Central baroreflex mechanisms of anesthetic action

描述(由申请人提供)： 尽管对影响心血管调节的细胞机制或特定中枢神经系统部位的了解相对较少，但在使用全麻药(GA)时，心血管功能障碍是常见的。我们将使用两种体外模型系统来研究一种主要的自主神经脑干反射--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是由于不同脑干部位的选择性作用造成的。目前的建议通过集中于GA对孤束核(NTS)和疑核(NA)神经元的作用来测试这一一般总体假设的重要方面。这项提议的一个主要总体目标是对NTS和NA进行对气体的不同敏感性的补充测试。NTS和NA是心脏调节副交感神经反射弧的核心部位。在我们的双团队方法中，我们结合了我们两个实验室的互补专业知识。我们的工作旨在解决控制NTS和NA神经元活动的关键因素，并评估它们对GA动作的敏感性。新提出的研究集中在异氟醚和异丙酚在BRX中的作用机制。该提案的问题集中在NTS和NA内的互补靶点上，我们将建立在对这些神经元的新理解的基础上，这些神经元是在我们之前的资助时期产生的。我们的新方法使我们能够研究接受压力感受器接触的NTS神经元和在独特的脑片制备中的NA心脏节前副交感神经元。根据轴突类别区分的传入引起非常不同的反射反应，初步发现这些通路在这些NTS神经元对麻醉剂的敏感性上有根本的不同。NTS研究将解决这一新发现的重要方面。心脏迷走神经NA神经元本质上是沉默的，谷氨酸能、GABA能和胆碱能输入是关键。因此，我们的重点放在兴奋性和突触传递的调节上。延髓内麻醉药的三个主要潜在细胞靶点包括：兴奋性突触传递、抑制性突触传递和电压门控离子通道。通过检查不同的麻醉药，我们也可以更好地了解潜在的新麻醉药是否可能被设计来避免这些心脏调节部位。

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.