Neural Control of the Circulation: Sex and Hypertension

循环的神经控制：性与高血压

• 批准号: 7984224
• 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/7984224
• 关键词: Abbreviations; Address; Affect; Agonist; Aldosterone; Aldosterone Receptors; Angiotensin II; Angiotensins; Animal Model; Antihypertensive Agents; Arts; 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; Small Interfering RNA; 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的动物模型中，高血压患病率和发病机理的性别差异已得到充分证明。我们实验室的最新发现表明，低剂量的血管紧张素II或醛固酮输注到小鼠中，而大鼠在男性中的高血压明显高于女性。此外，我们发现卵巢切除术（OVX）废除了这些与女性相关的降压作用，并且雌激素或雌激素受体受体激动剂对雌激素受体A（ERA）或雌激素受体B（ERB）的选择性为OVX女性的脑部恢复保护。雌激素的中央给药可防止男性实验诱导的高血压。在其他初步研究中，我们发现啮齿动物的大脑中减少活性氧（ROS）或增加一氧化氮（NO），可减少通过血管紧张素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）雌激素在大脑中在哪里唤起其降压保护？ 2）对于这种抗高血压保护是必需的，哪种脑雌激素受体亚型是必需的？ 3）[Ca2+] i的作用以及在雌激素保护作用的细胞介导中改变ROS与NO之间的平衡的作用是什么？用于回答以下问题的方法用于进行以下问题的方法包括：大鼠和小鼠血压和心率的慢性遥测测量，大鼠旁腔内核神经元的体外成像，以确定雌激素对血管紧张素II-和醛固酮诱导的旋转的变化的影响[CA2+] I in Inator septiped（ros）I in Anatomied（rosotied）神经元，药理学方法，小干扰RNA，可选择性地减弱脑中雌激素受体亚型的表达，以及遗传操纵的小鼠，以选择性去除（敲除）ER1或ER2。对性雌激素受体亚型以及性类固醇在高血压发病机理中影响的细胞和脑机制的全面理解对于在男性和女性中持续开发治疗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，与雄性相比，儿童承重年龄的女性受到保护不受高血压的保护，而新的证据表明，这种保护的一部分是由于雌激素对中枢神经系统的作用而导致的，理解雌激素在大脑中的作用可能导致预防和治疗这种疾病的新方法。