METABOLISM OF DIGITALIS LIKE FACTORS

洋地黄类因子的代谢

• 批准号: 6476821
• 负责人: Roland Valdes
• 金额: $ 29.43万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476821
• 关键词: antibody formation; biotransformation; cardiac glycosides; clinical research; digitalis; enzyme activity; enzyme inhibitors; heart contraction; hormone metabolism; hormone regulation /control mechanism; human subject; human tissue; immunomodulators; laboratory mouse; laboratory rabbit; laboratory rat; ouabain; postmortem; sodium potassium exchanging ATPase

The human adrenal synthesizes and secretes a variety of important regulatory hormones. The adrenal cortex secretes an endogenous digoxin- like immunoreactive factor (DLIF) into the circulation. The chemical composition of DLIF is remarkably similar to that of the cardioactive cardenolides. We have recently identified a precursor and several metabolic products of DLIF. However, the detailed structure of these compounds is not known. Several studies demonstrate elevated levels of endogenous DLIF in serum from patients with essential hypertension (EH), pregnancy induced hypertension (PIH), and during cardiac dysfunction. DLIF may control the ion-transport activity of ouabain-sensitive sodium- potassium ATPase. Several isoforms of the Na,K-ATPase (sodium pump) have been identified in tissue. Na/K-ATPase is the only known receptor for the cardenolides and is an important modulator of vascular smooth muscle tone in arterioles as well as other cardiovascular events. Inhibition of the sodium pump causes vasoconstriction which leads to systemic hypertension. A combination of DLIF from the adrenal cortex (as hormone) and sodium pump isoforms (as receptors) may form a regulatory hormonal-axis and play an important role in the etiology of EH and PIH. We propose a working hypothesis: DLIF from human adrenal cortex are endogenous inhibitors of ouabain-sensitive sodium-potassium ATPase and by this mechanism affect blood pressure in mammals. The aim of this project is to define the chemical structure of DLIF and its biotransformation in tissue. Several chemical-identification techniques will be used to determine the structure of DLIF and its metabolic congeners. Biotransformation will be studied using in vitro metabolic techniques. Four independent measures of digitalis-like activity (immunoreactivity; Na,K-ATPase receptor binding; Na,K-ATPase catalytic activity; and ion-transport activity) will be used to characterize the interaction of DLIF and its metabolic precursors and products with the sodium pump. This research will provide the much needed chemical structure of DLIF, define its structural changes during metabolism, and test the hypothesis that DLIF from adrenals are endogenous inhibitors of sodium-potassium ATPase. These factors may prove useful in elucidating the mechanism responsible for EH or PIH and provide much needed diagnostic markers for these and other cardiovascular diseases.

人类肾上腺合成和分泌多种重要的 调节荷尔蒙。肾上腺皮质分泌一种内源性地高辛- 如免疫反应因子(DLIF)进入循环。化学物质 DLIF的组成与心脏活性成分非常相似 卡登内酯。我们最近发现了一个前兆和几个 DLIF的代谢产物。然而，这些文件的详细结构 化合物尚不清楚。几项研究表明，体内的 高血压病患者血清内源性DLIF水平 妊娠高血压综合征(PIH)和心功能不全期间。 DLIF可控制哇巴因敏感钠的离子转运活性。 钾ATPase。Na，K-ATPase的几种异构体(钠泵) 已经在组织中被发现。Na/K-ATPase是唯一已知的受体 是血管顺畅的重要调节剂 小动脉的肌张力以及其他心血管事件。 抑制钠泵导致血管收缩，从而导致 系统性高血压。来自肾上腺皮质的DLIF的组合 (作为激素)和钠泵异构体(作为受体)可以形成 调节荷尔蒙-轴，在糖尿病的发病机制中起重要作用 呃和妊高征。 我们提出了一个工作假设：来自人肾上腺皮质的DLIF是 哇巴因敏感的钠钾ATPase和内源性抑制剂 通过这种机制影响哺乳动物的血压。这样做的目的是 项目是定义DLIF的化学结构及其 组织中的生物转化。几种化学鉴定技术 将用于确定DLIF的结构及其代谢 同类人。生物转化将利用体外代谢进行研究 技巧。洋地黄样活性的四个独立指标 (免疫反应性；Na，K-ATPase受体结合；Na，K-ATPase催化 活性和离子传输活性)将被用来表征 DLIF及其代谢前体和产物与血管内皮生长因子的相互作用 钠泵。 这项研究将提供DLIF急需的化学结构， 定义其在新陈代谢过程中的结构变化，并检验假设 肾上腺来源的DLIF是钠钾的内源性抑制物 ATPase。这些因素可能对阐明这种机制很有帮助。 负责EH或PIH，并提供急需的诊断标志物 这些和其他心血管疾病。