CIRCULATORY SHOCK, NITRIC OXIDE AND TETRAHYDROBIOPTERIN

一氧化氮（NO）是一种短效的血管扩张剂， 在调节血压和血管紧张度中的生理作用。 免疫刺激剂如细菌脂多糖（LPS）、触发剂 血管中NO的过量产生，导致低血压， 经常是血管塌陷免疫刺激剂还诱导 四氢生物蝶呤（BH 4）在各种细胞类型中的作用;诱导 BH 4及其诱导机制仍然不清楚， 需要NO的生产，我们假设， 免疫刺激剂诱导的BH 4是支持NO合酶。这种观点是 初步研究的有力支持。的总体目标 研究的目的是了解 免疫诱导血管平滑肌BH_4生成和NO合成 肌肉.研究将阐明：（1）BH 4的机理基础 NO合酶的需要，（2）LPS诱导BH 4的机制 BH_4及其代谢产物对NO合成的影响 （4）NO对LPS诱导细胞凋亡的影响 BH 4合成和代谢的LPS，和（5）的潜力， 干扰BH 4合成的试剂在治疗中的应用 LPS引起的循环性休克拟议的研究将导致 提高对调节免疫刺激剂诱导的 在血管壁中没有产生。此外，我们预计， 研究将揭示基于BH 4破坏的新药物疗法 合成，其可用于治疗脓毒性和阿托品诱导的休克。

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.