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: 7849753
• 负责人: Maureen Keller-Wood
• 金额: $ 30.82万
• 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/7849753
• 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; 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; public health relevance; 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）：在卵子妊娠以及人类妊娠中，皮质醇升高。我们实验室中的研究表明，正常妊娠结局需要皮质醇的增加，以及由调节皮质醇复位的结果。对艾迪生氏病女性的研究还表明，培养糖皮质激素的作用增加至关重要。我们发现，母体皮质醇的降低会导致母体血浆体积正常膨胀的缺乏。该模型还导致胎儿血压降低，胎儿缺氧以及胎儿和孕产妇死亡的发生率增加。在非怀孕的母羊中，皮质醇会增加血压和心率，并降低压力反射敏感性。肾上腺切除术和从肾上腺类固醇中的总戒断会导致血压的动脉压和急剧变化，这表明降低了压力反射。拟议的研究旨在解决以下假设，即皮质醇的增加有助于通过中枢神经系统内部的影响以及对血液体积的间接影响，导致妊娠中压力反射敏感性的正常降低。我们进一步假设这些作用是由孕酮和雌二醇调节的，并且晚期妊娠孕妇母羊降低血浆皮质醇的脆弱性是由血容量和/或孕酮的变化引起的。 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在允许或阻断引起的血浆体积变化的同时，4）在操纵皮质醇或胎盘类固醇水平（包括NTS，RVLM和Nucleus）之后，测试涉及压力反射的大脑区域中基因表达的变化。要检查的终点是血压和心率，压力反射的敏感性，以及对心脏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。尽管艾迪生氏病在怀孕中很少见，但了解皮质醇正常增加的作用以及糖皮质激素在怀孕中的潜在影响对于期限治疗孕妇和治疗怀孕中血容量或血压疾病的治疗至关重要。公共卫生相关性：与未怀孕的人相比，对孕妇的微小变化对血压的微小变化的敏感性不太敏感，这种变化有助于保持低静止的血压和相对较高的交感神经活动，这是妊娠的特征。在不怀孕的动物模型中，肾上腺激素，皮质醇和胎盘激素（孕酮）降低了压力反射的敏感性，而在人类中艾迪生氏病引起的孕妇皮质醇分泌的破坏似乎是人类的艾迪生氏病引起的，或者在动物中进行实验性操纵，导致下降症状在降低了炎症，并且在降低了血液中的降低。在该项目中，我们将研究妊娠中肾上腺类固醇和孕激素作用的机制，并检验假设皮质醇和孕酮的相互作用是妊娠正常降压反射变化所必需的。