Platelets play causal roles in a variety of acute ischemic syndromes and modulate vascular tone through their interaction with the blood vessel wall. The biochemical mechanism by which endothelium-derived relaxing factor (EDRF) inhibits platelets and regulates this interaction is not completely understood. The proposed work is designed to test the role of S-nitrosothiol adducts (RSNO) in modulating platelet inhibition by endothelium-derived relaxing factor (EDRF). Chemiluminescent and spectrophotometric analyses have led to the conclusion that EDRF is identical to nitric oxide (NO) which, under experimental physiologic conditions, reacts with reduced thiol to form S-nitrosothiol adducts. These compounds are reactive and display interesting chemical behavior that remains to be fully explored in biological systems. Plasma and platelets, the latter containing millimolar concentrations of glutathione, are rich sources of sulfhydryl groups which provide a conducive substrate for reaction with EDRF. However, the functional importance and chemical identity of endogenous S-nitrosothiols remains unknown. Thus, we propose to: 1) ascertain if S-nitrosothiols are important intermediates in the metabolism of EDRF in platelets; 2) determine the role of S-nitrosothiol adducts in modulating platelet function by EDRF and authentic NO; 3) establish the chemical identity of the endogenous antiplatelet S-nitrosothiol adduct(s); and 4) investigate the interaction between the endothelial cell and platelet in generation of S-nitrosothiol derivatives. In light of the chemical and pharmacological similarities among EDRF, organic nitrates, and other nitrosocompounds, this work has direct clinical relevance and potential therapeutic implications in cardiovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002582-03
Application #
3083000
Study Section
Special Emphasis Panel (SRC (JQ))
Project Start
1991-07-01
Project End
1993-11-30
Budget Start
1993-07-01
Budget End
1993-11-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Abraham, R Z; Kobzik, L; Moody, M R et al. (1998) Cyclic GMP is a second messenger by which nitric oxide inhibits diaphragm contraction. Comp Biochem Physiol A Mol Integr Physiol 119:177-83
Gaston, B; Sears, S; Woods, J et al. (1998) Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure. Lancet 351:1317-9
Creager, M A; Roddy, M A; Boles, K et al. (1997) N-acetylcysteine does not influence the activity of endothelium-derived relaxing factor in vivo. Hypertension 29:668-72
Campbell, D L; Stamler, J S; Strauss, H C (1996) Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 108:277-93
Stamler, J S; Slivka, A (1996) Biological chemistry of thiols in the vasculature and in vascular-related disease. Nutr Rev 54:1-30
Mohr, S; Stamler, J S; Brune, B (1996) Posttranslational modification of glyceraldehyde-3-phosphate dehydrogenase by S-nitrosylation and subsequent NADH attachment. J Biol Chem 271:4209-14
Hausladen, A; Privalle, C T; Keng, T et al. (1996) Nitrosative stress: activation of the transcription factor OxyR. Cell 86:719-29
Blitzer, M L; Loh, E; Roddy, M A et al. (1996) Endothelium-derived nitric oxide regulates systemic and pulmonary vascular resistance during acute hypoxia in humans. J Am Coll Cardiol 28:591-6
Simon, D I; Mullins, M E; Jia, L et al. (1996) Polynitrosylated proteins: characterization, bioactivity, and functional consequences. Proc Natl Acad Sci U S A 93:4736-41
Richards, W G; Stamler, J S; Kobzik, L et al. (1995) Role of nitric oxide in human esophageal circular smooth muscle in vitro. J Thorac Cardiovasc Surg 110:157-64

Showing the most recent 10 out of 24 publications