Circumventricular Organs: Gender and Hypertension

描述(由申请人提供)：在人类和动物模型中，高血压和心血管疾病发展的性别差异已经得到了很好的描述。小剂量血管紧张素转换酶抑制剂可通过中枢神经系统作用于脑干和下丘脑的脑室周围器官而引起神经源性高血压。越来越多的证据表明，血管紧张素转换酶的中枢和外周效应涉及到活性氧的激活。同样，对雌激素和睾酮的中枢外周研究表明，它们对心血管的许多相关作用可能与它们对活性氧(ROS)和一氧化氮(NO)生成的调节有关。我们实验室的最新数据表明，低剂量的血管紧张素转换酶Ⅱ输注会导致WT雄性小鼠高血压，但不会导致完整的WT雌性小鼠高血压。此外，我们有新的初步数据表明，中心输注肾上腺素受体氟他胺和中心输注超氧化物歧化酶(SOD)类似物Tempoll可以阻断男性Ang II诱导的高血压，并且在长期注射Ang II后，男性CVO神经元中的ROS水平高于女性。这项提议将使用对Angii高血压至关重要的脑室周围器官的脑干切片、最先进的成像技术、实时RT-PCR、腺载体基因转移和意识血压记录的遥测测量来检验性别和性类固醇通过与脑干和下丘脑的脑室周围器官内的自由基和NO生成途径相互作用来调节Angll的中枢活动的普遍假设。这一假说将通过四个特定的目的进行验证：特定的目的1.确定nNOS和SOD在AngiI诱导的雄性和雌性小鼠脑干和前脑CVO脑片[Ca++]i升高中的作用。具体目的2：确定性别和性激素对血管紧张素转换酶诱导的雄性和雌性小鼠脑干和前脑CVO细胞内ROS释放的影响。具体目的3：确定性别和性激素对雄性和雌性小鼠脑干和前脑CVO中SOD、nNOS和AT1受体表达的影响。特异性目标4：确定超氧化物歧化酶和神经元型一氧化氮合酶在血管紧张素转换酶诱导的高血压中的作用。

DESCRIPTION (provided by applicant): Sex differences in the development of hypertension and cardiovascular disease have been well described in humans and in animal models. Low dose AngII infusion is known to induce a neurogenic hypertension via CNS actions on circumventricular organs in the brainstem and hypothalamus. An increasing body of evidence has shown that Angll central and peripheral effects involve activation of reactive oxygen. Similarly, central peripheral studies with estrogen and testosterone have shown that many of their cardiovascular related effects may be related their modulation of the generation of reactive oxygen species (ROS) and nitric oxide (NO). Recent data from our laboratory have shown that low-dose infusion of AngII results in hypertension WT male mice but not in intact WT females. Further, we have new preliminary data showing that AngII induced hypertension in males is blocked by central infusions of the adrogen receptor flutamide and by central infusion of the superoxide dismutase (SOD) mimetic tempol and that males show greater levels of intracellular ROS in CVO neurons following Ang II long-term infusion than females. This proposal will use brainstem slices of circumventricular organs key to AngII hypertension, state-of-the-art imaging techniques, real-time RT-PCR, adeno-vector gene transfer and telemetry measurements of conscious blood pressure recordings to test the general hypothesis that sex and sex steroids modulate the central actions of Angll via interactions with free radical and NO generating pathways within the circumventricular organs of the brainstem and hypothalamus. This hypothesis will be tested with 4 specific aims: Specific Aim 1. Determine the roles of nNOS and SOD on AngII induced increases in [Ca++]i in the brainstem and forebrain CVO brain slices from male and female mice. Specific Aim 2: Determine the effects of sex and sex steroids on AngII induced release of intracellular ROS in the brainstem and forebrain CVOs of male and female mice. Specific Aim 3: Determine the effects of sex and sex steroids on expression of SOD, nNOS and AT1 receptors in the brainstem and forebrain CVOs of males and females mice. Specific Aim 4: Determine the role of SOD and nNOS in AngII induced hypertension in WT males and females.