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: 8081782
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081782
• 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）：在绵羊怀孕期间，以及人类怀孕期间，皮质醇都会升高。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，并且是受调节的皮质醇重置的结果。对患有阿迪森氏病的女性的研究也表明，足月时增加糖皮质激素的作用至关重要。我们发现，母体皮质醇的减少会导致母体血浆容量正常扩张不足。这种模型还会导致胎儿血压降低、胎儿缺氧以及胎儿和母亲死亡的发生率增加。对于未怀孕的母羊，皮质醇会增加血压和心率，并降低压力反射的敏感性；肾上腺切除术和完全戒断肾上腺类固醇会导致动脉压下降和血压发生剧烈的阶段性变化，表明压力反射受到破坏。拟议的研究旨在解决这样的假设：皮质醇的增加通过中枢神经系统内的影响以及对血容量的间接影响，导致怀孕期间压力反射敏感性的正常下降。我们进一步假设这些作用是由黄体酮和雌二醇调节的，并且妊娠晚期怀孕母羊血浆皮质醇降低的脆弱性是由血容量和/或黄体酮的变化引起的。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影响，2）使用含有皮质醇受体（MR或GR）拮抗剂的后脑植入物来测试皮质醇对脑干的影响，3）使用黄体酮和/或雌二醇或黄体酮戒断的全身植入物，测试雌二醇和黄体酮与皮质醇的相互作用，同时允许或阻断诱导的血浆容量的变化，4) 测试在控制皮质醇或胎盘类固醇水平后涉及压力反射的大脑区域中基因表达的变化，包括 NTS、RVLM 和核模糊。要检查的终点是血压和心率、压力反射敏感性，以及对心跳周期和收缩压变异性的分析，以确定相对交感神经和副交感神经张力。尽管妊娠期艾迪生氏病很少见，但了解皮质醇正常增加的作用以及妊娠期糖皮质激素戒断的潜在影响对于足月孕妇的治疗以及妊娠期血容量或血压紊乱的治疗非常重要。怀孕。公众健康相关性：压力感受反射负责调节血压的每时每刻的变化，它在孕妇中的敏感性低于非孕妇，这种变化有助于维持妊娠特有的低静息血压和相对较高的交感神经活动。在非妊娠动物模型中，肾上腺激素皮质醇和胎盘激素黄体酮似乎会降低压力反射敏感性，而人类艾迪生氏病或动物实验操作导致妊娠期母体皮质醇分泌中断，导致低血压危象如果发生在血浆黄体酮下降期间，则无法调节血压。在这个项目中，我们将研究肾上腺类固醇和黄体酮在妊娠期的作用机制，并检验妊娠期正常压力反射变化需要皮质醇和黄体酮相互作用的假设。