Cardiac Glycosides from the Adrenal Gland

来自肾上腺的强心苷

• 批准号: 6824311
• 负责人: JOHN M HAMLYN
• 金额: $ 29.3万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824311
• 关键词: adrenal glands; aldosterone; animal tissue; brain cell; cardiac glycosides; high performance liquid chromatography; hormone binding protein; hormone receptor; ion transport; liquid chromatography mass spectrometry; mass spectrometry; nuclear magnetic resonance spectroscopy; ouabain; scintillation spectrometry; sodium potassium exchanging ATPase; steroid hormone biosynthesis; tissue /cell culture

DESCRIPTION (provided by applicant): Virtually all animal cells depend upon the activity of sodium-potassium pumps (Na pumps) in their surface membrane. Cardiac glycosides (CG) are plant-derived steroids long recognized for their utility in medicine and the basic sciences. It is widely accepted that the binding of CG to Na pumps inhibits the active transport of sodium and potassium ions. Yet while CGs all target Na pumps, the consequences of their action differ dramatically among different cell types - and profound physiological actions occur with CG concentrations below the therapeutic level. In addition, the Na pump is heterogeneous - comprised of a family of four known isoforms. Three of the isoforms have retained the ability to bind CGs with extraordinary specificity and high affinity over the eons. The impression is that the Na pump, in addition to a role in ion transport, functions as a physiological receptor for one or more endogenous CGs. Indeed, overwhelming evidence has shown that an analog of the arrow poison, ouabain, is a ubiquitous component of the circulation in animals and humans. The endogenous "ouabain" (EO) together with aldosterone influences cardiovascular and electrolyte homeostasis. The inappropriate elevation of circulating EO is linked with common essential hypertension. In spite of the importance and novelty of this system, the origin of the endogenous "ouabain" remains uncertain. The adrenal cortex has been repeatedly implicated as a major source of EO but the biosynthetic pathway is not described. This proposal investigates the metabolism of the adrenal gland and specifically explores the possibility of EO biosynthesis by bovine adrenocortical tissue and cells. The approach is multifaceted. It involves the investigation of classical steroid intermediates as possible fuels for EO biosynthesis and studies of the fate of labeled compounds to probe for possible similarities and differences from known steroid biosynthetic pathways. The investigation will be complemented by studies of the bioactivity and structure of EO and its precursors as well as novel binding proteins. The successful outcome of the proposed studies would be revolutionary - representing the first new physiologically significant steroid to be identified from the adrenal since the discovery of aldosterone. The implications for the life sciences and medicine are both broad and profound and will form the basis for fundamentally new therapeutic modalities for hypertension and heart failure.

描述（由申请人提供）：几乎所有动物细胞都依赖于其表面膜上钠钾泵（Na泵）的活性。心糖苷（CG）是植物衍生的类固醇，长期以来被认为在医学和基础科学中具有重要作用。人们普遍认为，CG与Na泵的结合抑制了钠离子和钾离子的主动转运。然而，尽管CG都以钠泵为靶点，但其作用的结果在不同的细胞类型中存在显著差异——当CG浓度低于治疗水平时，会发生深刻的生理作用。此外，钠泵是异质的-由四种已知的同工异构体组成。其中三种同工异构体保留了结合cg的能力，具有非凡的特异性和高亲和力。结果表明，Na泵除了在离子运输中起作用外，还作为一种或多种内源性cg的生理受体。事实上，大量证据表明，一种类似箭毒的物质，瓦巴因，在动物和人类的血液循环中无处不在。内源性“瓦巴因”（EO）与醛固酮一起影响心血管和电解质稳态。循环EO不适当升高与普通原发性高血压有关。尽管这一系统的重要性和新颖性，但内源性“瓦巴因”的起源仍然不确定。肾上腺皮质多次被认为是EO的主要来源，但其生物合成途径尚未被描述。本课题研究了肾上腺的代谢，并特别探讨了牛肾上腺皮质组织和细胞生物合成EO的可能性。这种方法是多方面的。它包括研究经典类固醇中间体作为EO生物合成的可能燃料，以及研究标记化合物的命运，以探索与已知类固醇生物合成途径可能存在的相似性和差异性。该研究将通过对EO及其前体以及新型结合蛋白的生物活性和结构的研究来补充。拟议研究的成功结果将是革命性的-代表自醛固酮发现以来从肾上腺中鉴定出的第一个新的具有生理意义的类固醇。这对生命科学和医学的影响既广泛又深刻，并将为高血压和心力衰竭的全新治疗方式奠定基础。