ALPHA ADRENERGIC RECEPTORS IN BLOOD PRESSURE REGULATION

α 2-肾上腺素能受体（α 2-AR）与 发展或维持高血压。我们假设 α 2-AR功能或表达的改变有助于 通过增加交感神经流出和/或 通过影响肾功能和血管反应性。但据 尚不清楚哪种α 2-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） 每种α 2-AR亚型在血压调节中的作用和（B） 确定控制α 2-AR表达水平的机制。 我们的具体目标是：（1）确定每个α 2-AR在 正常的心血管调节，利用敲除小鼠， 缺失α A2-、α 2B-或α 2C-AR基因，并分析 对血压、神经体液因子水平和 其余α 2-AR基因的表达。此外，我们将测量 钠负荷对肾功能、血压和心脏的影响 速率，并将测试是否消除特定的α 2-AR亚型 影响血管对去甲肾上腺素的反应 (2)为了评估角色， 每种α 2-AR亚型在发展和维持 通过在实验方案中利用基因敲除小鼠来治疗高血压， 在野生型小鼠中产生高血压。 血压、心率和 将测量神经体液因子的水平以测试是否 α 2-AR的特定亚型的消除改变了 发展成高血压(3)为了确定神经体液的影响 通过研究胰岛素对α 2-AR表达的影响， 去甲肾上腺素、血管加压素和血管紧张素II对肾上腺素受体α 2-AR mRNA水平的影响 血管平滑肌细胞细胞的影响 还将检测α 2-AR表达的增殖。(4)到 确定影响α 2-AR转录的核因子 基因，特别是对具体目标3中所用物质的反应，以及 为了研究这些核因子在正常血压和高血压患者中的分布， 高血压动物模型。我们相信这些研究将使我们能够 确定哪种α 2-AR亚型是血压的关键 控制，将有助于我们制定未来的战略，向上和向下 调节体内α 2-AR基因表达，以影响α 2-AR基因表达。 AR功能，长期目标是开发更具体的治疗方法 来控制血压

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.