Impact of Stress and Obesity on Sodium Balance

压力和肥胖对钠平衡的影响

• 批准号: 7479056
• 负责人: DAVID M POLLOCK
• 金额: $ 26.71万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479056
• 关键词: Acute; Address; African American; Aldosterone; Aldosterone Receptors; Angiotensins; Animal Model; Antihypertensive Agents; Antioxidants; Attention; Attenuated; Biochemical; Biological Assay; Biometry; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Communication; Creatinine; Dahl Hypertensive Rats; Data; Diet; Disease; Elevation; Endothelin; Endothelin A Receptor; Endothelin B Receptor; Endothelin-1; Epidemic; Equilibrium; Essential Hypertension; Etiology; Excretory function; Fatty acid glycerol esters; Functional disorder; Genetic; Genetic Models; Genotype; Human; Human Characteristics; Hypertension; Hypotension; Individual; Investigation; Kidney; Laboratories; Link; Mediating; Mineralocorticoid Receptor; Modeling; NADPH Oxidase; NOS1 protein, human; Natriuresis; Nitric Oxide Synthase; Numbers; Obesity; Oral; Oxidative Stress; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Play; Population; Potassium; Prevention; Principal Investigator; Production; Protein Isoforms; Protocols documentation; Rattus; Reactive Oxygen Species; Receptor Activation; Relative (related person); Renin; Renin-Angiotensin-Aldosterone System; Research Personnel; Risk; Risk Factors; Role; Scheme; Services; Signal Transduction; Sodium; Sodium Chloride; Stress; System; Testing; United States; acute stress; blood pressure regulation; data management; feeding; human subject; hypertension treatment; improved; kidney vascular structure; moderate obesity; novel strategies; parent grant; pressure; programs; receptor function; research study; response; salt sensitive; saluretic

Renal control of sodium excretion is a critical factor in determining long-term regulation of blood pressure. The Dahl salt sensitive (DS) rat is a well-established animal model of salt-sensitivity that has many of the characteristics of human hypertension that is common in African Americans. We have observed that DS rats have an exaggerated blood pressure response to an acute stress and this is exacerbated by a high fat diet. Studies from Project 1 investigators have shown that African Americans have a shift in the relationship between arterial pressure and natriuresis during an acute stress protocol such that blood pressure is inappropriately high relative to the sodium excretion. When given a high salt diet, the DS rat develops hypertension due to its inability to appropriately excrete a salt load. In recent years, our laboratory has generated considerable evidence that the renal endothelin B (ETB) receptor plays a critical role in promoting the excretion of an acute and chronic salt load by activation of nitric oxide synthase 1 (NOS1). Lack of ETB receptor function leads to endothelial dysfunction and salt sensitive hypertension in various animal models. To the contrary, treatment with an ETA receptor antagonist will lower blood pressure in salt-dependent models of hypertension such as the DS rat. We have hypothesized that an imbalance between ETA and ETB mediated actions contributes to salt-dependent hypertension and associated changes in renal and vascular function. We further hypothesize that the endothelin and renin-angiotensin-aldosterone systems play a role in modulating renal excretory function following stress-induced changes in blood pressure. Surprisingly little is known about the influence of obesity on the ability of the kidney to excrete salt especially in the context of environmental stress. The overall hypothesis of the current proposal is that an imbalance of ETA/ETB receptor function and over activity of the renin-angiotensin-aldosterone system contributes to a reduced ability to excrete salt in the Dahl salt-sensitive rat and that moderate obesity exacerbates this effect. The following aims will address more specific hypotheses. Specific Aim 1: To test the hypothesis that stressinduced pressure natriuresis is facilitated by activation of the ETB/NOS1 pathway and that the ETA and renin-angiotensin-aldosterone pathways attenuate the response in genetically salt-sensitive rats; Specific Aim 2: To test the hypothesis moderate obesity attenuates stress-induced pressure natriuresis in genetically salt-sensitive rats; Specific Aim 3: To test the hypothesis that moderate obesity interferes with the ability of the ETB/NOS1 pathway to promote sodium excretion by increasing oxidative stress. Relevance: A shift in the relationship between arterial pressure and sodium excretion is a well-established hallmark of every form of hypertension. Understanding the mechanisms responsible for pressure-natriuresis in the setting of major risk factors, such as environmental stress and obesity, will be critically important for developing new approaches towards the prevention and treatment of hypertension and related disorders.

肾脏对钠排泄的控制是决定血压长期调节的关键因素。 Dahl盐敏感（DS）大鼠是一种成熟的盐敏感性动物模型，其具有许多与盐敏感性相关的特征。 高血压是非洲裔美国人常见的人类高血压的特征。我们观察到DS大鼠 对急性压力有夸大的血压反应，高脂肪饮食会加剧这种反应。 项目1调查人员的研究表明，非裔美国人的关系发生了转变 在急性应激协议期间动脉压和尿钠排泄之间的关系， 相对于钠排泄量过高。当给予高盐饮食时， 由于不能适当地排出盐负荷而引起的高血压。近年来，我们的实验室 产生了相当多的证据表明，肾内皮素B（ET B）受体在促进 通过激活一氧化氮合酶1（NOS 1）排泄急性和慢性盐负荷。缺乏ETB 受体功能在各种动物模型中导致内皮功能障碍和盐敏感性高血压。 相反，使用ETA受体拮抗剂治疗会降低盐依赖性血压 高血压模型，如DS大鼠。我们假设ETA和 ETB介导的作用导致盐依赖性高血压和肾脏和肾脏的相关变化。 血管功能我们进一步假设内皮素和肾素-血管紧张素-醛固酮系统 在压力诱导的血压变化后调节肾排泄功能中起作用。 令人惊讶的是，关于肥胖对肾脏排泄盐的能力的影响， in the context背景of environmental环境stress应力.目前提案的总体假设是， ETA/ETB受体功能和肾素-血管紧张素-醛固酮系统的过度活性有助于 Dahl盐敏感大鼠排泄盐的能力降低，中度肥胖加剧了这种影响。 以下目标将涉及更具体的假设。具体目标1：检验压力诱导 压力性尿钠排泄通过ETB/NOS 1通路的激活而促进， 肾素-血管紧张素-醛固酮途径减弱遗传性盐敏感大鼠的反应;特异性 目的2：验证中度肥胖在遗传上减弱应激诱导的压力性尿钠排泄的假设。 盐敏感大鼠;具体目的3：检验中度肥胖干扰盐敏感大鼠的能力的假设。 ETB/NOS 1途径通过增加氧化应激促进钠排泄。相关性： 动脉压和钠排泄之间关系是每种形式的公认标志 高血压了解压力性尿钠排泄的机制 风险因素，如环境压力和肥胖，对于开发新的 预防和治疗高血压及相关疾病的方法。