VASCULAR ALPHA2 ADRENOCEPTORS IN NITRIC OXIDE SYNTHASE I

一氧化氮合酶 I 中的血管 ALPHA2 肾上腺素受体

• 批准号: 6388463
• 负责人: Nancy L Kanagy
• 金额: $ 12.13万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-25 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388463
• 关键词: alpha adrenergic receptor; enzyme inhibitors; flow cytometry; hypertension; laboratory rat; nitric oxide synthase; polymerase chain reaction; receptor binding; receptor coupling; receptor expression; vascular resistance; vascular smooth muscle; vascular smooth muscle nervous control; vasoconstriction; western blottings

DESCRIPTION (Adapted from applicant's abstract) Nitric oxide synthase (NOS) inhibition causes a sustained increase in systemic blood pressure. In this experimental model of hypertension, the rise in blood pressure is mediated by elevated peripheral vascular resistance that requires an intact sympathetic nervous system. However, the mechanism of the elevated resistance has not been clearly defined. Our preliminary evidence suggest that a portion of this resistance is caused by increased a2-adrenoceptor (AR) vasoconstriction and the current proposal will evaluate the role of a2-AR contraction in NOS-inhibition-induced hypertension. The hypothesis proposed is that NOS-inhibition upregulates a2-AR mediated contraction in vascular smooth muscle cells (VSMC). The three specific aims of this proposal are to determine: 1) What is the contribution of vascular VSMC a2-AR to the hypertension and arterial contraction that develop following NOS inhibition?; 2) What is the mechanism of altered vascular smooth muscle a2-AR signaling following in vivo NOS inhibition?; and 3) does NO directly regulate vascular a2-ARs in arterial smooth muscle? Specific Aim 1 will use contractile studies and blood pressure measurements to determine how large of a contribution this upregulation makes. Specific Aim 2 will measure expression levels to determine if the vascular a2-AR contribution observed under Specific Aim 1 is dependent on elevated receptor expression or on alterations in receptor coupling/signaling. The studies under Specific Aim 3 will determine if NO directly regulates vascular a2-AR or if the changes are an indirect effect of the hypertension that develops during in vivo NOS inhibition. Together, these studies will determine if the mechanism for the elevated resistance in NOS-inhibition-induced hypertension is upregulation of a2-AR signaling in VSMC and if NO regulates this receptor system. The information obtained will increase our understanding of NO regulation of blood pressure and vascular reactivity and will provide important information leading to more effective pharmacological applications of a2-AR ligands. In addition, the new techniques of RT-PCR, flow cytometry measurements, quantitative Western analysis and ligand binding assays will increase the ability of the PI to conduct future studies examining vascular function at the cellular/molecular level. (End of Abstract)

描述 （改编自申请人的摘要）一氧化氮合酶（NOS）抑制 导致全身血压持续升高 在这 高血压实验模型中，血压升高是介导的 由于外周血管阻力升高，需要完整的 交感神经系统 然而，升高的机制 阻力没有明确定义。 我们的初步证据显示 这种抵抗的一部分是由增加的α 2肾上腺素受体引起的， (AR)血管收缩和目前的建议将评估的作用， NOS抑制诱导的高血压中的α 2-AR收缩。 的假设 提出NOS抑制上调a2-AR介导的收缩， 血管平滑肌细胞（VSMC）。 这三个具体目标 我们的研究目的是：1）血管平滑肌细胞在血管中的作用 a2-AR对高血压和动脉收缩的影响， NOS抑制？2)血管平滑肌改变的机制是什么 体内NOS抑制后的α 2-AR信号传导？（3）NO直接 调节动脉平滑肌中的血管α 2-AR？ 具体目标1将使用收缩研究和血压测量 以确定这种上调的贡献有多大。 具体 目的2将测量表达水平以确定血管α 2-AR是否 具体目标1下观察到的贡献取决于受体升高 表达或受体偶联/信号传导的改变。 研究 将确定NO是否直接调节血管α 2-AR 或者这些变化是高血压的间接影响， 在体内NOS抑制期间。 这些研究将共同确定， NOS抑制诱导的细胞耐药性升高的机制 高血压是VSMC中α 2-AR信号的上调，如果NO调节 这个受体系统。 获得的信息将增加我们的 了解NO对血压和血管反应性的调节， 将提供重要的信息，导致更有效的药理学 α 2-AR配体的应用。 此外，RT-PCR新技术， 流式细胞术测量、定量Western分析和配体分析 结合试验将提高PI进行未来研究的能力 在细胞/分子水平上检查血管功能。 (End的 摘要）