CENTRAL BAROREFLEX MECHANISMS OF ANESTHETIC ACTION

麻醉作用的中枢压力反射机制

• 批准号: 6043986
• 负责人: Michael Christian Andresen
• 金额: $ 31.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6043986
• 关键词: GABA receptor; anesthetics; baroreflex; beta adrenergic receptor; blood pressure; brain mapping; brain stem; cardiovascular disorder; efferent nerve; glutamate receptor; halothane; heart rate; isoflurane; ketamine; laboratory rat; muscarinic receptor; neurotransmitter metabolism; nitroferricyanide; pharmacokinetics; vascular smooth muscle nervous control; vasoactive agent

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.

描述：（根据申请人的摘要进行了改编）统一 假设是全身麻醉药引起心血管功能障碍 部分通过损害脑干通过动作来控制心率 在细胞核中，索他叶（NTS）和歧义核（Na）。 将进行体内和孤立的大脑切片的实验。 初步研究表明，脑干上方没有CNS站点 对心脏系统上的一般麻醉作用所必需的。 在 这些研究的异氟烷和丙泊酚抑制了随后的心动过缓 IV苯乙烯在完整和杂交大鼠中诱导的地图增加。 特定目的1通过提出NTS是关键而扩展了这些研究 麻醉作用的区域对心率的压力反射控制。 当线性拟合的斜率适合 血压变化引起的心率变化，响应于 在节拍到甲基苯丙胺或硝化钠的基础上输注苯肾上腺素或硝化钠 或更接近稳态，作为心率与峰值地图变化的拟合 由血管活性剂的分级注射剂量诱导。 在后者中， 对降压力变化的同情和迷走神经的贡献将是 通过注射外周作用β-肾上腺素受体和 毒蕈碱拮抗剂。 将全身麻醉剂显微注射将 用于确定此应用程序是否模仿系统交付。 特定的谷氨酸和GABA受体激动剂将被注入测试 负责的受体。 主动脉抑制神经的刺激会 用于确定全身性药物的全身性麻醉药 改变对注入NTS的氨基酸神经递质的反应。 具体的 AIM 2询问NTS中的一般麻醉作用是否影响对这两者的控制 交感神经和副交感神经流出。 体内研究将进行 与毒蕈碱或β-肾上腺素能的药理学阻滞剂一起 受体。 录音将是由两个系统中的传出神经制成的 将更改分配给流出与直接心血管动作对心脏和直接的心血管动作 血管平滑肌。 特定目标3-5用 NTS中的一系列实验，将一般麻醉作用分配给各种 神经递质和电压依赖性离子通道通过比较 这些影响的敏感性会改变心率和 血压。 将检查四种不同的一般麻醉药，即 异氟烷，氟烷，丙泊酚和氯胺酮，以对比而选择 对心率和平均动脉压的影响。