Central baroreflex mechanisms of anesthetic action

描述（由申请人提供）： 在使用全身麻醉药（GA）期间经常观察到心血管功能障碍，尽管相对 关于影响心血管调节的细胞机制或特定CNS位点知之甚少。我们 将使用两个体外系统模型来研究主要自主脑干反射（心脏压力感受器反射（BRX））神经元的麻醉机制。一个主要的总体假设是，GA对心血管调节作用的差异来自不同脑干部位的选择性作用。本建议测试的重要方面，这个一般的整体假设，专注于GA行动孤束核（NTS）和疑核（NA）神经元。该提案的一个主要总体目标是对NTS和NA进行补充测试，以确定对GA的不同敏感性。NTS和NA是核心心脏调节副交感神经反射弧中的站点。在我们的双团队方法中，我们将联合收割机在两个实验室中的互补专业知识结合起来。我们的工作是针对解决控制NTS和NA神经元的活动，并评估其敏感性GA行动的关键要素。新提出的研究重点是异氟烷和丙泊酚在BRX内的作用机制。该提案的问题集中在NTS和NA内的互补目标上，我们将建立在对这些神经元的新理解的基础上，这些神经元来自我们以前的资助期。我们的新方法使我们能够研究NTS神经元接受压力感受器接触和NA心脏节前副交感神经元在独特的脑切片制备。由轴突类别区分的传入神经引起非常不同的反射反应，初步研究结果表明，这些途径在这些NTS神经元对麻醉剂的敏感性方面存在根本差异。NTS研究将解决这一新发现的重要方面。心脏迷走神经NA神经元被发现本质上是沉默的，多巴胺能、GABA能和胆碱能输入是关键。因此，我们的重点是整体的兴奋性和突触传递的调制。在髓质内，麻醉剂的三个主要潜在的广泛细胞靶点包括：兴奋性突触传递、抑制性突触传递和电压门控离子通道。通过研究不同的麻醉剂，我们也可以更好地了解是否有可能设计新的麻醉剂来保护这些心脏调节部位。

DESCRIPTION (provided by applicant): Cardiovascular dysfunction is frequently observed during use of general anesthetics (GA), although relatively little is known about the cellular mechanisms or specific CNS sites affecting cardiovascular regulation. We will use two model in vitro systems to study anesthetic mechanisms in neurons of a major autonomic brainstem reflex, the cardiac baroreceptor reflex (BRX). A major overall hypothesis is that differences in GA actions on cardiovascular regulation results from selective actions at different brainstem sites. The present proposal tests important aspects of this general overall hypothesis by focusing on GA actions on nucleus tractus solitarius (NTS) and nucleus ambiguus (NA) neurons. A major overall goal of this proposal is complementary testing of NTS and NA for differential sensitivities to GAs. NTS and NA are stations in the core cardioregulatory parasympathetic reflex arc. In our dual team approach, we combine complementary expertise in our two labs. Our work is directed toward addressing key elements controlling the activity of NTS and NA neurons and evaluating their susceptibility to GA actions. The new proposed studies focus on the mechanisms by which isoflurane and propofol act within the BRX. The issues of the proposal focus on complementary targets within NTS and NA and we will build upon new understanding of these neurons arising from our previous funding period. Our novel approaches allow us to study NTS neurons receiving baroreceptor contacts and NA cardiac preganglionic parasympathetic neurons in unique brain slice preparations. Afferents differentiated by their axon class evoke very different reflex responses and preliminary findings suggest that these pathways differ fundamentally in the sensitivity of these NTS neurons to anesthetics. NTS studies will address important aspects of this new finding. Cardiac vagal NA neurons were found to be intrinsically silent and glutamatergic, GABAergic, and cholinergic inputs are key. Thus, our focus overall is on modulation of excitability and synaptic transmission. Three major potential broad cellular targets of anesthetics within the medulla include: excitatory synaptic transmission, inhibitory synaptic transmission, and voltage-gated ion channels. By examining different anesthetics, we may also better understand whether potentially new anesthetics might be designed to spare these cardioregulatory sites.