ALPHA ADRENERGIC RECEPTORS IN BLOOD PRESSURE REGULATION

阿尔法肾上腺素受体在血压调节中的作用

• 批准号: 6302395
• 负责人: DIANE E HANDY
• 金额: $ 32.8万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302395
• 关键词: RNase protection assay; alpha adrenergic receptor; angiotensin II; cell type; disease /disorder model; familial hypertension; gene expression; gene targeting; genetically modified animals; heart rate; in situ hybridization; insulin; kidney function; laboratory mouse; messenger RNA; molecular genetics; neurohormones; norepinephrine; receptor expression; sodium; tissue /cell culture; transcription factor; transforming growth factors; vasoconstriction; vasomotion; vasopressins

Alpha2-adrenergic receptor (alpha2-AR) have been implicated in the development or maintenance of hypertension. It is our hypothesis that alterations in the function or expression of alpha2-AR contribute to the development of hypertension by increasing the sympathetic outflow and/or by affecting kidney function and vascular responsiveness. However, it is not clear which alpha2-AR subtype contributes to the control of the sympathetic outflow or kidney function. It is our goal to study (a) the role of each alpha2-AR subtype in blood pressure regulation and (b)to determine the mechanisms that control the levels of alpha2-AR expression. Our specific aims are: (1) To determine the role of each alpha2-AR in normal cardiovascular regulation by utilizing knockout mice that are missing either the alphaA2-, alpha2B- or alpha2C-AR gene and analyzing the effects on blood pressure, levels of neurohumoral factors and pattern of expression of the remaining alpha2-AR genes. In addition, we will measure the effects of sodium loading on kidney function, blood pressure and heart rate, and will test whether elimination of a particular alpha2-AR subtype affects vascular reactivity to norepinephrine. (2) To evaluate the role of each alpha2-AR subtype in the development and maintenance of hypertension by utilizing the knockout mice in experimental protocols that produce hypertension in wild type mice. Blood pressure, heart rate and leyels of neurohumoral factors will be measured to test whether elimination of a particular subtype of alpha2-AR alters the course of developing hypertension. (3) To determine the influence of neurohumoral factors on the expression of alpha2-AR by studying the effects of insulin, norepinephrine, vasopressin and angiotensin II on alpha2-AR mRNA levels in cultured vascular smooth muscle cells. The effects of cellular proliferation on alpha2-AR expression will also be examined. (4) To determine nuclear factors affecting the transcription of the alpha2-AR gene, especially in response to the substances used in specific aim 3, and to study the distribution of these nuclear factors in normotensive and hypertensive animal models. We believe these studies will allow us to determine which alpha2-AR subtype(s) is (are) key to blood pressure control and will help us to develop future strategies to up and down regulate alpha2-AR gene expression in vivo, in order to influence alpha2- AR function with a long-term goal of developing more specific treatments to control blood pressure.

α2-肾上腺素能受体(α2-AR)参与了 高血压的发展或维持。我们的假设是 α2-AR功能或表达的改变有助于 交感神经流出和/或增加导致高血压的发生 通过影响肾功能和血管反应性。然而，它是 不清楚哪个Alpha2-AR亚型有助于控制 交感神经流出或肾功能。我们的目标是研究(A) 各α2-AR亚型在血压调节中的作用和(B) 确定控制α2-AR表达水平的机制。 我们的具体目标是：(1)确定每个α2-AR在 通过利用基因敲除小鼠进行正常的心血管调节 缺失alphaA2-、alpha2B-或alpha2C-AR基因 对血压、神经体液因子水平及模式的影响 剩余的α2-AR基因的表达。此外，我们还将测量 钠负荷对肾功能、血压和心脏的影响 率，并将测试特定的Alpha2-AR亚型的消除 影响血管对去甲肾上腺素的反应性。(2)评价角色 每个α2-AR亚型在开发和维护中的作用 在实验方案中利用基因敲除小鼠产生高血压 在野生型小鼠中产生高血压。血压、心率和 将测定神经体液因子的水平，以测试 消除特定的Alpha2-AR亚型改变了 发展为高血压。(3)测定神经体液的影响 通过研究胰岛素对α2-AR表达的影响， 去甲肾上腺素、加压素和血管紧张素II对大鼠脑内α2-AR基因表达的影响 培养的血管平滑肌细胞。细胞因子的作用 还将检测细胞增殖对α2-AR表达的影响。(4)至 确定影响α2-AR转录的核因素 基因，特别是对特定目标3中使用的物质的反应，以及 为了研究这些核因子在正常血压和正常血压人群中的分布。 高血压动物模型。我们相信这些研究将使我们能够 确定哪个α2-AR亚型(S)是影响血压的关键 控制，并将帮助我们制定未来的战略，以提高和下降 在体内调节α2-AR基因的表达，从而影响α2-AR AR功能，长期目标是开发更具体的治疗方法 来控制血压。