PARACRINE REGULATIONOF RENAL FUNCTION BY DOPAMINE IN NORMOT& HYPERTENSIVE HUMANS

多巴胺对诺莫特肾功能的旁分泌调节

• 批准号: 7608458
• 负责人: ARUNA R NATARAJAN
• 金额: $ 2.19万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608458
• 关键词: Adrenal Glands; Affect; Agonist; Aldosterone Synthase; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Award; Basic Science; Biology; Biophysics; Blood Pressure; Blood Vessels; Clinic; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Condition; Coronary; Coronary artery; Creatinine; Crossover Design; Development; Diet; Disease; Doctor of Philosophy; Dopamine; Dopamine Agonists; Dopamine D1 Receptor; Dopamine Receptor; Double-Blind Method; Effective Renal Plasma Flow; Electrolyte Balance; Enalapril; Enzyme Inhibition; Equilibrium; Essential Hypertension; Excretory function; Fenoldopam; Funding; G-Protein-Coupled Receptors; GRK4 gene; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glomerular Filtration Rate; Grant; Hour; Human; Hypertension; In Vitro; Infusion procedures; Institution; Intake; Internal Medicine; Intervention; Kidney; Liquid substance; Lithium; Measures; Mediating; Mentors; Methods; NCI Scholars Program; National Center for Research Resources; Natriuresis; Neurotransmitters; Pathogenesis; Peptidyl-Dipeptidase A; Physiology; Placebo Control; Placebos; Potassium Channel; Preparation; Protocols documentation; Proximal Kidney Tubules; Randomized; Receptor Signaling; Receptor, Angiotensin, Type 1; Recruitment Activity; Regulation; Renal function; Renin; Renin-Angiotensin System; Reporting; Research; Research Design; Research Personnel; Resources; Role; Signal Pathway; Smooth Muscle Myocytes; Sodium; Sodium Chloride; Sodium-Restricted Diet; Source; System; Testing; Tubular formation; United States National Institutes of Health; Universities; Urine; Variant; Week; Work; abstracting; adducin; computerized; day; di-n-hexyl sulfosuccinate; genetic variant; human GPRK2L protein; human subject; in vivo; normotensive; paracrine; posters; receptor; response; salt intake; salt sensitive; saluretic; sex; urinary; volunteer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As of 2/07/06 Background Blood pressure is influenced by dietary salt intake; indeed 30% of people with normal blood pressure and 50-70% of people with hypertension are salt-sensitive. Dopamine, a well-known neurotransmitter, has been identified as an important modulator of blood pressure, sodium balance, renal function and adrenal function through an independent, paracrine effect on the kidneys. Angiotensin II is also an important paracrine regulator of sodium balance and blood pressure. The dopaminergic and renin-angiotensin systems have been shown to interact in vitro and in vivo. In this protocol, we will study the effects of inhibition of the renin-angiotensin system on the effects of stimulation of the dopaminergic system, in salt loaded and salt depleted states, in normotensive and hypertensive human subjects. We will correlate these effects with the presence or absence of recently described genetic polymorphisms in the post-receptor signaling pathway of the dopamine receptor in the proximal tubule of the kidney, specifically the G protein- coupled receptor kinase, GRK4. Together, this information will help us better understand the effects of salt and genotype on the pathogenesis of essential hypertension, a disease that affects more than a billion people worldwide. Hypothesis The angiotensin converting enzyme (ACE) inhibitor, Enalapril, augments natriuresis caused by D1 receptor stimulation, in normotensive and hypertensive human subjects, in salt loaded and salt depleted states. These effects are reduced in subjects who have polymorphisms of the G protein-coupled receptor kinase, GRK4. The augmentation of natriuresis is increased in hypertensive subjects with increased renin-angiotensin tone. Methods/Study Design This is a double blind, placebo-control, crossover design. 20 normotensive volunteers and 28 hypertensive subjects, recruited from an Internal Medicine clinic, of both sexes, between 18-55 years will participate in the study. They will all have 5 days each of low (50meq/day) sodium, and moderate (300meq/day) sodium diet, 4 weeks apart. Each subject will have four interventions applied in sequence, the first intervention being randomized as per a computerized plan. The four interventions are: high salt diet + placebo, high salt diet + Enalapril, low salt diet +placebo, and low salt diet + Enalapril. All subjects will undergo renal function tests, before, during and after a 3-hour infusion of Fenoldopam, which is a selective dopamine (D1) receptor agonist. We will measure urinary sodium excretion, and, by measuring creatinine , PAH and lithium clearance, we will estimate glomerular filtration rate, effective renal plasma flow, and proximal tubular sodium reabsorption of sodium respectively. All subjects will be genotyped for the common polymorphisms associated with the development of essential hypertension, specifically, GRK4, alpha adducin, aldosterone synthase, and genetic variants of the human D5 receptor. Statistical Analysis We will compare the change in the excretion of sodium from baseline between Enalapril/placebo treatments, and between low and moderate salt diet periods, in each subject. Urinary sodium excretion will be studied separately in normotensive and hypertensive groups, and then compared. We will genotype all subjects and using single locus and multi loci analyses to determine differences in the occurrence of polymorphisms between hypertensive and normotensive subjects. Anticipated Results In normotensive subjects, inhibition of angiotensin II formation by ACE inhibition will augment Fenoldopam -induced natriuresis in the moderate sodium diet, and also in the low sodium diet, where normally the renin-angiotensin system has an important sodium-retaining role. In hypertensive subjects, where the natriuretic response to Fenoldopam has been reported to be impaired, we anticipate that Enalapril will enhance natriuresis to a greater extent in those subjects with increased renin-angiotensin tone. Basic Science Component We study the function of dopamine, specifically dopaminergic post receptor signaling pathways in the human coronary vascular smooth muscle cells in humans, specifically its possible role in activation of big potassium channels, abnormalities in which may contribute to the increase in myogenic vascular tone seen in hypertension. This work has led to a first author abstract entitled 'D5 receptor mediates Dopamine effects on Big KCa channels in human coronary artery smooth muscle cells' Aruna Natarajan, Guichun Han, Richard White and Pedro Jose, which will be presented as a poster at the Experimental Biology meeting in April 2006. This work will comprise Aruna Natarajan's thesis report for a PhD in Physiology and Biophysics at Georgetown University, currently in preparation. 3. Please provide scientific progress achieved to date (since last year's report if applicable): Initial abstract Dopamine is a well-known neurotransmitter, with paracrine effects on the kidney that have recently been elucidated. These effects result in natriuresis in response to a sodium load, mediated by a G-protein coupled receptor, the D1 receptor. Post-receptor signaling pathways have been found to be impaired in people with salt sensitive hypertension, attributed to a polymorphism of a G-protein coupled receptor kinase, GRK4. This study aims to elucidate the interaction between the renal dopaminergic system and the renin-angiotensin system (RAS) in salt-loaded and depleted states, by studying the effect of angiotensin converting enzyme (ACE) inhibition on the effect of Fenoldopam, a D-1 receptor agonist on salt excretion in the urine. The study will correlate these effects with the presence or absence of genetic polymorphisms of GRK4, aldosterone synthase, alpha-adducin and other polymorphisms, all of which have been described in people with salt-sensitive hypertension. This study will help us understand the interactions of salt, dopamine, RAS and genetic makeup in the pathogenesis of essential hypertension. SPECIFIC AIMS: This is an investigator-initiated study supported by the mentored Clinical Research Scholar Program Award, Grant RR 17613, from the NCRR, NIH, DHSS. The dopaminergic system has a major regulatory effect on fluid and electrolyte balance and blood pressure. The objective of this project is to determine the interaction of the renal dopaminergic and RAS in the regulation of sodium excretion during varying amounts of sodium intake. The specific aims are to determine: 1. The effect of sodium intake on the interaction between the RAS and D1 dopamine receptors on sodium excretion. 2. The effect of GRK4 gene variants on the natriuretic response to D1 dopamine receptor agonist and its modulation by ACE inhibition. Hypothesis: The natriuretic effect of D1 dopamine receptors, which is best manifest under conditions of sodium loading is antagonized by the antinatriuretic effect of AT1 angiotensin receptors. In essential hypertension the natriuretic effect of D1 receptors is impaired because of activating variants of GRK4 while the antinatriuretic effect of AT1 receptors is enhanced. The overall hypothesis is that ACE inhibition augments the natriuresis caused by D1 receptor stimulation in normotensive subjects, only in the salt loaded state. These effects are reduced in those subjects with GRK4 gene variants, in hypertensive subjects.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 截至2/07/06 背景 血压受饮食盐摄入的影响；实际上，有30％的血压正常和50-70％的高血压患者对盐敏感。 多巴胺是一种众所周知的神经递质，已被确定为血压，钠平衡，肾功能和肾上腺功能的重要调节剂，通过对肾脏的独立旁分泌作用。血管紧张素II也是钠平衡和血压的重要旁分泌调节剂。多巴胺能和肾素 - 血管紧张素系统已显示出在体外和体内相互作用。在该方案中，我们将研究抑制肾素 - 血管紧张素系统对盐负荷和盐分耗尽状态，正常且高血压的人类受试者刺激刺激的影响。我们将将这些作用与肾脏近端小管中多巴胺受体的受体后信号传导途径中最近描述的遗传多态性的存在相关联，具体是G蛋白偶联受体激酶GRK4。共同，这些信息将有助于我们更好地了解盐和基因型对基本高血压发病机理的影响，这种疾病影响了全球超过十亿人。 假设 血管紧张素转化酶（ACE）抑制剂依那倍lil在盐负荷和盐分耗尽的状态下，在正常和高血压的人类受试者中增加了由D1受体刺激引起的苏纳氏菌。在具有G蛋白偶联受体激酶的多态性的受试者中，这些作用降低了。肾上腺素 - 血管紧张素张力升高的高血压受试者的纳地尿症的增强增加。 方法/研究设计 这是双盲，安慰剂控制，跨界设计。从两性的内科诊所招募的20名正常血统的志愿者和28名高血压受试者将参与这项研究。他们将每人5天的低（50meq/day）钠和中等（300meq/day）的钠饮食，相距4周。每个受试者将采用四种干预措施，第一个干预措施按计算机计划随机化。这四种干预措施是：高盐饮食 +安慰剂，高盐饮食 +依那普利，低盐饮食 +安慰剂和低盐饮食 +依那倍氏氏菌。所有受试者将在3小时输注Fenoldopam之前，之中和之后进行肾功能测试，该芬多巴是一种选择性多巴胺（D1）受体激动剂。我们将测量尿钠排泄，通过测量肌酐，PAH和锂清除率，我们将分别估计肾小球滤过率，有效的肾血浆流量和近端管状钠的钠钠。 所有受试者均将针对与基本高血压发展有关的常见多态性，特别是GRK4，α添加剂，醛固酮合酶和人类D5受体的遗传变异。 统计分析 我们将比较每个受试者中依那普利/安慰剂治疗之间以及低盐饮食期之间基线的钠排泄物的变化。将在正常和高血压组中分别研究尿钠排泄，然后进行比较。 我们将所有受试者的基因型，并使用单位基因座和多基因座分析来确定高血压和正常受试者之间多态性发生的差异。 预期的结果 在正常的受试者中，通过ACE抑制对血管紧张素II形成的抑制作用将增强fenoldopam诱导的中度钠饮食中的纳地尿症，以及在低钠饮食中，通常在低钠饮食中，通常肾素 - 血管紧张素系统具有重要的钠钠作用。在高血压受试者中，据报道，纳特三钠对芬诺匹胺的反应受到损害，我们预计依那普利将在肾素 - 血管紧张素张力增加的受试者中更大程度地增强纳特里雷氏菌。 基础科学组成部分 我们研究了人类人类冠状动脉血管平滑肌细胞中多巴胺，特异性多巴胺能的受体信号通路的功能，特别是其在大钾通道激活中的可能作用，其中异常可能导致高血压中肌源性血管张力的增加。这项工作导致了第一作者摘要 “ D5受体介导了人类冠状动脉平滑肌细胞中的大型KCA渠道的影响，Aruna Natarajan，Guichun Han，Richard White和Pedro Jose将在2006年4月的实验生物学会议上作为海报介绍。 准备。 3。请提供迄今为止取得的科学进展（自去年的报告是否适用）： 初始摘要 多巴胺是一种众所周知的神经递质，对最近已经阐明的肾脏有旁分泌作用。这些作用导致源自钠负荷的纳地尿，由G蛋白偶联受体D1受体介导。已经发现受体后的信号通路受到盐敏感高血压患者的损害，这归因于G蛋白偶联受体激酶GRK4的多态性。 这项研究旨在通过研究血管紧张素转化酶（ACE）抑制对盐剂对盐分对盐分灭绝剂的影响的影响，以阐明肾脏多巴胺能系统与盐载和耗尽状态中肾素 - 血管紧张素系统（RAS）之间的相互作用。这项研究将与GRK4，醛固酮合酶，α-亚杜氏蛋白和其他多态性的GRK4，醛固酮合酶和其他多态性的遗传多态性的存在或不存在相关，所有这些都在患有盐敏感性高血压的人中进行了描述。这项研究将有助于我们了解盐，多巴胺，RAS和基因组成在基本高血压的发病机理中的相互作用。 具体目的： 这是一项研究人员发起的研究，由NIH，NIH，DHSS的指导临床研究学者计划奖，Grant RR 17613。多巴胺能系统对流体和电解质平衡和血压具有重大调节作用。该项目的目的是确定肾多巴胺能和RA在不同量的钠摄入量中的钠排泄调节中的相互作用。 具体目的是确定： 1。钠摄入量对Ras和D1多巴胺受体之间相互作用对钠排泄的影响。 2。grk4基因变异对纳地胺对D1多巴胺受体激动剂的反应及其对ACE抑制的调节作用。 假设：D1多巴胺受体的亚催化作用，在钠负荷条件下最好地表现出来，这是AT1血管紧张素受体的抗钠抗能作用。 在必需的高血压中，由于GRK4的激活变异，D1受体的亚替摄氏度受损，而AT1受体的抗催化作用得到了增强。 总体假设是，ACE抑制增加了仅在盐负荷状态下，由正常性受试者D1受体刺激引起的鼻natriuresis。在高血压受试者中，在患有GRK4基因变异的受试者的那些受试者中，这些影响降低了。