CENTRAL BAROREFLEX MECHANISMS OF ANESTHETIC ACTION

描述：(改编自申请人的摘要)统一 假说是全身麻醉药会导致心血管功能障碍 部分是通过动作影响脑干压力感受性反射对心率的控制 孤束核(NTS)和疑核(NA)。 实验将在体内和在离体脑切片上进行。 初步研究表明，脑干上方没有中枢神经系统部位 对心血管系统的全身麻醉作用是必要的。在……里面 这些研究表明异氟醚和异丙酚抑制了随后的心动过缓。 去大脑大鼠和正常大鼠静脉注射苯肾上腺素引起的MAP升高。 具体目标1扩展了这些研究，提出NTS是关键 压力感受性反射控制心率的麻醉作用区域。 压力反射增益将以两种方式测量，作为线性拟合的斜率 血压阶梯变化引起的心率变化 在节拍的基础上输注苯肾上腺素或硝普钠， 或更接近稳定状态，因为心率与峰值图的配合发生变化 由血管活性物质的分级团注诱导。在后者中， 交感神经和迷走神经对压力感受器反射变化的贡献将是 通过注射外周作用的β-肾上腺素受体和 毒鼠强的对抗剂。NTS内微量注射全身麻醉药将 用于确定此应用程序是否模仿系统交付。 将注射特定的谷氨酸和GABA受体激动剂来测试 负责的受体。刺激降主动脉神经将 用于确定全身麻醉药的全身给药 改变对注入NTS的氨基酸神经递质的反应。特定的 目标2询问NTS的全身麻醉作用是否影响对两者的控制 交感神经和副交感神经流出。将进行体内研究 停用毒鼠强或β-肾上腺素能的药理阻滞剂 感受器。记录将从两个系统的传出神经进行 将流出的变化与对心脏和心脏的直接心血管作用进行比较 血管平滑肌。特定目标3-5移动到脑片上 NTS的一系列实验将全身麻醉作用分配给不同的 通过比较神经递质和电压依赖性离子通道 这些影响的敏感度与改变心率和 血压。将检查四种不同的全身麻醉药，即 异氟醚、氟烷、异丙酚和氯胺酮 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.