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下降有关。怀孕动物的相压反射交感神经抑制增强，而压反射交感神经兴奋减弱。强直性基线交感神经流出在妊娠期维持良好或适度增加。孕酮的主要代谢物，3a-羟基二氢孕酮（3a-OH-DHP），在怀孕期间升高，是中枢神经系统抑制性GABAA受体的有效正调节剂（Paul & Purdy, 1992）。初生动物外源性给药3a-OHDHP可模拟妊娠效应：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相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。在目前的建议中，实验旨在评估阶段性交感神经兴奋反应（可能不依赖于动脉压力反射）衰减的潜在机制，以及怀孕期间维持基线交感神经张力的机制。要验证的一般假设是：怀孕改变了对传出交感神经流出的强直性抑制和兴奋性影响之间的平衡，使强直性（基线）交感神经驱动得到很好的维持，而交感神经活动的相性（反射）增加被减弱。计划中的实验研究了妊娠大鼠延髓吻侧腹外侧（RVLM）增强的强直抑制机制和下丘脑室旁核（PVN）增强的强直兴奋。区域传出交感神经活动将在实验中被记录下来，在实验中，抑制性传入输入、中枢神经系统的抑制性影响、RVLM和PVN的兴奋性和抑制性影响将被改变。实验将评估观察到的反应的来源和潜在介质。了解正常妊娠动物交感神经兴奋反应被抑制的机制和维持强直性交感神经流出，对研究与交感神经兴奋反应过度相关的妊娠期高血压疾病具有重要意义。

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.