Neural Control of the Circulation: Sex and Hypertension

循环的神经控制：性与高血压

• 批准号: 8102985
• 负责人: ALAN Kim JOHNSON
• 金额: $ 37.89万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102985
• 关键词: Abbreviations; Address; Affect; Agonist; Aldosterone; Angiotensin II; Angiotensins; Animal Model; Antihypertensive Agents; Atherosclerosis; Attenuated; Bibliography; Blindness; Blood Circulation; Blood Pressure; Blood Vessels; Body Fluids; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Chronic; Clinical; Data; Development; Disease; Dose; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Experimental Models; Female; Female of child bearing age; Generations; Gonadal Steroid Hormones; Heart Diseases; Heart Rate; Homeostasis; Hormonal; Human; Hypertension; Image; Imaging Techniques; In Vitro; Infusion procedures; Injury; Kidney Diseases; Knock-out; Knowledge; Laboratories; Lead; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Mineralocorticoid Receptor; Mus; Neuraxis; Neurons; Neurosecretory Systems; Nitric Oxide; Nitric Oxide Synthase; Ovariectomy; Oxidative Stress; Oxygen; Pathogenesis; Pathway interactions; Peripheral; Play; Prevalence; Prevention; Prosencephalon; RNA Interference; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin-Aldosterone System; Risk Factors; Rodent; Role; Sex Characteristics; Signal Transduction; Site; Sodium Chloride; Stroke; Superoxide Dismutase; Telemetry; Testing; Testosterone; Text; Water; Woman; cellular imaging; hypertension treatment; hypertensive heart disease; insight; male; men; mimetics; neuromechanism; neuroregulation; paraventricular nucleus; prevent; protective effect; public health relevance; receptor; research study; sex; tempol; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Sex differences in the prevalence and pathogenesis of hypertension are well documented in humans and in animal models of cardiovascular disease. Recent findings from our laboratory indicate that infusions of low doses of angiotensin II or of aldosterone into mice and rats produce markedly greater hypertension in males than in females. In addition, we find that ovariectomy (OVX) abolishes these female-related antihypertensive effects and that administration of estrogen or estrogen receptor agonists selective for estrogen receptor a (ERa) or for estrogen receptor b (ERb) into the brain restores protection in OVX females. Central administration of estrogen prevents experimentally-induced hypertension in males. In other preliminary studies we have found that either decreasing reactive oxygen species (ROS) or increasing nitric oxide (NO) in the brains of rodents attenuates hypertension induced by systemic treatment with angiotensin II or aldosterone. The present proposal will extend these unique findings by addressing the following questions: 1) Where does estrogen act in the brain to evoke its antihypertensive protection? 2) What brain estrogen receptor subtype(s) is/are necessary for this antihypertensive protection? and 3) What are the roles of [Ca2+]i and of altering the balance between ROS and NO in the cellular mediation of estrogen's protective effects? Methods to be used in conducting experiments to answer these questions include: chronic telemetric measurements of blood pressure and heart rate in rats and mice, in vitro imaging of rat paraventricular nucleus neurons to determine the effects of estrogen on angiotensin II- and aldosterone-induced changes in [Ca2+]i and [ROS]i in anatomically identified ("tagged"), putative premotor sympathetic neurons, pharmacological methods, small interference RNA to selectively attenuate expression of estrogen receptor subtypes in the brain, and genetically manipulated mice to selectively remove (knockout) ER1 or ER2. A full understanding of cellular and brain mechanisms underlying the effects of sex estrogen receptor subtypes, and sex steroids in the pathogenesis of hypertension is critical for the continued development of therapies to treat cardiovascular disease in both men and women. PUBLIC HEALTH RELEVANCE: Hypertension is a major risk factor for heart disease, stroke, atherosclerosis, renal disease and blindness. There is a substantial body of evidence indicating that females of child bearing age in comparison to males are protected against high blood pressure and new evidence indicates that part of this protection results from the action of estrogen on the central nervous system Understanding the role of estrogen on the brain to prevent high blood pressure is likely to lead to new methods for prevention and treatment of this disorder.

描述（由申请人提供）：在人类和心血管疾病动物模型中，高血压患病率和发病机制的性别差异已得到充分记录。我们实验室的最新研究结果表明，向小鼠和大鼠输注低剂量的血管紧张素 II 或醛固酮，雄性小鼠产生的高血压明显高于雌性小鼠。此外，我们发现卵巢切除术（OVX）消除了这些与女性相关的抗高血压作用，并且对雌激素受体a（ERa）或雌激素受体b（ERb）选择性的雌激素或雌激素受体激动剂注射到大脑中可以恢复对OVX女性的保护。雌激素的集中给药可预防男性实验诱发的高血压。在其他初步研究中，我们发现，减少啮齿类动物大脑中的活性氧 (ROS) 或增加一氧化氮 (NO) 可以减轻血管紧张素 II 或醛固酮全身治疗引起的高血压。本提案将通过解决以下问题来扩展这些独特的发现：1）雌激素在大脑中的哪个部位发挥作用以激发其抗高血压保护作用？ 2) 这种抗高血压保护需要哪种脑雌激素受体亚型？ 3) [Ca2+]i 以及改变 ROS 和 NO 之间的平衡在雌激素保护作用的细胞介导中的作用是什么？用于回答这些问题的实验方法包括：大鼠和小鼠血压和心率的长期遥测测量、大鼠室旁核神经元的体外成像以确定雌激素对血管紧张素 II 和醛固酮诱导的变化的影响[Ca2+]i 和 [ROS]i 中的解剖学鉴定（“标记”）、推定的运动前交感神经元、药理学方法、选择性减弱雌激素受体表达的小干扰 RNA大脑中的亚型，以及基因操纵小鼠以选择性去除（敲除）ER1 或 ER2。充分了解性雌激素受体亚型和性类固醇在高血压发病机制中影响的细胞和大脑机制对于持续开发治疗男性和女性心血管疾病的疗法至关重要。 公共卫生相关性：高血压是心脏病、中风、动脉粥样硬化、肾脏疾病和失明的主要危险因素。有大量证据表明，与男性相比，育龄女性可以预防高血压，而新的证据表明，这种保护的部分原因是雌激素对中枢神经系统的作用。大脑预防高血压可能会带来预防和治疗这种疾病的新方法。