NORADRENERGIC CONTROL OF CEREBRAL OXIDATIVE METABOLISM

拟议中的实验的目的是继续研究 内源性脑去甲肾上腺素在脑血管紧张素转换酶抑制中的生物学作用 脑氧化代谢及其局部血管灌流 渗透性，特别注意提供葡萄糖作为 大脑新陈代谢的主要底物。生理机制 去甲肾上腺素的这种影响及其意义的潜在原因是 调查过了。为这些研究选择的模型包括 大鼠蓝斑核化学损伤。轨迹 蓝宝石是大多数去甲肾上腺素的起源，如果不是全部的话。 大脑皮层的神经支配。房间隔消融的影响 蓝宝石将在体内使用各种生理学方法进行研究 方法学及体外生化和药理学研究 和活体技术。生理学技术测量脑血 大脑提取葡萄糖的流动，监测大脑的氧化还原状态 双波长反射法测定细胞色素氧化酶与局部血容量 分光光度法，以及血管内皮细胞排除 大分子(如白蛋白)不能进入大脑。结果是 从这些实验中获得的结果将与定量 儿茶酚胺类神经递质的生化分析 合成它们和它们的代谢物以及参与其中的化合物 中间代谢。因为在清醒的动物中，蓝斑是 通常在压力条件下被激活，实验将探索 去甲肾上腺素耗竭大脑皮层的异常反应 在这种紧张的情况下，通常会与 增加新陈代谢需求，如固定压力和状态 癫痫。去甲肾上腺素影响血管紧张素转换酶的机制 脑生理学研究将与脑组织密度 大脑皮层去甲肾上腺素受体及其药理学研究进展 不同去甲肾上腺素受体激动剂和拮抗剂对上述指标的影响 功能。

The aim of the proposed experiments is to continue the study of the biological role of endogenous cerebral norepinephrine in the control of brain oxidative metabolism and its local vascular perfusion and permeability with particular attention to the provision of glucose as the major substrate for brain metabolism. The physiological mechanisms underlying this influence of norepinephrine and their significance will be investigated. The models chosen for these studies include effects of chemical lesion of the nucleus locus ceruleus in the rat. The locus ceruleus is the site of origin of most, if not all, the noradrenergic innervation of the cerebral cortex. The effects of ablation of the locus ceruleus will be studied using a variety of physiological in vivo methodologies and concomitantly by biochemical and pharmacological in vitro and in vivo techniques. Physiological techniques measure cerebral blood flow, the extraction of glucose by the brain, monitoring the redox state of cytochrome oxidase and local blood volume by dual wavelength reflection spectrophotometry, and the ability of the vascular endothelium to exclude large molecules (such as albumin) from entering the brain. The results obtained from these experiments will be correlated with quantitative biochemical analyses of catecholamine neurotransmitters, the enzymes that synthesize them and their metabolites and of compounds involved in intermediary metabolism. Since the locus ceruleus, in awake animals, is ordinarily activated during stressful conditions, experiments will explore the abnormal responses of the norepinephrine-depleted cerebral cortex during such stressful conditions, that are usually associated with increased metabolic demands such as immobilization stress and status epilepticus. The mechanisms underlying the influence of norepinephrine on cerebral physiology will be investigated vis-a-vis the density of noradrenergic receptors in the cerebral cortex and the pharmacological effect of various noradrenergic receptor agonists and antagonists on these functions.