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.
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