The baroreflex in pregnancy: effects of adrenal and placental steroids

怀孕期间的压力反射：肾上腺和胎盘类固醇的作用

• 批准号: 8284437
• 负责人: Maureen Keller-Wood
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284437
• 关键词: Addison' s disease; Address; Adrenal Cortex Hormones; Adrenal Glands; Adrenal hormone preparation; Adrenalectomy; Aldosterone; Animal Model; Animals; Antihypertensive Agents; Area; Baroreflex; Blood Plasma Volume; Blood Pressure; Blood Volume; Brain; Brain Stem; Cardiovascular system; Cell Nucleus; Cessation of life; Characteristics; Chronic; Data; Diuretics; Estradiol; Estrogens; Fetal Death; Gene Expression; Glucocorticoids; Health; Heart; Heart Rate; Hormones; Human; Hydrocortisone; Implant; Incidence; Individual; Infusion procedures; Laboratories; Mediating; Modeling; Neuraxis; Placental Hormones; Plasma; Play; Pregnancy; Pregnancy Outcome; Pregnancy Tests; Pregnant Women; Progesterone; Regulation; Relative (related person); Research Design; Rest; Role; Steroids; Systolic Pressure; Testing; Withdrawal; Woman; blood pressure regulation; fetal; fetal blood; fetus hypoxia; hindbrain; hydrocortisone receptor; neuromechanism; pregnant; pressure; prevent; response; steroid hormone

DESCRIPTION (provided by applicant): In ovine pregnancy, as well as human pregnancy, cortisol is elevated. Studies in our laboratory suggest that the increase in cortisol is required for normal pregnancy outcome, and results from reset of regulated cortisol. Studies in women with Addison's disease also suggest that increased glucocorticoid action at term is crucial. We have found that reduction in maternal cortisol results in a deficiency in the normal expansion of maternal plasma volume. This model also causes reduced fetal blood pressure and increased incidence of fetal hypoxia and fetal and maternal death. In nonpregnant ewes cortisol increases blood pressure and heart rate, and decreases baroreflex sensitvity; adrenalectomy and total withdrawal from adrenal steroids causes decreased arterial pressure and dramatic phasic changes in blood pressure, suggesting disruption of the baroreflex. The proposed studies are designed to address the hypothesis that increases in cortisol contribute to the normal decrease in baroreflex sensitivity in pregnancy by effects within the CNS, as well as by indirect effects on blood volume. We further hypothesize that these effects are modulated by progesterone and estradiol, and that the vulnerability of the late gestation pregnant ewe to decreases in plasma cortisol is caused by changes in blood volume and/or progesterone. Four aims are proposed: 1) to test for effects of cortisol by inducing increases and decreases in cortisol, 2) to test for an effect of cortisol in the brainstem, using hindbrain implants containing cortisol receptor (MR or GR) antagonists, 3) to test for interactions of estradiol and progesterone with cortisol, using systemic implants of progesterone and/or estradiol or progesterone withdrawal, while allowing for or blocking the induced changes in plasma volume, 4) to test for changes in gene expression in brain areas involved in the baroreflex after manipulation of cortisol or placental steroid levels, including NTS, RVLM, and nucleus ambiguous. Endpoints to be examined are blood pressure and heart rate, baroreflex sensistivity, and analysis of the heart period and systolic pressure variability to determine relative sympathetic and parasympathetic tone. Although Addison's disease in pregnancy is rare, understanding of the role of the normal increase in cortisol, and potential effects of glucocorticoid withdrawal in pregnancy, is important to treatment of pregnant women at term and to the treatment of disturbances in blood volume or blood pressure in pregnancy. PUBLIC HEALTH RELEVANCE: The baroreflex, which regulates minute to minute changes in blood pressure, is less sensitive in pregnant women than in the nonpregnant individual, and this change helps to maintain the low resting blood pressure and relatively high sympathetic activity that are characteristic of pregnancy. In nonpregnant animal models, the adrenal hormone, cortisol, and the placental hormone, progesterone, appear to decrease baroreflex sensitivity, whereas disruption of maternal cortisol secretion in pregnancy caused with Addison's disease in humans, or with experimental manipulation in animals, results in hypotensive crisis and inability to regulate blood pressure if it occurs during the period of decreased plasma progesterone. In this project we will investigate the mechanism of adrenal steroids and progesterone effects in pregnancy, and test the hypothesis that interaction of cortisol and progesterone are required for the normal baroreflex changes in pregnancy.

描述（由申请人提供）：在绵羊妊娠和人类妊娠中，皮质醇升高。我们实验室的研究表明，皮质醇的增加是正常妊娠结局所必需的，并且是调节皮质醇重置的结果。对艾迪生氏病妇女的研究也表明，足月时增加糖皮质激素的作用是至关重要的。我们发现母体皮质醇的减少导致母体血浆容量的正常扩张不足。这种模式也会导致胎儿血压降低，胎儿缺氧和胎儿和母亲死亡的发生率增加。在非妊娠母羊皮质醇增加血压和心率，并降低压力反射敏感性;肾上腺切除术和肾上腺类固醇的总撤退导致动脉压降低和血压的戏剧性阶段性变化，这表明压力反射中断。拟议的研究旨在解决这一假设，即皮质醇的增加有助于正常降低压力反射敏感性在怀孕的中枢神经系统内的影响，以及间接影响血容量。我们进一步假设，这些影响是由孕激素和雌二醇调制的，并且妊娠晚期妊娠母羊对血浆皮质醇降低的脆弱性是由血容量和/或孕激素的变化引起的。提出了四个目标：1）通过诱导皮质醇的增加和减少来测试皮质醇的作用，2）使用含有皮质醇受体的后脑植入物来测试皮质醇在脑干中的作用（MR或GR）拮抗剂，3）测试雌二醇和孕酮与皮质醇的相互作用，使用孕酮和/或雌二醇或孕酮戒断的全身植入物，同时允许或阻断血浆体积的诱导变化，4）在操纵皮质醇或胎盘类固醇水平后，测试压力感受器反射所涉及的脑区域（包括NTS、RVLM和疑核）中基因表达的变化。待检查的终点是血压和心率、压力反射敏感性以及分析心动周期和收缩压变异性以确定相对交感神经和副交感神经张力。虽然妊娠期阿狄森氏病是罕见的，但了解皮质醇正常增加的作用以及妊娠期糖皮质激素停药的潜在影响，对于足月妊娠妇女的治疗以及妊娠期血容量或血压紊乱的治疗非常重要。公共卫生相关性：压力感受器反射调节血压的每一分钟的变化，在怀孕的女性中比在非怀孕的个体中不那么敏感，并且这种变化有助于维持低的静息血压和相对高的交感神经活动，这是怀孕的特征。在非妊娠动物模型中，肾上腺激素皮质醇和胎盘激素孕酮似乎会降低压力感受器反射敏感性，而在人类阿狄森氏病或动物实验操作引起的妊娠期母体皮质醇分泌中断，如果发生在血浆孕酮降低期间，则会导致水肿危象和无法调节血压。在这个项目中，我们将探讨肾上腺皮质激素和孕激素在妊娠中的作用机制，并测试假设，皮质醇和孕激素的相互作用是必要的正常压力感受性反射变化在怀孕。