Neural Circulatory Control: Pregnancy & Ovarian Hormones

描述(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。在怀孕动物中，压力感受性交感神经抑制增强，而压力感受性交感神经兴奋减弱。强直基线交感神经流出在妊娠期间维持良好或适度增加。孕酮的主要代谢产物3a-羟基二氢孕酮(3a-OH-DHP)在妊娠期间升高，是中枢神经系统抑制性GABAA受体的强有力的正向调节剂(Paul&Purdy，1992)。外源性给予处女动物3a-OHDHP可以模拟怀孕的效果：通过中枢神经系统机制，增强动脉压力感受性反射交感神经抑制和减弱交感神经兴奋。以往的研究主要集中在时相性动脉压力感受性反射反应和增强的动脉压力感受性反射交感抑制。在目前的方案中，实验旨在评估交感兴奋时相性反应(可能不依赖于动脉压力感受器反射)减弱的潜在机制，以及在怀孕期间维持基线交感神经张力的机制。需要检验的一般假设是：怀孕改变了紧张性抑制和兴奋对传出交感神经流出的影响之间的平衡，使得紧张性(基线)交感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。计划中的实验解决了怀孕大鼠延髓头端腹外侧核(RVLM)和下丘脑室旁核(PVN)的增强紧张性兴奋机制。在改变RVLM和PVN的抑制性传入传入、中枢神经系统抑制性影响、兴奋性和抑制性影响的实验中，将记录局部传出交感神经活动。实验将评估观察到的反应的来源和潜在的介体。了解正常妊娠动物交感兴奋时相反应抑制和紧张性交感神经流出的维持机制，对于与交感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.