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ESTROGEN AND CEREBRAL VASODILATION

雌激素和脑血管舒张

基本信息

批准号：
6125793
负责人：
DALE Alan PELLIGRINO
金额：
$ 35.66万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-12-01 至 2000-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6125793
关键词：
cerebral ischemia /hypoxia cerebrovascular system estrogens female histopathology hormone regulation /control mechanism laboratory rat neuropathology neuroprotectants nitric oxide nitric oxide synthase oxidative stress vasodilation

项目摘要

The mechanisms involved in estrogen-related brain protection are unclear, but based on findings in the periphery, improved vasodilating capacity through upregulation of a constitutive nitric oxide synthase (cNOS) is an attractive possibility. The proposed studies are designed to examine the effects of estrogens on cerebral vasodilating function and the role of NO in this regard. Results will be compared in 17 beta- estradiol (E2)-treated and untreated ovariectomized (OVX) rats and normal females. There are 3 principal aims. For aim 1, the studies will evaluate: a) No-dependent cerebral vasodilatory responses, in the 3 groups, via monitoring changes in pial arteriolar diameters during suffusions of a NO donor (SNAP), a NO-independent vasodilator (adenosine), and endothelial cNOS (eNOS) and neuronal cNOS (nNOS)- dependent vasodilators (acetylcholine and NMDA, respectively); b) NOS activity and eNOS/nNOS mRNA and protein expression in the 3 groups; c) dose (0.01 to 5 mg kg -1 day) and time (1-14 days) -related changes in eNOS/nNOS activity and expression and vasodilating function associated with E2 treatment and withdrawal in OVX rats; d) variations in cNOS isoform expression and NO-dependent vasodilation that may occur during the estrous cycle in normal females; and e) using estrogen receptor (ER) antagonists (1C1 182780, tamoxifen--co-administered with E2), whether ERs are involved in E2-related changes in cNOS expression/function. In addressing aim 2, experiments will examine acute dose-dependent effects of E2 suffusions on pial arteriolar relaxation in the presence and absence of NOS inhibition and in the presence and absence of ER antagonists. NOS isoform specificity will be tested using the nNOS inhibitor, ARL 17477AR and the non-specific inhibitor, nitro-L-arginine (L-NA) eNOS contributions are estimated by difference. For aim 3, a transient forebrain ischemia (TFI) model will be used (carotid occlusion + hypotension). Using laser-Doppler flowmetry (LDF), intra-ischemic cerebral cortical blood flow (CCBF) changes will be monitored and compared in the 3 groups, followed by postischemic assessments of neuropathology. As for aim 1 studies, the data will be evaluated with respect to estrous cycle stage (normals), time and dose-related effects of E2 treatment and withdrawal (OVX), and ER antagonist effects (chronic co-administration with E2). The relative roles of nNOS vs eNOS in contributing to intra-ischemic vasodilation (using iv ARL 17477AR and L- NA) will also be examined. In several groups (i.e., those showing the greatest CCBF fall during ischemia [e.g., untreated OVX]), the intra- ischemic CCBF reductions (instead of arterial pressure) will be matched to that observed in the OVX group showing the greatest E2 treatment benefit. These results should provide important information about the cerebrovascular influences of estrogen.

参与雌激素相关脑保护的机制有不清楚，但根据外周的发现，血管扩张得到改善通过上调结构性一氧化氮合酶的能力中国石油天然气集团公司(CNOS)是一个有吸引力的可能性。建议的研究是设计的探讨雌激素对脑血管扩张功能的影响以及NO在这方面的作用。结果将在17个测试版中进行比较- 雌二醇(E_2)处理和未处理的卵巢切除(OVX)大鼠正常的雌性。有三个主要目标。对于目标1，研究将评估：A)非依赖型脑血管扩张反应，在3个组，通过监测软脑膜小动脉直径的变化一氧化氮供体(SNAP)，一种NO非依赖性血管扩张剂的止血作用 (腺苷)、内皮型cNOS(ENOS)和神经型cNOS(NNOS)- 依赖性血管扩张剂(分别为乙酰胆碱和NMDA)；b)一氧化氮合酶 3组的活性及eNOS/nNOS的mRNA和蛋白表达；剂量(0.01至5 mg kg-1天)和时间(1-14天)相关的变化 ENOS/nNOS活性和表达与血管扩张功能相关去卵巢大鼠雌激素治疗和停药；d)cNOS的变化可能发生的异构体表达和NO依赖的血管扩张正常女性的发情周期；和e)使用雌激素受体(ER) 拮抗剂(1c1-182780，三苯氧胺--与雌二醇联用)，是否雌激素受体参与了雌激素引起的cNOS表达/功能的改变。在……里面为了达到目标2，实验将检验急性剂量依赖效应。在存在和存在的情况下，雌二醇对软膜小动脉松弛的影响无一氧化氮合酶抑制及内质网存在和不存在时对抗者。将使用nNOS来测试NOS异构体的特异性抑制剂ARL 17477AR和非特异性抑制剂硝基L精氨酸 (L那)eNOS的贡献是按差额估算的。对于目标3，a 将使用短暂性前脑缺血(TFI)模型(颈动脉闭塞 +低血压)。使用激光多普勒血流仪(LDF)，脑缺血将监测大脑皮质血流量(CCBF)的变化并比较3组之间的差异，然后进行缺血后评估神经病理学。至于AIM 1研究，数据将通过以下方式评估关于发情周期阶段(正常)、时间和剂量相关效应 E2治疗和停药(OVX)以及ER拮抗剂效应(慢性与E2共同管理)。内皮型一氧化氮合酶与一氧化氮合酶在血管内皮细胞中的相对作用有助于缺血内血管扩张(使用静脉注射ARL 17477 AR和L- NA)也将受到审查。在几个组中(即，显示缺血时最大CCBF下降[例如，未经治疗的OVX])，将匹配缺血性CCBF降低(而不是动脉压) 与OVX组观察到的E2治疗效果最好的情况相比利益。这些结果应该会提供有关雌激素对脑血管的影响。