Central baroreflex mechanisms of anesthetic action

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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.