STEROID HORMONE METABOLITES & NEURAL CIRCULATORY CONTROL

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 较低的操作压力范围，以及增加的能力减弱， 交感神经流出高于基线水平。 这些机制 变化尚不清楚，但卵巢激素的影响可能有所贡献， 因为雌激素和孕激素的循环水平都升高了 怀孕期间 类固醇激素的经典作用机制 需要与核受体结合，然后进行蛋白质合成， 其产物介导类固醇激素的作用（基因组 效果）。 然而，最近有令人信服的证据表明， 类固醇激素代谢物如初级孕酮代谢物， 3 α-羟基-二氢孕酮（3 α-OH-DHP），具有立即和 不需要蛋白质合成的立体特异性膜效应 （非基因组效应）。 事实上，3alpha-OH-DHP，这是升高， 妊娠，是中枢神经系统最有效的内源性正调节剂， 神经系统GABA（A）受体。 我们实验室最近的实验 提供了令人兴奋的初步数据，表明立即采取行动， 3 α-OH-DHP模拟妊娠对压力反射控制的影响， 交感神经流出 要检验的一般假设是， 类固醇激素对交感神经流出控制的作用是 部分由孕酮代谢物的非基因组作用介导， 3 α-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 卵巢激素基因组效应与非基因组效应的相互作用 和孕酮代谢物;以确定是否急性施用 孕酮的作用与其代谢产物相似， 机制;评价3 α-OH-DHP和/或 孕酮是通过调节GABA（A）受体介导的， 脑干;以确定GABA（A）配体的3 α-OH-DHP调节 与脑干中心血管相关区域的结合 生理反应;最后确定是否异质性 GABA（A）受体的亚基组成与 中枢神经系统对3 α- - DHP。

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.