Renal Vascular Reactivity in Genetic Hypertension

遗传性高血压中的肾血管反应性

基本信息

批准号：
7275953
负责人：
WILLIAM J ARENDSHORST
金额：
$ 50.08万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7275953
关键词：
ADP-ribosyl Cyclase AGTR2 gene Accounting Adult Affect Affinity Age Agonist Animals Area Attenuated Binding Blood Vessels Blood Volume Blood flow Buffers Caliber Cardiovascular system Cells Chemosensitization Chronic Competitive Binding Constriction procedure Defect Development Dilator Disease Dose Elements Endothelin-1 Enhancers Enzymes Equilibrium Event Excretory function Feedback Figs - dietary Flowmetry Foundations Functional disorder Future G-Protein-Coupled Receptors Glomerular Filtration Rate Goals Health Hormonal Hydrogen Peroxide Hypertension Immunoblotting In Vitro Inbred SHR Rats Inbred WKY Rats Indium Individual Infusion procedures Injection of therapeutic agent Inositol Investigation Isoprostanes Kidney Knowledge Measures Mediating Mediator of activation protein Messenger RNA Metabolism Microcirculation Microscopy Modeling Molecular NAD(P)H oxidase Natriuresis Nitric Oxide Organ Oxidative Stress Pathway interactions Perfusion Peroxonitrite Phase Phospholipase C Plasma Play Prevention Production Prostaglandins Protein Isoforms Proteins Reaction Receptor Signaling Regulation Relative (related person)Renal Blood Flow Renin Research Resistance Reverse Transcriptase Polymerase Chain Reaction Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Signal Pathway Signal Transduction Signal Transduction Pathway Sodium Superoxide Dismutase Superoxides System Testing Thromboxane Receptor Thromboxanes Time Tissues Transcriptional Activation Ultrasonics Up-Regulation Vascular resistance Vasoconstrictor Agents Vasodilator Agents Vasomotor Western Blotting Work arteriole autocrine base critical developmental period density early onset experience familial hypertension feeding human AKAP13 protein in vivo innovation insight isoprostaglandin F2alpha type-III kidney vascular structure mimetics neutrophil cytosol factor 67K paracrine pressure prevent radioligand receptor receptor coupling receptor density renal NAD(P)H oxidase renal artery response tempol vasoactive agent vasoconstriction ward

项目摘要

DESCRIPTION (provided by applicant): A balance between vasoconstrictor and dilator systems plays a critical role in the kidney, setting the blood flow, glomerular filtration rate and sodium excretion. Our goal is to gain a better understanding of hormonal, paracrine and autocrine control of vasomotor tone in the renal microcirculation in health and disease, with particular emphasis on regulation of vascular reactivity and receptor signaling pathways in preglomerular resistance arterioles in genetic hypertension. Our previous studies on hypertensive adult spontaneously hypertensive rats (SHR) indicate that excessive renal vasoconstriction is mediated by an imbalance of actions of the vasoconstrictors Ang II and thromboxane (TxA2) and vasodilator systems (prostanoids, nitric oxide (NO)). Our recent work indicates that Ca2+ and contractile responses are mediated by signaling cascade involving ADP ribosyl cyclase and Ca2+ release from ryanodine receptors (RyR). In new studies, we shall focus on pro-hypertensive events before the development of hypertension which are most likely to be causative. We shall characterize interactions among Ang II, endothelin-1 (ET1), and TxA2 and their stimulation of NAD(P)H oxidase and superoxide anion (O2-) on vasomotor tone and Ca2+ signaling in afferent arterioles of prehypertensive 4-5-wk-old SHR. We hypothesize that exaggerated reductions in renal blood flow (RBF) in SHR are mediated by direct actions of constrictor agents on VSMC, either alone, due to enhanced receptor density or post-receptor signaling, or in concert with deficient buffering by the vasodilator NO. We propose that vasoconstriction favored by O2- is due to interactions with Ca2+ signaling in VSMC plus scavenging of NO. Specific aims will test the hypotheses that: 1) Renal vascular reactivity to Ang II, ET1 and TxA2 is exaggerated in prehypertensive SHR and that the O2-, ADP ribosyl cyclase, RyR and Ca2+ mobilization pathway plays a critical role; 2) Ca2+ signaling in afferent arterioles is enhanced in response to Ang II, ET1 and TxA2 and that the O2- / ADP ribosyl cyclase / RyR pathway is central; and 3) mRNA and protein levels of receptors for Ang II, ET1, and TxA2 and NAD(P)H subunits are up-regulated in the preglomerular vasculature of 4-5-wk-old SHR. Innovative complementary in vivo RBF studies of integrative pathophysiology and in vitro studies of cellular effector signal transduction in isolated arterioles will provide insight into pro-hypertensive mechanisms responsible for renal vasoconstriction in prehypertensive SHR.

描述（由申请人提供）：血管收缩系统和扩张系统之间的平衡在肾脏中发挥着关键作用，决定血流量、肾小球滤过率和钠排泄。我们的目标是更好地了解健康和疾病中肾微循环中血管舒缩张力的激素、旁分泌和自分泌控制，特别强调遗传性高血压中肾小球前阻力小动脉的血管反应性和受体信号传导途径的调节。我们之前对高血压成年自发性高血压大鼠 (SHR) 的研究表明，肾血管过度收缩是由血管收缩剂 Ang II 和血栓素 (TxA2) 以及血管舒张系统（前列腺素类、一氧化氮 (NO)）作用失衡介导的。我们最近的工作表明，Ca2+ 和收缩反应是由涉及 ADP 核糖基环化酶和兰尼碱受体 (RyR) 释放 Ca2+ 的信号级联介导的。在新的研究中，我们将重点关注高血压发生前最有可能致病的促高血压事件。我们将描述 Ang II、内皮素-1 (ET1) 和 TxA2 之间的相互作用以及它们对 NAD(P)H 氧化酶和超氧阴离子 (O2-) 的刺激对高血压前期 4-5 周传入小动脉血管舒缩张力和 Ca2+ 信号传导的影响-老SHR。我们假设 SHR 中肾血流量 (RBF) 的过度减少是由收缩剂对 VSMC 的直接作用介导的，无论是单独的，由于增强的受体密度或受体后信号传导，还是与血管舒张剂 NO 的缓冲不足相一致。我们认为 O2- 有利于血管收缩是由于与 VSMC 中 Ca2+ 信号传导的相互作用以及 NO 的清除。具体目标将检验以下假设：1）高血压前期 SHR 中肾血管对 Ang II、ET1 和 TxA2 的反应性被夸大，并且 O2-、ADP 核糖基环化酶、RyR 和 Ca2+ 动员途径发挥着关键作用； 2) 传入小动脉中的 Ca2+ 信号传导因 Ang II、ET1 和 TxA2 的响应而增强，并且 O2-/ADP 核糖基环化酶/RyR 途径是核心； 3) Ang II、ET1、TxA2 和 NAD(P)H 亚基受体的 mRNA 和蛋白水平在 4-5 周龄 SHR 的肾小球前血管系统中上调。综合病理生理学的创新互补体内 RBF 研究和离体小动脉细胞效应信号转导的体外研究将深入了解高血压前期 SHR 中肾血管收缩的促高血压机制。