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: 8712518
• 负责人: JAMES C. ROSE
• 金额: $ 14.92万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8712518
• 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; Nephrons; Nucleus solitarius; Organ; Peptides; Phenotype; Predisposition; Pregnancy; Premature Birth; Process; Reflex action; Regulation; Renin-Angiotensin System; Research Personnel; Risk; Risk Factors; Role; Sheep; Steroids; Structure of choroid plexus; Therapeutic Intervention; Third Pregnancy Trimester; Time; Tissues; Very Low Birth Weight Infant; brain tissue; 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.

项目研究人员发现，妊娠 80 天的怀孕母羊服用糖皮质激素会导致后代 6 个月大时血压升高，这可能是由于对肾素-血管紧张素系统 (RAS) 产生广泛影响的结果。类固醇暴露导致的 RAS 变化似乎针对每个组织，并且在男性和女性中有所不同，但 Ang II 优于 Ang-(1-7) 的转变是更新申请中要探索的总体假设。产前接触类固醇的青少年（项目 4）显示出心率变异性 (HRV) 降低，但压力却没有升高，这表明年轻人类受试者中存在自主神经功能改变。在项目 3 中，我们表明，控制心率和 HRV 的压力反射敏感性 (BRS)、自主控制的重要指标以及靶器官损伤和死亡率增加的危险因素，在血压升高之前受到损害，这表明人类受试者和绵羊胎儿编程模型之间存在直接相似之处。在绵羊中，ATi 受体阻断可显着减弱或逆转 BRS 损伤，这支持了暴露动物中 Ang II 效应夸大的作用。 Ang-(1-7) 的保护作用在暴露的动物中被证明不存在或减弱，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 的贡献增加和 Ang-(1-7) 的丧失对 BRS 的控制。我们认为，NTS 中 Ang II 表达升高或 Ang-(1-7) 或其受体减少是导致产前类固醇暴露后血压升高和靶器官损伤的自主神经功能障碍的基础。目标 1：在血压升高、肾或心功能障碍之前或同时（产后 6 周至 6 个月），在产前接受倍他米松治疗的绵羊中，受体的表达、Ang II 和 Ang-(1-7) 形成/代谢的加工酶或背髓质（包括 NTS 和第四心室脉络丛）的肽水平是否发生改变？目标 2：6 周龄暴露羊的 NTS 中 BRS 的调节是否转向 Ang II？目标 3：阻断对照绵羊大脑第四脑室的 Ang-(1-7) 受体是否会损害 BRS 并引发压力增加以模拟产前类固醇暴露？目标 4：通过第四心室输注 Ang-(1-7) 或 ATi 拮抗剂能否纠正受损的 BRS、血压升高和类固醇暴露的肾脏表现？行政核心的主要目标是为该计划提供全面的行政支持。