Antenatal Steroid Exposure and Neural Control of Blood Pressure

项目调查人员证实，怀孕80天的母羊服用糖皮质激素会导致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。激素暴露引起的RAS的变化似乎特定于每个组织，并且在男性和女性中有所不同，但在更新应用中，偏向Ang II而不是Ang-(1-7)是总体假设。出生前接触类固醇的青少年(项目4)显示心率变异性(HRV)降低，但没有升高压力，这表明年轻受试者的自主神经功能存在变化。在项目3中，我们展示了用于控制心率和心率变异性的压力感受器敏感性(BRS)，这是自主神经控制的重要指标，也是导致更高的靶器官损伤和死亡率增加的风险因素，在血压升高之前就受到了损害，显示出人类受试者和绵羊胎儿编程模型之间的直接相似之处。在绵羊中，ATI受体的阻断可以显著减弱或逆转BRS的损伤，支持在暴露的动物中发挥夸大的Ang II效应。在暴露的动物中，Ang-(1-7)的保护作用缺失或减弱，导致雄性和雌性动物BRS的损害。新的初步研究表明，在孤束核(NTS)内，Ang II的贡献增加，Ang-(1-7)的丢失对BRS的控制起作用。我们认为，血管紧张素Ⅱ的表达增加或血管紧张素Ⅱ及其受体的减少是导致产前激素暴露后血压升高和靶器官损害的自主神经功能障碍的基础。目的1：绵羊出生后服用倍他米松后，在血压升高、肾功能不全或心功能不全时(出生后6周至6个月)，第四脑室背侧延髓(包括NTS和脉络丛)血管紧张素Ⅱ和血管紧张素转换酶(1-7)形成/代谢的受体、加工酶的表达或多肽水平是否发生变化？目的2：在6周龄暴露的绵羊NTS中，BRS的调节是否向Ang II转移？目的3：阻断对照绵羊第四脑室的Ang-(1-7)受体是否会损害BRS，并启动模拟产前类固醇暴露的压力增加？目的4：血管紧张素转换酶抑制剂(Ang-(1-7))或血管紧张素转换酶抑制剂(ATI)拮抗剂能否纠正激素暴露所致的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。

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.