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.

计划InvesFigators确定，糖皮质激素在80 d妊娠时给予怀孕母羊 导致后代的血压升高，高达6个月大，这可能是由于广泛而导致的 对肾素 - 血管紧张素系统（RAS）的影响。 RAS因类固醇暴露的重硫的变化 似乎特定于每种组织，并且在男性和女性中有所不同，但是Ang II比Ang-（1-7）的转变为 在续签应用中将探讨的总体假设。产前类固醇的青少年 暴露（项目4）显示心率变异性降低（HRV）而没有压力升高，建议改变了 年轻的人类受试者存在自主功能。在项目3中，我们显示了BaroreFlex敏感性 （BRS）控制心率和HRV，自主控制的重要指标以及较高的风险因素 目标器官损伤和死亡率增加，在血压中的高升高之前受到损害 显示人类受试者与胎儿编程的绵羊模型之间的直接相似之处。在羊中， BRS损伤被ATI受体阻滞急剧衰减或逆转，支持了 暴露的动物中夸张的ANG TL效应。显示Ang-（1-7）的蛋白质影响不存在或 裸露的动物减少，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）对控制的贡献增加 核心核（NTS）中的BR。我们建议ANG II的表达升高或 NTS中的Ang-（1-7）或其受体减少了自主神经功能障碍，易于较高 产前类固醇暴露后血压和靶器官损伤。目标1：是表达 受体，ANG II和ANG-（1-7）形成/代谢的加工酶，或肽水平 背髓包括第四脑室的NTS和脉络丛，在绵羊上改变了。 与替他的血压，肾脏或心脏功能障碍升高之前或偶然 （在产后6周到6个月之间）？目的2：BRS的调节是向NTS中的Ang II转移的 裸露在6周年的绵羊？ AIM 3：将封锁大脑第四脑室中的Ofang-（1-7）受体 控制绵羊会损害BRS，并启动模仿产前类固醇暴露的压力增加？ AIM 4：Ang-（1-7）或ATI拮抗剂通过第四脑室纠正受损的BRS， 血压增加和类固醇暴露的肾脏表现？ 相关性（请参阅说明）： 该项目将提供有关提高易感性涉及的大脑机制的信息 暴露于产前类固醇的动物中的自主性功能障碍。了解所涉及的机制 在改变Ang II和Ang-（1-7）的平衡时，对于控制的发展很重要 高血压和目标器官损伤与产前类固醇暴露有关，可能会提供潜力 人类受试者随后的心血管问题的治疗干预措施。