HYPERTENSION AND VASCULAR SUPEROXIDE GENERATION

描述：（改编自摘要）超氧阴离子（SO）抑制 血管舒张和增强血管收缩。 虽然血 血管具有产生自由基的能力，包括SO， SO的来源没有明确定义。 申请人的研究表明 在正常兔主动脉中，SO产生的主要来源被揭示 通过抑制内源性超氧化物歧化酶。 这显然是 来源于一种新的酶源， 来自嗜中性粒细胞NADPH氧化酶。 调查员已经定位了 平滑肌细胞膜部分内的活性， 外膜细胞，并已部分纯化的蛋白质。 初步 数据显示，SO的这种来源在调节血管 松弛，因为抑制SO产生增加一氧化氮 诱导放松。 最近的一些研究表明， SO对血管紧张素II（ANGII）中血管的有害作用 高血压和一般高血压。 最近，一个直接 刺激这类SO生成酶（NADH/NADPH氧化酶） 血管紧张素II（ANG II）。 的基本假设 该建议是ANGII依赖性高血压模型表现出 增加NADPH氧化酶SO生成的活性和表达 酶，导致SO生成增加并抑制一氧化氮 氧化物依赖性舒张和增强内皮依赖性 收缩导致高血压。 本提案将：（1） 比较和对比SO的血管水平和活性， 血管NADPH氧化酶源SO的水平在正常血压和 ANG II依赖性和非依赖性高血压兔;（2）测定 SO衍生的NADPH氧化酶是否对损伤有贡献 血管紧张素II的血管舒张和收缩增强- （3）观察ANG Ⅱ对高血压兔血压的影响， 培养的中膜平滑肌NADPH氧化酶水平和活性 细胞和外膜细胞。 拟议的研究将确定是否 ANG II和/或血压升高可刺激NADPH氧化酶 SO源，从而加剧异常血管张力。

DESCRIPTION: (Adapted from abstract) Superoxide anion (SO) inhibits vascular relaxation and enhances vascular contraction. Although blood vessels possess the capacity to produce free radicals, including SO, the sources of SO are not clearly defined. The applicant's studies suggest that in normal rabbit aorta, a major source of SO production is unmasked by inhibition of endogenous superoxide dismutase. This SO is apparently derived from a novel enzymatic source which resembles but is distinct from neutrophil NADPH oxidase. The investigator has localized the activity within the membrane fraction of smooth muscle cells and adventitial cells, and has partially purified the protein. Preliminary data show that this source of SO is important in modulating vascular relaxation, since inhibition of SO production increases nitric oxide induced relaxations. A number of recent studies have shown an increased deleterious role of SO on the vasculature in angiotensin II (ANGII) hypertension and hypertension in general. More recently, a direct stimulation of this class of SO generating enzymes (NADH/NADPH oxidase) by angiotensin II (ANG II) was reported. The underlying hypothesis of this proposal is that ANGII dependent models of hypertension exhibit an increased activity and expression of the NADPH oxidase SO generating enzyme(s), which leads to increased SO generation and inhibits nitric oxide dependent relaxation and enhances endothelium dependent contraction contributing to the hypertension. This proposal will: (1) compare and contrast the vascular levels of SO and the activity and levels of the vascular NADPH oxidase source of SO in normotensive and ANG II-dependent and -independent hypertensive rabbits; (2) determine whether there is a contribution of NADPH oxidase derived SO to impaired relaxations and enhanced constrictions of blood vessels in ANG II- dependent hypertensive rabbits; (3) examine the effect of ANG II on NADPH oxidase levels and activity from cultured medial smooth muscle cells and adventitial cells. The proposed studies will determine whether ANG II and/or blood pressure elevation can stimulate the NADPH oxidase source of SO, and thereby exacerbate aberrant vascular tone.