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.

计划研究人员确定，在80 d妊娠的80 d妊娠时糖皮质激素对怀孕的母羊进行给药会导致后代的血压升高，可能是6个月大，这可能是由于对肾素 - 血管紧张素系统（RAS）的广泛影响而导致的。类固醇暴露引起的RAS的变化似乎特定于每种组织，并且在男性和女性中有所不同，但是在续签应用中探索了Ang II的转变比Ang II相比 - （1-7）。产前类固醇暴露的青少年（项目4）显示心率变异性降低而没有压力升高，表明年轻的人类受试者存在自主功能的改变。在项目3中，我们表明，用于控制心率和HRV的压力反射灵敏度（BRS），自主神经控制的重要指标以及较高的目标器官损害和死亡率增加的风险因素，在血压的升高之前是人类受试者之间直接相似之处的血压升高和胎儿模型的直接相似之处。在绵羊中，BRS损伤被ATI受体阻塞急剧衰减或逆转，这支持了在暴露动物中夸张的ANG II效应的作用。在暴露的动物中，Ang-（1-7）的保护作用被证明不存在或减少，导致男性和女性的BRS损害。新的初步研究揭示了ANG II的贡献和ANG-（1-7）对控制核片内BRS（NTS）内BR的贡献的增加。我们提出，ANG II的表达升高，或者在NTS中降低ANG-（1-7）或其受体的降低是自主神经功能障碍易受性血压和靶心器官损害后，产前类固醇暴露后。目的1：受体的表达，ANG II和ANG的加工酶是（1-7）形成/代谢/代谢或背侧髓质中的肽水平，包括NTS和第四个心室的脉络丛在绵羊治疗，在与β-次甲酮相结合之前，绵羊治疗的绵羊和肾小球均与6个月相结合的6个月（6个月）（肾脏压力）增加了6个月（肾脏）（6个月）。 AIM 2：BRS的调节是否在6周龄裸露的绵羊的NT中转向ANG II？ AIM 3：在脑第4个心室中阻断Ang-（1-7）受体会损害BRS，并启动模仿触及类固醇暴露的压力增加吗？ AIM 4：通过第四脑室通过第四个心室纠正受损的BR，血压增加和类固醇暴露的肾脏表现，ANG-（1-7）或ATI拮抗剂会纠正吗？行政核心的主要目的是为该计划提供总体行政支持。