Budget End
1998-03-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Medical College of Wisconsin
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226

  Publications

Nilakantan, Vani; Halligan, Nadine L N; Nguyen, Thanh K et al. (2005) Post-translational modification of manganese superoxide dismutase in acutely rejecting cardiac transplants: role of inducible nitric oxide synthase. J Heart Lung Transplant 24:1591-9
Pieper, Galen M; Nilakantan, Vani; Hilton, Gail et al. (2004) Variable efficacy of N6-(1-iminoethyl)-L-lysine in acute cardiac transplant rejection. Am J Physiol Heart Circ Physiol 286:H525-34
Bretscher, Lynn E; Li, Huiying; Poulos, Thomas L et al. (2003) Structural characterization and kinetics of nitric-oxide synthase inhibition by novel N5-(iminoalkyl)- and N5-(iminoalkenyl)-ornithines. J Biol Chem 278:46789-97
Pieper, Galen M; Halligan, Nadine L N; Hilton, Gail et al. (2003) Non-heme iron protein: a potential target of nitric oxide in acute cardiac allograft rejection. Proc Natl Acad Sci U S A 100:3125-30
Raman, C S; Li, H; Martasek, P et al. (2001) Implications for isoform-selective inhibitor design derived from the binding mode of bulky isothioureas to the heme domain of endothelial nitric-oxide synthase. J Biol Chem 276:26486-91
Shi, Y; Pritchard Jr, K A; Holman, P et al. (2000) Chronic myocardial hypoxia increases nitric oxide synthase and decreases caveolin-3. Free Radic Biol Med 29:695-703
Babu, B R; Frey, C; Griffith, O W (1999) L-arginine binding to nitric-oxide synthase. The role of H-bonds to the nonreactive guanidinium nitrogens. J Biol Chem 274:25218-26
Babu, B R; Griffith, O W (1998) Design of isoform-selective inhibitors of nitric oxide synthase. Curr Opin Chem Biol 2:491-500
Babu, B R; Griffith, O W (1998) N5-(1-Imino-3-butenyl)-L-ornithine. A neuronal isoform selective mechanism-based inactivator of nitric oxide synthase. J Biol Chem 273:8882-9
Spack, L; Havens, P L; Griffith, O W (1997) Measurements of total plasma nitrite and nitrate in pediatric patients with the systemic inflammatory response syndrome. Crit Care Med 25:1071-8

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