Antenatal Steroid Exposure and Neural Control of Blood Pressure

产前类固醇暴露与血压的神经控制

• 批准号: 8918007
• 负责人: JAMES C. ROSE
• 金额: $ 15.37万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918007
• 关键词: 6 year old; Acute; Adipose tissue; Adolescence; Adolescent; Age; Age-Months; Age-Years; Angiotensin Receptor; Animals; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Baroreflex; Betamethasone; Blood Pressure; Brain; Cardiac; Cardiovascular system; Data; Development; Disease; Dorsal; Enzymes; Equilibrium; Event; Exhibits; Exposure to; Female; Functional disorder; Glucocorticoids; Guidelines; Heart Rate; Hypertension; Impairment; Incidence; Infant; Infusion procedures; Injury; Kidney; Lead; Literature; Metabolism; Modeling; Myocardial dysfunction; Nephrons; Nucleus solitarius; Organ; Peptides; Phenotype; Predisposition; Pregnancy; Premature Birth; Process; Reflex action; Regulation; Renin-Angiotensin System; Research Personnel; Risk Factors; Role; Sheep; Steroids; Structure of choroid plexus; Therapeutic Intervention; Third Pregnancy Trimester; Time; Tissues; Very Low Birth Weight Infant; brain tissue; cardiometabolic risk; cohort; design; early onset; emerging adult; fetal programming; heart rate variability; human subject; improved; male; mortality; neuroregulation; offspring; postnatal; pregnant; premature; prenatal; pressure; prognostic; programs; protective effect; receptor; receptor expression; young adult

Program investigators established that glucocorticoid administration to pregnant ewes at 80 d gestation results in elevated blood pressure in offspring as early as 6 months of age, likely as a result of widespread effects on the renin-angiotensin system (RAS). The changes in the RAS resulting from steroid exposure appear specific to each tissue and differ in males and females, but a shift in favor Ang II over Ang-(1-7) is the overall hypothesis to be explored in the renewal application. Adolescents with antenatal steroid exposure (Project 4) show reduced heart rate variability (HRV) without elevated pressure, suggesting altered autonomic function exists in the young human subjects. In Project 3, we show that baroreflex sensitivity (BRS) for control of heart rate and HRV, important indicators of autonomic control and risk factors for higher target organ damage and increased mortality, are impaired preceding the elevation in blood pressure showing direct parallels between the human subjects and the sheep model of fetal programming. In sheep, the BRS impairments are attenuated or reversed acutely with ATi receptor blockade, supporting a role for exaggerated Ang II effects in exposed animals. Protective effects of Ang-(1-7) were shown to be absent or reduced in exposed animals, contributing to the BRS impairment in both males and females. New preliminary studies reveal the increased contribution of Ang II and loss of Ang-(1-7) for control of BRS within the nucleus tractus solitarius (NTS). We propose that elevated expression of Ang II, or decreased Ang-(1-7) or its receptor in the NTS underlies the autonomic dysfunction predisposing to higher blood pressure and target organ damage following antenatal steroid exposure. Aim 1: is expression of receptors, processing enzymes for Ang II and Ang-(1-7) formation/ metabolism, or peptide levels in the dorsal medulla including NTS and choroid plexus of the 4th ventricle altered in sheep treated antenatally with betamethasone, prior to or coincident with increased blood pressure, renal or cardiac dysfunction (between 6 wks and 6 months post-natal)? Aim 2: is regulation of the BRS shifted towards Ang II in the NTS of exposed sheep at 6 wks of age? Aim 3: will blockade of Ang-(1-7) receptors in brain 4th ventricle of control sheep impair BRS and initiate an increase in pressure to mimic antenatal steroid exposure? Aim 4: will Ang-(1-7) or an ATi antagonist infusion via 4th ventricle correct the impaired BRS, increased blood pressure and renal manifestations of steroid exposure? The primary objective ofthe Administrative Core is to provide overall administrative support to the program.

项目研究人员确定，妊娠80 d的妊娠母羊给予糖皮质激素导致早在6个月大的后代血压升高，这可能是由于对肾素-血管紧张素系统（RAS）的广泛影响。由类固醇暴露引起的RAS变化似乎对每个组织特异，并且在男性和女性中不同，但有利于Ang II而不是Ang-（1-7）的转变是在更新申请中探索的总体假设。产前类固醇暴露的青少年（项目4）显示心率变异性（HRV）降低，但血压不升高，表明年轻人受试者存在自主神经功能改变。在项目3中，我们表明，压力反射敏感性（BRS）的控制心率和HRV，自主控制的重要指标和风险因素，更高的靶器官损伤和死亡率增加，受损前的血压升高，显示直接平行之间的人类受试者和羊模型的胎儿编程。在绵羊中，BRS损伤被ATi受体阻断剂急性减弱或逆转，支持了暴露动物中放大的Ang II效应的作用。Ang-（1-7）的保护作用在暴露的动物中不存在或减少，导致雄性和雌性的BRS损伤。新的初步研究揭示了孤束核（NTS）内Ang II对BRS控制的贡献增加和Ang-（1-7）的损失。我们认为，NTS中Ang II表达升高或Ang-（1-7）或其受体表达降低是产前类固醇暴露后导致高血压和靶器官损伤的自主神经功能障碍的基础。目标1：在产前接受倍他米松治疗的绵羊中，在血压升高、肾功能或心脏功能障碍（出生后6周至6个月）之前或同时，受体表达、Ang II和Ang-（1-7）形成/代谢的加工酶或第四脑室背侧髓质（包括NTS和脉络丛）中的肽水平是否发生改变？目的2：在6周龄暴露绵羊的NTS中，BRS的调节是否转向Ang II？目标3：阻断对照绵羊脑第四脑室中的Ang-（1-7）受体是否会损害BRS并引起压力升高以模拟产前类固醇暴露？目标4：通过第四脑室输注Ang-（1-7）或ATi拮抗剂是否能纠正类固醇暴露引起的BRS受损、血压升高和肾脏表现？行政核心的主要目标是为该计划提供全面的行政支持。