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: 8381684
• 负责人: JAMES C. ROSE
• 金额: $ 15.62万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8381684
• 关键词: Adolescent; Age; Age-Months; Animals; Attenuated; Autonomic Dysfunction; Award; Baroreflex; Betamethasone; Blood Pressure; Brain; Cardiac; Cardiovascular system; Development; Dorsal; Enzymes; Equilibrium; Event; Female; Funding; Glucocorticoids; Heart Rate; Human Resources; Hypertension; Impairment; Infusion procedures; Instruction; Kidney; Metabolism; Modeling; Nucleus solitarius; Organ; Peptides; Predisposition; Pregnancy; Process; Renin-Angiotensin System; Risk Factors; Role; Sheep; Steroids; Structure of choroid plexus; Therapeutic Intervention; Tissues; fetal programming; heart rate variability; human subject; male; mortality; neuroregulation; offspring; postnatal; pregnant; prenatal; pressure; programs; receptor; receptor expression

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.

项目研究人员确定，对妊娠 80 天的怀孕母羊施用糖皮质激素 早在 6 个月大时就会导致后代血压升高，这可能是由于广泛的 对肾素-血管紧张素系统（RAS）的影响。类固醇暴露导致 RAS 的变化 似乎对每个组织都有特异性，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。使用产前类固醇的青少年 暴露（项目 4）显示心率变异性 (HRV) 降低但压力不升高，表明发生了改变 年轻人类受试者中存在自主功能。在项目 3 中，我们展示了压力反射敏感性 （BRS）用于控制心率和 HRV，自主控制的重要指标和较高风险因素 靶器官损伤和死亡率增加，在血压升高之前受到损害 显示人类受试者和绵羊胎儿编程模型之间的直接相似之处。在羊身上， BRS 损伤可通过 ATi 受体阻断而急剧减弱或逆转，支持 夸大了 Ang tl 对暴露动物的影响。 Ang-(1-7) 的保护作用被证明不存在或 暴露动物中的 BRS 减少，导致雄性和雌性的 BRS 损伤。新的 初步研究揭示了 Ang II 的贡献增加和 Ang-(1-7) 的损失对控制 BRS 位于孤束核 (NTS) 内。我们建议 Ang II 的表达升高，或 NTS 中 Ang-(1-7) 或其受体的减少是自主神经功能障碍的基础，容易导致更高的 产前类固醇暴露后的血压和靶器官损伤。目标 1：表达 受体、Ang II 和 Ang-(1-7) 形成/代谢的加工酶或肽水平 产前治疗的绵羊背髓质（包括 NTS 和第四脑室脉络丛）发生改变 在血压升高、肾功能或心脏功能障碍之前或同时服用倍他米松 （产后 6 周到 6 个月之间）？目标 2：BRS 的监管是否转向 NTS 中的 Ang II 6 周龄暴露的羊？目标3：将阻断大脑第四脑室的Ang-(1-7)受体 控制羊损害 BRS 并启动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 拮抗剂是否可以纠正受损的 BRS， 类固醇暴露导致血压升高和肾脏表现？ 相关性（参见说明）： 该项目将提供有关与增加的易感性有关的大脑机制的信息。 暴露于产前类固醇的动物的自主神经功能障碍。了解所涉及的机制 改变 Ang II 和 Ang-(1-7) 的平衡对于控制 Ang II 和 Ang-(1-7) 的发展非常重要 与产前类固醇暴露相关的高血压和靶器官损伤，可能提供潜在的 针对人类受试者随后的心血管问题的治疗干预。