METABOLISM OF DIGITALIS LIKE FACTORS

洋地黄类因子的代谢

• 批准号: 6330142
• 负责人: Roland Valdes
• 金额: $ 28.71万
• 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 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330142
• 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.

人体肾上腺合成并分泌多种重要的 调节激素 肾上腺皮质分泌内源性地高辛- 类免疫反应因子（DLIF）进入循环。化学 DLIF的组成与心脏活性药物的组成非常相似。 强心内酯 我们最近发现了一个前兆和几个 DLIF的代谢产物。 然而，这些的详细结构 化合物未知。 几项研究表明， 原发性高血压（EH）患者血清中的内源性DLIF， 妊娠高血压综合征（PIH）和心功能不全。 DLIF可能控制哇巴因敏感的钠离子转运活性， 钾ATP酶 Na，K-ATP酶（钠泵）的几种亚型 已经在组织中被识别出来。 Na/K-ATP酶是唯一已知的受体 是一种重要的血管平滑肌调节剂， 小动脉中的肌肉张力以及其他心血管事件。 钠泵的抑制引起血管收缩， 全身性高血压 肾上腺皮质的DLIF (as激素）和钠泵同种型（作为受体）可以形成 调节神经轴，并发挥重要作用的病因 EH和PIH。 我们提出了一个工作假设：人肾上腺皮质的DLIF是 哇巴因敏感性钠-钾ATP酶的内源性抑制剂， 影响哺乳动物的血压。的目的 该项目旨在确定DLIF的化学结构及其 组织中的生物转化 几种化学鉴别技术 将用于确定DLIF的结构及其代谢 同源物。 将使用体外代谢试验研究生物转化 技术. 四种独立的数字类活动指标 （免疫反应性; Na，K-ATP酶受体结合; Na，K-ATP酶催化 活性;和离子传输活性）将用于表征 DLIF及其代谢前体和产物与 钠泵 这项研究将提供急需的DLIF化学结构， 定义其在代谢过程中的结构变化，并检验假设 肾上腺DLIF是内源性钠-钾抑制剂， ATP酶 这些因素可能有助于阐明机制 负责EH或PIH，并提供急需的诊断标志物， 以及其他心血管疾病。