CENTRAL BAROREFLEX MECHANISMS OF ANESTHETIC ACTION

描述：（改编自申请人的摘要） 假设全身麻醉药引起心血管功能障碍， 部分通过损害脑干压力反射控制心率通过行动 孤束核（NTS）和疑核（NA）。 将进行活体和离体脑切片实验。 初步研究表明，脑干以上的中枢神经系统部位 对心血管系统的全身麻醉作用所必需的。 在 这些研究表明，异氟烷和异丙酚抑制了随后的心动过缓， 在正常和去大脑大鼠中iv苯妥英钠引起MAP增加。 具体目标1扩展了这些研究，提出NTS是关键的 麻醉剂对心率压力反射控制作用的区域。 压力反射增益将以两种方式测量，作为线性拟合的斜率， 由血压的斜坡变化引起的心率变化 逐搏输注苯巴比妥或硝普钠， 或更接近稳定状态，如心率与峰值MAP变化的拟合 由血管活性剂的分级推注诱导。 在后者中， 交感神经和迷走神经对压力反射变化的贡献将是 通过注射外周作用β-肾上腺素受体和 毒蕈碱拮抗剂。 将全身麻醉药微量注射到NTS中， 用于确定该应用是否模拟全身递送。 将注射特定的谷氨酸和GABA受体激动剂，以检测 负责的受体。 刺激降主动脉神经 用于确定全身麻醉剂的全身给药 改变对注入NTS的氨基酸神经递质的反应。 具体 目的2询问全身麻醉在NTS中的作用是否影响两者的控制 交感神经和副交感神经流出。 将进行体内研究 使用毒蕈碱或β-肾上腺素能药物阻滞剂 受体。 将从两个系统的传出神经进行记录， 将变化分配给流出量与心脏的直接心血管作用， 血管平滑肌 具体目标3 - 5移动到大脑切片， 在NTS中进行了一系列实验，以将全身麻醉作用分配给各种 神经递质和电压依赖性离子通道， 这些效应对改变心率的浓度的敏感性， 血压. 将检查四种不同的全身麻醉剂，即 异氟烷、氟烷、丙泊酚和氯胺酮，选择用于其对比 对心率和平均动脉压的影响

DESCRIPTION: (Adapted from the applicant's abstract) The unifying hypothesis is that general anesthetics cause cardiovascular dysfunction in part by compromising brainstem baroreflex control of heart rate via actions in the nucleus tractus solitarius (NTS) and nucleus ambiguus (NA). Experiments both in vivo and in isolated brain slices will be carried out. Preliminary studies suggest that no CNS sites above the brainstem are necessary for general anesthetic actions on the cardiovasular system. In these studies isoflurane and propofol depressed the bradycardia that follows MAP increase induced by iv phenyephrine in both intact and decerebrate rats. Specific Aim 1 extends these studies by proposing that NTS is the critical region for anesthetic action on baroreflex control of heart rate. Baroreflex gain will be measured in two ways, as slope of a linear fit for heart rate changes induced by ramp changes of blood pressure in response to infusion of phenylephrine or sodium nitroprusside on a beat-to-beat basis, or closer to steady state, as a fit of heart rate to peak MAP changes induced by graded bolus injections of the vasoactive agents. In the latter, sympathetic and vagal contributions to changes in baroreflex will be assessed by injections of peripherally acting beta-adrenoceptor and muscarinic antagonists. Microinjection of general anesthetics into NTS will be used to determine whether this application mimics systemic delivery. Specific glutamate and GABA receptor agonists will be injected to test for the responsible receptors. Stimulation of the aortic depressor nerve will be used to determine whether systemic administration of general anesthetics alters response to amino acid neurotransmitters injected into NTS. Specific Aim 2 asks whether general anesthetic action in NTS affects control of both sympathetic and parasympathetic outflow. In vivo studies will be carried out with pharmacologic blockers of either muscarinic or beta-adrenergic receptors. Recordings will be made from efferent nerves in both systems to assign changes to outflow versus direct cardiovascular actions on heart and vascular smooth muscle. Specific aims 3 - 5 move to brain slices with a series of experiments in NTS to assign general anesthetic actions to various neurotransmitters and voltage-dependent ion channels by comparing the sensitivity of these effects with concentrations which alter heart rate and blood pressure. Four different general anesthetics will be examined, namely isoflurane, halothane, propofol, and ketamine, chosen for their contrasting effects on heart rate and mean arterial pressure.