SYMPATHOADRENAL AND CATECHOLAMINERGIC FUNCTION IN HEALTH AND DISEASE

健康和疾病中的交感肾上腺和儿茶酚胺能功能

• 批准号: 5203972
• 负责人: D S GOLDSTEIN
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5203972
• 关键词: Menkes' syndrome; alpha adrenergic receptor; angiotensin II; beta adrenergic receptor; catecholamines; clozapine; congestive heart failure; dopamine; familial dysautonomia; glucocorticoids; gravity; human subject; hypertension; hypotension; isozymes; multiple myeloma; neurochemistry; neurotransmitter biosynthesis; neurotransmitter transport; peripheral nervous system disorders; stress; sympathetic nervous system; syncope

Distinctive neurochemical patterns associated with specific abnormalities in catecholamine biosynthesis, storage, release, disposition, and metabolism were described in several genetic or acquired diseases. Children with Menkes' disease, a disorder of copper metabolism, had evidence for decreased activity of dopamine-beta-hydroxylase (DBH), with DOPA:dihydroxyphenylglycol (DHPG) ratios invariably increased, enabling in utero diagnosis and early treatment. Dihydropteridine reductase (DHPR) deficiency causes an atypical form of phenylketonuria. Our finding of low but detectable levels of DOPA and other catechols in a patient with absent DHPR implies that in humans, DHPR is not absolutely required for catecholamine synthesis. Patients with familial dysautonomia (FD) had a characteristic, distinct neurochemical pheno-type, with high ratios of plasma DOPA:DHPG and normal plasma NE, DA, and dihydroxyphenylacetic acid (DOPAC) levels. The phenotype predicts a mutation that produces arrested differentiation of peripheral catecholaminergic systems. Patients with inherited deficiency of MAO-A had very low levels of DHPG, whereas patients with deficiency of MAO-B did not, providing a means to distinguish neurochemically deficiencies of the two isoforms of the enzyme. Plasma levels of free (unconjugated) metanephrines diagnosed pheochromocytoma better than did any other neurochemical test. Several studies assessed catecholaminergic neurochemical correlates of physiological and pathophysiologic states or drug treatments. A study combining direct sympathetic nerve recording with neurochemical methods provided the first evidence for glucocorticoid-induced sympathoinhibition in humans, indicating a potentially important interaction between two of the body's main stress effector systems. Prolonged head-down bed rest was used as a model of chronic exposure to zero-gravity during space flight. Neurochemical findings indicated that chronic sympathoinhibition accompanies the orthostatic intolerance that always occurs during re- exposure to the earth's gravity. A characteristic neurocirculatory pattern was found to precede neurocardiogenic syncope, with blunted increases in forearm NE spillover during nonhypotensive LBNP and augmented plasma epinephrine (EPI) responses. In a patient with the Shy- Drager syndrome and multiple myeloma, in vitro testing supported an autoimmune causal mechanism for the disease. Results of a collaborative study of clozapine indicated that this novel neuroleptic affects several aspects of peripheral noradrenergic function. We obtained evidence for functional stimulatory beta-adrenoceptors on sympathetic terminals in the human forearm, without evidence for functional stimulatory receptors for angiotensin II. In humans, the main identified modulator of transmitter release from sympathetic nerves appeared to be inhibitory, mediated by alpha2-adrenoceptors.

与特定异常相关的独特神经化学模式 在儿茶酚胺生物合成、储存、释放、处置和 代谢在几种遗传性或获得性疾病中有描述。 患有门克斯病的儿童，一种铜代谢紊乱， 多巴胺-β-羟化酶（DBH）活性降低的证据， 多巴：二羟基苯乙二醇（DHPG）的比例总是增加， 子宫内诊断和早期治疗。二氢蝶啶还原酶 缺乏会导致非典型形式的苯丙酮尿症。 我们发现， 低但可检测的多巴和其他儿茶酚水平的患者， DHPR的缺失意味着人类并不绝对需要DHPR 儿茶酚胺合成家族性自主神经功能障碍（FD）患者 特征性的，独特的神经化学表型， 血浆DOPA、DHPG和正常血浆NE、DA和二羟苯乙酸 （DOPAC）水平。 表型预测了一个突变， 外周儿茶酚胺能系统的分化。 患者 遗传性MAO-A缺乏症的DHPG水平非常低，而 MAO-B缺乏的患者则没有，这提供了一种方法， 区分两种亚型的神经化学缺陷， 酵素诊断的游离（未结合）变肾上腺素的血浆水平 嗜铬细胞瘤比任何其他神经化学测试。几 研究评估了 生理和病理生理状态或药物治疗。研究 交感神经直接记录与神经化学方法相结合 为糖皮质激素诱导的交感神经抑制提供了第一个证据 在人类中，这表明两个潜在的重要相互作用， 身体的主要压力效应系统。长时间头低位卧床休息 在太空飞行中长期暴露在零重力环境下的模型。 神经化学结果表明，慢性交感神经抑制， 伴随着直立不耐受，总是发生在重新- 暴露在地球引力下一种典型的神经循环系统 在神经心源性晕厥之前发现了一种模式， 非扩张性LBNP期间前臂NE溢出增加， 增强的血浆肾上腺素（EPI）反应。在一个害羞的病人身上， Drager综合征和多发性骨髓瘤，体外试验支持 自身免疫性疾病的病因机制。合作成果 氯氮平的研究表明，这种新的精神抑制剂影响几个 外周去甲肾上腺素能功能方面。我们获得了 交感神经末梢上的功能性刺激性β-肾上腺素受体 人类前臂，没有证据表明功能性刺激受体 血管紧张素II 在人类中，主要确定的递质调节剂 从交感神经释放似乎是抑制性的，由 α 2肾上腺素受体。