ANG II: Permissive role to maintain vascular relaxation

ANG II：维持血管松弛的许可作用

• 批准号: 7367209
• 负责人: JULIAN H LOMBARD
• 金额: $ 30.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7367209
• 关键词: AGTR2 gene; ANG gene; Address; African American; Angiotensin II; Angiotensin II Receptor; Animals; Arteries; Biochemical; Blood Pressure; Blood Vessels; Blood Volume; Chromosomes, Human, Pair 13; Chronic; Complex; Condition; Development; Diet; Dose; Endothelium; Excision; Exhibits; Genes; Genetic; Genetic Models; Genome; Human; Hypertension; Impairment; Inbred BN Rats; Inbred Dahl Rats; Infusion procedures; Kidney; Laboratories; Losartan; Maintenance; Measurement; Mediating; Mediator of activation protein; Norway; PD 123319; Physiological; Plasma; Play; Rat Strains; Rattus; Regulation; Relative (related person); Relaxation; Renin; Renin-Angiotensin System; Resistance; Role; Signal Transduction; Smooth Muscle Myocytes; Sodium Chloride; Sodium-Restricted Diet; Sprague-Dawley Rats; Staging; Stimulus; Testing; Vascular resistance; Vasodilator Agents; Water; Water consumption; angiogenin; base; cerebral artery; congenic; consomic; innovation; insight; middle cerebral artery; normotensive; novel; prevent; protective effect; receptor; response; salt intake; salt sensitive; tool

Elevated dietary salt intake in normotensive animals leads to impaired relaxation of resistance arteries in response to a variety of vasodilator stimuli. This appears to be mediated by suppression of the renin-angiotensin system (RAS), since it can be prevented by i.v. infusion of a low dose of angiotensin II (ANGII). This project will study the response of the middle cerebral artery (MCA) to vasodilator stimuli in four novel inbred genetic rat strains: 1) Dahl salt sensitive (Dahl S; SS/Mcw) rats, a genetic model of salt sensitive hypertension that exhibits impaired relaxation to vasodilator stimuli and an impaired ability to regulate plasma ANGII levels in response to changes in dietary salt intake; 2) normotensive Brown Norway (BN/Mcw) rats; 3) SS.BN13 consomic rats, with chromosome 13 of BN rat on the Dahl S background; and 4), renin congenic rats, with the Dahl R renin gene on the Dahl S genetic background. These rat strains will be used to test two fundamental hypotheses related to the role of ANGII in maintaining normal vascular relaxation mechanisms. The first hypothesis is that ANGII, acting through its specific receptor subtypes, plays a role in the maintenance of vascular relaxation mechanisms in middle cerebral arteries under normal physiological conditions. The second hypothesis is that the impaired relaxation of the middle cerebral artery to vasodilator stimuli that occurs in Dahl S rats on a low salt diet is due to defective regulation of plasma ANGII levels in these animals. In Aim 1, we will compare the response of isolated middle cerebral arteries to a variety of vasodilator stimuli acting via different signal transduction mechanisms in inbred normotensive BN/Mcw rats, SS/Mcw rats, and SS.BN13 consomic rats on a low salt diet, in order to demonstrate that SS/Mcw rats on low salt diet exhibit impaired relaxation mechanisms that are not shared by BN/Mcw rats, SS.BN13 rats, or other normotensive rat strains e.g., Sprague-Dawley rats, that have been extensively characterized in studies by our laboratory and others. Aim 2 will utilize pharmacological tools, endothelial removal, and measurement of key biochemical mediators of vascular relaxation in order to determine the mechanisms that mediate vascular relaxation in response to vasodilator stimuli in isolated middle cerebral arteries of SS.BN13 consomic rats on a low salt diet, and to identify vascular relaxation mechanisms that are impaired in vessels of SS/Mcw rats on low salt diet. Aim 3 will utilize i.v. infusions of the ANGII receptor antagonists losartan (ATI) and PD123319 (AT2) to determine the role of specific ANGII receptor subtypes in maintaining vascular relaxation mechanisms in the middle cerebral artery under normal physiological conditions in SS.BN13 rats and in renin congenic rats, and to assess the role of specific ANGII receptor subtypes in mediating any protective effect of low dose ANGII infusion to restore normal responses of the middle cerebral artery to vasodilator stimuli in SS/Mcw rats on a low salt diet. The demonstration that ANGII may have a permissive role in maintaining vascular relaxation mechanisms in normotensive animals is a completely new aspect of ANGII's complex physiological role that has only recently been described and is largely unexplored. In this respect, the studies proposed in this project address a conceptually innovative aspect of the physiological role of ANGII in regulating vascular function. When completed, these studies will not only enhance our understanding of the role of ANGII and its receptors in regulating vascular reactivity under normal physiological conditions, but will also provide insight into the mechanisms of the impaired reactivity of resistance vessels to vasodilator stimuli in SS/Mcw rats, a genetic model of salt sensitive hypertension that has many similarities to the salt sensitive forms of hypertension that develop in humans, particularly in African-Americans.

在血压正常的动物中，膳食盐摄入量升高导致阻力动脉对各种血管扩张剂刺激的舒张受损。这似乎是通过抑制肾素-血管紧张素系统（RAS）介导的，因为它可以通过静脉输注低剂量的血管紧张素II（ANGII）来预防。本课题将在四个新的近交遗传大鼠品系中研究大脑中动脉（MCA）对血管扩张刺激的反应：1）Dahl盐敏感性（Dahl S; SS/Mcw）大鼠，盐敏感性高血压的遗传模型，其表现出对血管舒张刺激的松弛受损和响应饮食盐摄入量变化调节血浆ANGII水平的能力受损; 2）血压正常的Brown Norway（BN/Mcw）大鼠; 3）SS. BN 13同源大鼠，BN大鼠的13号染色体在Dahl S遗传背景上;和4）肾素同源大鼠，Dahl R肾素基因在Dahl S遗传背景上。这些大鼠品系将用于测试与ANGII在维持正常血管舒张机制中的作用相关的两个基本假设。第一个假设是ANGII通过其特异性的 受体亚型，在正常生理条件下维持大脑中动脉的血管舒张机制中起作用。第二个假设是，在低盐饮食的Dahl S大鼠中发生的大脑中动脉对血管舒张剂刺激的松弛受损是由于这些动物中血浆ANGII水平的调节缺陷。在目的1中，我们将比较分离的大脑中动脉对通过不同信号转导机制起作用的各种血管扩张剂刺激的反应， 大鼠、SS/Mcw大鼠和SS. BN 13 consomic大鼠进行低盐饮食，以证明低盐饮食的SS/Mcw大鼠表现出BN/Mcw大鼠、SS. BN 13大鼠或其他血压正常大鼠品系（例如，Sprague-Dawley大鼠，在我们实验室和其他实验室的研究中已被广泛表征。目的2将利用药理学工具、内皮细胞去除和测量血管舒张的关键生化介质，以确定介导血管舒张的机制 在低盐饮食的SS. BN 13 consomic大鼠的分离的大脑中动脉中响应血管舒张剂刺激，并鉴定在低盐饮食的SS/Mcw大鼠的血管中受损的血管舒张机制。目的3将利用血管紧张素Ⅱ受体拮抗剂氯沙坦（ATI）和PD 123319（AT 2）的静脉内输注来确定特定的血管紧张素Ⅱ受体亚型在正常生理条件下在SS. BN 13大鼠和肾素同类大鼠中维持大脑中动脉血管舒张机制中的作用，并评估血管紧张素Ⅱ受体拮抗剂氯沙坦（ATI）和PD 123319（AT 2）在维持正常生理条件下大脑中动脉血管舒张机制中的作用。 特异性ANGII受体亚型介导低剂量ANGII输注的任何保护作用，以恢复低盐饮食的SS/Mcw大鼠中大脑中动脉对血管扩张刺激的正常反应。ANGII在维持正常血压动物的血管舒张机制中可能具有允许作用的证明是ANGII复杂生理作用的一个全新方面，其仅在最近才被描述并且在很大程度上未被探索。在这方面，本项目中提议的研究从概念上创新了 ANGII在调节血管功能中的生理作用。当完成时，这些研究不仅将增强我们对ANGII及其受体在正常生理条件下调节血管反应性的作用的理解，而且还将提供对SS/Mcw大鼠中阻力血管对血管扩张剂刺激的受损反应性的机制的深入了解，SS/Mcw大鼠是盐敏感性高血压的遗传模型，其与人类中发展的盐敏感性高血压形式具有许多相似之处，尤其是在非裔美国人中。