CHRONIC NEURAL CONTROL OF BLOOD PRESSURE

中枢神经系统(CNS)在动脉血压的调节中起着关键作用，中枢神经控制的异常可能导致高血压或易因其他因素而发展为高血压。在目前的授权期内进行的研究强调了中枢神经系统在压力感受器非依赖性长期血压控制中的作用。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舒缩张力的紧张性驱动中的作用，目前尚不清楚。在当前的授予期间，我们发现阻断RVLM中兴奋性氨基酸神经递质(EAA)的受体可以降低血压，降压程度与完全阻断自主神经相同，前提是尾侧延髓腹外侧区的神经元受到抑制。主要基于这一观察结果，我们提出了一种假说，即通过尾侧延髓腹外侧部的回路兴奋RVLM交感兴奋神经元，并同时兴奋这些神经元的抑制性输入。此外，我们假设，兴奋性和抑制性传入RVLM的交感兴奋神经元之间的这种平衡是由EAA介导的RVLM的输入控制的，这种平衡控制着交感血管收缩的长期控制，这种平衡的改变可能导致高血压。此外，根据初步数据，我们提出，强直激活的EAA介导的对RVLm的输入来自脑桥网状结构的特定区域。为了验证这些假设，我们建议在麻醉和清醒的大鼠身上进行一系列实验。大多数实验包括记录血压和交感神经活动，同时通过微量注射神经活性药物改变脑干离散区域的功能。具体目标有五个：[1]进一步研究EAA介导的RVLM输入在交感血管舒张性张力调节中的作用；[2]确定强直激活的EAA介导的RVLM输入是否起源于脑桥网状结构；[3]确定在慢性缺乏压力感受器反馈给大脑的情况下，强直激活的EAA介导的RVLM输入的效果是否改变；[4]确定在实验性高血压模型中，由强直活动的EAA介导的RVLM的兴奋性和抑制性输入之间的平衡是否改变；以及[5]开始确定RVLm中的C1群神经元在调节RVLm的音调活动输入所驱动的反应中所起的作用。这些研究将有助于我们理解血压的神经控制，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.