The baroreflex in pregnancy: effects of adrenal and placental steroids

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，也是调节皮质醇重置的结果。对患有艾迪生病的妇女的研究也表明，足月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正常扩张的不足。这种模式还会导致胎儿血压降低，胎儿缺氧以及胎儿和产妇死亡的发生率增加。在未怀孕的母羊中，皮质醇增加血压和心率，降低气压反射敏感性；肾上腺切除术和完全停用肾上腺类固醇可导致动脉压下降和血压的显著阶段性变化，提示压力反射中断。提出的研究旨在解决这样一个假设，即皮质醇的增加通过影响中枢神经系统以及间接影响血容量来促进妊娠期气压反射敏感性的正常下降。我们进一步假设，这些影响是由孕酮和雌二醇调节的，妊娠后期妊娠母羊血浆皮质醇降低的脆弱性是由血容量和/或孕酮的变化引起的。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作用，2)测试皮质醇在脑干中的作用，使用含有皮质醇受体（MR或GR）拮抗剂的后脑植入物，3)测试雌二醇和黄体酮与皮质醇的相互作用，使用全身植入黄体酮和/或雌二醇或黄体酮戒断，同时允许或阻止诱导的血浆容量变化。4)检测皮质醇或胎盘类固醇水平改变后，包括NTS、RVLM和歧见核在内的与压力反射有关的脑区基因表达的变化。检查的终点是血压和心率，压力反射敏感性，心脏周期和收缩压变异性分析，以确定交感神经和副交感神经的相对张力。虽然Addison病在妊娠期很少见，但了解皮质醇正常升高的作用，以及妊娠期糖皮质激素停用的潜在影响，对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都很重要。与公共健康相关：调节血压每分钟变化的压力反射，在孕妇中比在未怀孕的个体中更不敏感，这种变化有助于维持低静息血压和相对较高的交感神经活动，这是怀孕的特征。在未怀孕的动物模型中，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Addison病或动物实验操作导致妊娠期母体皮质醇分泌中断，如果发生在血浆黄体酮下降期间，则会导致低血压危象和无法调节血压。在本项目中，我们将探讨肾上腺激素和孕激素在妊娠期的作用机制，并验证皮质醇和孕激素的相互作用是妊娠期正常的压力反射变化所必需的假设。

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.