Antenatal Steroid Exposure and Neural Control of Blood Pressure

计划发起人确定在怀孕80天时给怀孕的母羊使用糖皮质激素 导致6个月大的后代血压升高，可能是由于广泛的 对肾素血管紧张素系统(RAS)的影响。激素暴露对血管紧张素转换酶的影响 似乎特定于每个组织，在男性和女性中有所不同，但Ang II相对于Ang-(1-7)的偏爱是 在续签申请中要探索的总体假设。患有产前类固醇的青少年 暴露(项目4)显示心率变异性(HRV)降低，但没有升高压力，提示改变 青年受试者存在自主神经功能。在项目3中，我们展示了压力感受器反射的敏感性 (BRS)用于控制心率和HRV，是自主神经控制的重要指标，也是高血压的危险因素 靶器官损害和死亡率增加，在血压升高之前受损 显示了人类受试者和羊的胎儿编程模型之间的直接相似之处。在绵羊身上， ATI受体阻滞剂可显著减轻或逆转BRS损伤，从而支持 在暴露的动物中夸大了血管紧张素转换酶的影响。Ang-(1-7)的保护作用被证明是不存在的 暴露的动物减少，导致雄性和雌性的BRS损伤。新的 初步研究表明，Ang II的贡献增加，Ang-(1-7)的损失对控制 孤束核(NTS)内的BRS。我们认为Ang II的表达升高，或 NTS内Ang-(1-7)或其受体减少是导致高血压的自主神经功能障碍的基础 产前应用类固醇后的血压和靶器官损害。目标1：表达 受体，Ang II和Ang-(1-7)形成/代谢的处理酶，或体内的多肽水平 绵羊经前处理后第四脑室的延髓背侧包括NTS和脉络丛的改变 在血压升高、肾功能或心功能不全之前或同时服用倍他米松 (出生后6周至6个月之间)？目标2：在NTS中BRS的调节是否向Ang II转移 6周龄裸露的绵羊？目的3：Will阻断大鼠第四脑室Ang-(1-7)受体 控制绵羊损害BRS，并开始增加压力，以模拟产前类固醇暴露？ 目的4：血管紧张素-(1-7)或血管紧张素转换酶拮抗剂(ATI)能否纠正受损的BRS， 接触类固醇会增加血压和肾脏表现吗？ 相关性(请参阅说明)： 该项目将提供有关大脑机制的信息，这些机制涉及到增加对癌症的易感性 孕期接触类固醇的动物自主神经功能障碍。了解所涉及的机制 在改变Ang II和Ang-(1-7)的平衡中将对控制高血压的发展具有重要意义 高血压和靶器官损害与产前激素暴露有关，可能提供潜在的 对人类受试者随后的心血管问题的治疗干预。

Program invesfigators established that glucocorticoid administration to pregnant ewes at 80 d gestation results in elevated blood pressure in offspring as eariy as 6 months of age, likely as a result of widespread effects on the renin-angiotensin system (RAS). The changes in the RAS resulfing 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 applicafion. Adolescents with antenatal steroid exposure (Project 4) show reduced heart rate variability (HRV) without elevated pressure, suggesfing 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 elevafion 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 tl effects in exposed animals. Protecfive 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 dysfuncfion (between 6 wks and 6 months post-natal)? Aim 2: is regulafion of the BRS shifted towards Ang II in the NTS of exposed sheep at 6 wks of age? Aim 3: will blockade ofAng-(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? RELEVANCE (See Instructions): The project will provide informafion on the brain mechanisms involved in the increased susceptibility to autonomic dysfuncfion in animals exposed to antenatal steroids. Understanding the mechanisms involved in altering the balance of Ang II and Ang-(1-7) will be important to controlling the development of the hypertension and target organ damage related to the antenatal steroid exposure and may provide potential therapeutic interventions for the subsequent cardiovascular problems in human subjects.