STEROID HORMONE METABOLITES & NEURAL CIRCULATORY CONTROL

类固醇激素代谢物

• 批准号: 2028243
• 负责人: Cheryl M Heesch
• 金额: $ 14.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2028243
• 关键词: GABA receptor; autoradiography; baroreceptors; baroreflex; brain stem; efferent nerve; electrophysiology; female; hemodynamics; homeostasis; hormone regulation /control mechanism; in situ hybridization; laboratory rat; mechanoreceptors; neurochemistry; nitric oxide; pregnancy circulation; progesterone; reflex; steroid hormone; sympathetic nervous system; vasodilation

Normal pregnancy is associated with a decrease in arterial blood pressure, a shift in the arterial baroreflex function curve towards a lower operating pressure range, and an attenuated ability to increase sympathetic outflow above baseline levels. The mechanisms for these changes are not known, but effects of ovarian hormones may contribute, since circulating levels of both estrogen and progesterone are elevated in pregnancy. The classical mechanism of action for steroid hormones requires binding to a nuclear receptor, followed by protein synthesis, the products of which mediate the steroid hormone's action (genomic effect). However, recently it has been convincingly demonstrated that steroid hormone metabolites such as the primary progesterone metabolite, 3alpha-hydroxy-dihydroprogesterone (3alpha-OH-DHP), have immediate and stereospecific membrane effects not requiring protein synthesis (nongenomic effect). In fact, 3alpha-OH-DHP, which is elevated in pregnancy, is the most potent endogenous positive modulator of central nervous system GABA(A) receptors. Recent experiments in our laboratory have provided exciting preliminary data suggesting that immediate actions of 3alpha-OH-DHP mimic the effects of pregnancy on baroreflex control of sympathetic outflow. The general hypothesis to be tested is that the effects of steroid hormones on control of sympathetic outflow are mediated in part by nongenomic actions of the progesterone metabolite, 3alpha-OH-DHP, on GABAergic mechanisms in cardiovascularly relevant sites in the brainstem. Experiments are designed to evaluate a possible interaction between genomic and nongenomic effects of ovarian hormones and progesterone metabolites; to determine if acute administration of progesterone has effects similar to its metabolite and possible mechanisms; to evaluate if the effects of 3alpha-OH-DHP and/or progesterone are mediated through a modulation of GABA(A) receptors in the brainstem; to determine if 3alpha-OH-DHP modulation of GABA(A) ligand binding to cardiovascularly relevant areas in the brainstem correlates with physiological responses; and lastly to determine if heterogeneity of the GABA(A) receptor in regard to subunit composition correlates with regional variations in central nervous system responsiveness to 3alpha- OH-DHP.

正常妊娠与动脉血减少有关 压力，动脉压力感受器反射功能曲线向 较低的工作压力范围，增加的能力减弱 同情性流出高于基线水平。实现这些目标的机制 变化尚不清楚，但卵巢激素的影响可能会起作用， 因为血液中雌激素和孕激素的水平都升高了 在怀孕期间。类固醇激素的经典作用机制 需要与核受体结合，然后是蛋白质合成， 调节类固醇激素作用的产物(基因组 效果)。然而，最近令人信服地证明， 类固醇激素代谢物，如初级孕酮代谢物， 3α-羟基-二氢孕酮(3α-OH-DHP)，有即刻和 不需要蛋白质合成的立体专一性膜效应 (非基因组效应)。事实上，3Alpha-OH-DHP在 妊娠，是最有力的内源性中枢正向调节因子 神经系统GABA(A)受体。最近在我们实验室进行的实验 提供了令人兴奋的初步数据，表明立即采取行动 模拟妊娠对压力感受器反射控制的影响 感同身受的流出。需要检验的一般假设是， 类固醇激素在控制交感神经流出中的作用 部分由黄体酮代谢物的非基因组作用所介导， 3α-OH-DHP对心血管相关部位GABA能机制的影响 在脑干里。实验旨在评估一种可能的 卵巢激素的基因组效应与非基因组效应的相互作用 和黄体酮代谢物；以确定急性给药 黄体酮的作用类似于它的代谢物，可能 机制：评价3α-OH-DHP和/或 孕酮是通过调节GABA(A)受体介导的。 脑干；确定3α-OH-DHP对GABA(A)配体的调节作用 脑干中与心血管相关的区域的结合 生理反应；最后，确定异质性 亚基组成方面的GABA(A)受体与 中枢神经系统对3α-羟色胺反应性的区域差异 哦-DHP。