CIRCULATORY SHOCK, NITRIC OXIDE AND TETRAHYDROBIOPTERIN

一氧化氮(NO)是一种短暂的血管扩张剂，作用于 在调节血压和血管张力方面的生理作用。 免疫刺激剂，如细菌脂多糖(LPS)，触发 血管中产生过量的一氧化氮，导致低血压和 通常是血管塌陷。免疫刺激剂也能诱导合成 四氢生物蝶呤(BH4)在不同细胞类型中的作用 BH4及其诱导机制一直不清楚，因为BH4 不需要生产，我们假设角色是 免疫刺激剂诱导的BH4是为了支持一氧化氮合酶。这一观点是 得到了初步研究的有力支持。该计划的总体目标 建议的研究是为了了解两者之间的关系 免疫诱导血管平滑肌细胞BH4的产生和NO的合成 肌肉。研究将阐明：(1)BH4的机理基础 对一氧化氮合酶的需求，(2)脂多糖诱导BH4的机制(S) 合成；(3)BH4及其代谢产物对NO诱导的影响 内毒素诱导的合酶基因和蛋白，(4)NO对其诱导的影响 内毒素对BH4的合成和代谢的影响，以及，(5) 干扰BH4合成的药物在治疗中的应用 内毒素引起的循环休克。拟议的研究将导致 对免疫刺激剂诱导的调节因素的进一步了解 血管壁没有产生任何物质。此外，我们预计我们的 研究将揭示基于BH4干扰的新药物疗法 合成，可用于治疗感染性和细胞因子诱导的休克。

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.