CHRONIC NEURAL CONTROL OF BLOOD PRESSURE

中枢神经系统（CNS）在动脉血压的调节中起关键作用，并且中枢神经控制的异常可导致高血压或使个体响应于其他因素而易患高血压。在当前资助期内进行的研究突出了CNS在压力感受器非依赖性长期控制血压中的作用。这些研究主要集中在延髓头端腹外侧区（RVLM）神经元在维持交感血管紧张素的紧张性驱动中的作用。在目前的资助期间，我们发现，阻断RVLM中兴奋性氨基酸神经递质（EAA）的受体将降低血压到与完全自主神经阻断相同的程度，只要尾侧腹外侧髓质中的神经元被抑制。主要基于这一观察结果，我们已经开发了一个假设，即紧张性活性EAA介导的输入RVLM兴奋RVLM交感神经元，同时激发抑制性输入这些神经元通过一个电路通过尾侧延髓腹外侧。此外，我们假设，这种平衡之间的兴奋性和抑制性输入RVLM-交感神经兴奋性神经元控制紧张的EAA介导的输入RVLM管理交感血管紧张素的长期控制，这种平衡的改变可能会导致高血压。此外，基于初步数据，我们提出，紧张性活性EAA介导的输入到RVLM来自脑桥网状结构的特定区域。为了验证这些假设，我们提出了一系列的实验进行麻醉以及清醒的大鼠。大多数实验涉及记录血压和交感神经活动，同时通过显微注射神经活性药物来改变脑干离散区域的功能。本研究的目的有五个：[1]进一步研究EAA介导的RVLM输入在交感神经血管紧张性调节中的作用; [2]确定EAA介导的RVLM输入是否来自脑桥网状结构;[3]确定在长期缺乏对大脑的压力感受器反馈的情况下，对RVLM的紧张性活性EAA介导的输入的影响是否改变;[4]以确定在实验性高血压模型中，由紧张性活性EAA介导的对RVLM的输入驱动的对RVLM交感兴奋性神经元的兴奋性和抑制性输入之间的平衡是否改变;以及[5]以开始确定RVLM中C1群神经元在介导由对RVLM的紧张性活性输入驱动的响应中的作用。这些研究将有助于我们了解血压的神经控制，从而为高血压的发病机制和治疗提供新的见解。

The central nervous system (CNS) plays a key role in regulation of arterial blood pressure and an abnormality of the central neural control may result in hypertension or predispose an individual to develop hypertension in response to other factors. Studies conducted the current grant period have highlighted the role of the CNS in baroreceptor- independent long-term control of blood pressure. These studies have focused on the role of neurons in the rostral ventrolateral medulla (RVLM) in maintaining the tonic drive of sympathetic vasomotor tones are unknown. During the current grant period we have found that blockade receptors for excitatory amino acid neurotransmitters (EAA) in the RVLM will reduce blood pressure to the same extend as total autonomic blockade provide that neurons in the caudal ventrolateral medulla are inhibited. Based primarily on this observation, we have developed the hypothesis that tonically active EAA-mediated inputs to the RVLM excite RVLM-sympathoexcitatory neurons and simultaneously excite inhibitory inputs to these neurons via a circuit through the caudal ventrolateral medulla. Furthermore, we hypothesize that this balance between excitatory and inhibitory inputs to RVLM- sympathoexcitatory neurons controlled tonically by EAA-mediated inputs to the RVLM governs the long-term control of sympathetic vasomoter tone, and alteration of this balance may result in hypertension. Furthermore, based on preliminary data we proposed that the tonically- active EAA-mediated input to the RVLM comes from a specific region of the pontine reticular formation. To test these hypothesis, we propose a series of experiments to be conducted in anesthetized as well as conscious rats. Most experiments involved recording blood pressure and sympathetic nerve activity while altering the function of discrete regions of the brain stem by microinjection of neuroactive drugs. Five specific aims will be addressed: [1] to further examine the role of EAA-mediated inputs to the RVLM in the tonic regulation of sympathetic vasomotor tone; [2] to determine whether tonically-active EAA-mediated inputs to the RVLM originate from the pontine reticular formation; [3] to determine if the effects of tonically-active EAA-mediated inputs to the RVLM are altered in the chronic absence of baroreceptor feedback to the brain; [4] to determine whether the balance between excitatory and inhibitory inputs to RVLM sympathoexcitory neuron driven by tonically- active EAA-mediated inputs to the RVLM is altered in models of experimental hypertension; and [5] to begin to determine the role of the C1 population of neurons in the RVLM in mediating the responses driven by tonically-active inputs to the RVLM. These studies will contribute to our understanding of the neural control of blood pressure, and therefore may provide new insight to the pathogenesis and treatment of hypertension.