Neural Circulatory Control: Pregnancy & Ovarian Hormones

描述（由申请人提供）：正常妊娠与血容量和心输出量增加40%，轻微心动过速和动脉血压降低有关。 妊娠动物的时相性压力反射交感神经抑制增强，而压力反射交感神经兴奋减弱。 紧张性基线交感神经流出在妊娠期维持良好或适度增加。 孕激素的主要代谢物3a-羟基二氢孕激素（3a-OH-DHP）在妊娠期升高，是中枢神经系统抑制性GABAA受体的有效正调节剂（Paul & Purdy，1992）。 向未交配动物外源性施用3a-OHDHP模拟妊娠的影响：通过中枢神经系统机制，动脉压力反射交感神经抑制增强，交感神经兴奋减弱。 以往的研究主要集中在阶段性动脉压力反射反应和增强的动脉压力反射交感神经抑制。 在当前的提案中，实验旨在评估阶段性交感神经兴奋性反应减弱的潜在机制（可能不是动脉压力反射依赖性的），以及维持怀孕期间基线交感神经张力的机制。 待检验的一般假设是：妊娠改变了对传出交感神经流出的紧张性抑制和兴奋性影响之间的平衡，使得紧张性（基线）交感神经驱动得到良好维持，而交感神经活性的相位（反射）增加减弱。 计划的实验地址增强紧张性抑制机制在延髓头端腹外侧（RVLM）和增强紧张性兴奋起源于下丘脑室旁核（PVN）在怀孕的大鼠。 将在实验中记录区域传出交感神经活动，其中将改变RVLM和PVN中的抑制性传入输入、中枢神经系统抑制性影响以及兴奋性和抑制性影响。 实验将评估观察到的反应的来源和潜在介质。 了解机制抑制阶段性交感神经兴奋性反应和维持紧张性交感神经流出在正常妊娠动物将有重要意义的妊娠期高血压疾病与夸张的交感神经兴奋性反应。

DESCRIPTION (provided by applicant): Normal pregnancy is associated with a 40 percent increase in blood volume and cardiac output, slight tachycardia and a decrease in arterial blood pressure. Phasic baroreflex sympathoinhibition is enhanced, while baroreflex sympathoexcitation is attenuated in pregnant animals. Tonic baseline sympathetic outflow is well maintained or moderately increased in pregnancy. The primary metabolite of progesterone, 3a-hydroxydihydroprogesterone (3a-OH-DHP), which is elevated in pregnancy, is a potent positive modulator of central nervous system inhibitory GABAA receptors (Paul & Purdy, 1992). Exogenous administration of 3a-OHDHP to virgin animals mimics the effects of pregnancy: arterial baroreflex sympathoinhibition is enhanced and sympathoexcitation is attenuated, through a central nervous system mechanism. Previous studies focused mainly on phasic arterial baroreflex responses and enhanced arterial baroreflex sympathoinhibition. In the current proposal, experiments are designed to evaluate potential mechanisms for the attenuation of phasic sympathoexcitatory responses (likely not arterial baroreflex dependent), and the mechanisms for maintenance of baseline sympathetic tone in pregnancy. The general hypothesis to be tested is: Pregnancy alters the balance between tonic inhibitory and excitatory influences on efferent sympathetic outflow, such that tonic (baseline) sympathetic drive is well maintained, while phasic (reflex) increases in sympathetic nerve activy are attenuated. Planned experiments address enhanced tonic inhibitory mechanisms in the rostral ventrolateral medulla (RVLM) and enhanced tonic excitation originating from the paraventricular nucleus of the hypothalamus (PVN) in pregnant rats. Regional efferent sympathetic nerve activity will be recorded in experiments in which inhibitory afferent inputs, central nervous system inhibitory influences, and excitatory and inhibitory influences in the RVLM and PVN will be altered. Experiments will evaluate the source and potential mediators of observed responses. Understanding the mechanism for suppressed phasic sympathoexcitatory responses and maintenance of tonic sympathetic outflow in normal pregnant animals will have important implications for hypertensive disorders of pregnancy which are associated with exaggerated sympathoexcitatory responses.