CIRCULATORY SHOCK, NITRIC OXIDE AND TETRAHYDROBIOPTERIN

循环休克、一氧化氮和四氢生物蝶呤

• 批准号: 2226897
• 负责人: Steven S Gross
• 金额: $ 21.21万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2226897
• 关键词: amine oxidoreductase; cardiovascular pharmacology; enzyme induction /repression; enzyme mechanism; immunomodulators; interleukin 1; laboratory rat; lipopolysaccharides; muscle metabolism; nitric oxide; pteridine analog; shock; toxic shock syndrome; tumor necrosis factor alpha; vascular smooth muscle

Nitric oxide (NO) is a short-lived vasodilator which serves a physiological role in the regulation of blood pressure and vascular tone. lmmunostimulants such as bacterial lipopolysaccharides (LPS), trigger overproduction of NO in the blood vessel, resulting in hypotension and often vascular collapse. lmmunostimulants also induce the synthesis of tetrahydrobiopterin (BH4) in various cell types; the function of induced BH4 and mechanisms for its induction have remained obscure Since BH4 is required for NO production, we hypothesize that the role of immunostimulant-induced BH4 is to support NO synthase. This view is strongly supported by preliminary studies. The overall goal of the proposed research is to understand the relationship between immunologically-evoked BH4 production and NO synthesis in vascular smooth muscle. Studies will elucidate: (1) the mechanistic basis for the BH4 requirement of NO synthase, (2) mechanism(s) for LPS-elicited BH4 synthesis, (3) the effect of BH4 and metabolites on the induction of NO synthase mRNA and protein by LPS, (4) the influence of NO on the induction of BH4 synthesis and metabolism by LPS, and, (5) the potential for therapeutic use of agents which interfere with BH4 synthesis for treatment of LPS-induced circulatory shock. The proposed studies will lead to an improved understanding of factors which regulate immunostimulant-induced NO production in the blood vessel wall. Moreover, we anticipate that our research will reveal novel pharmacotherapies, based on disruption of BH4 synthesis, which can be used to treat septic- and cytokine-induced shock.

一氧化氮（NO）是一种短寿命的血管扩张剂