Cardiac Glycosides from the Adrenal Gland

来自肾上腺的强心苷

• 批准号: 6953685
• 负责人: JOHN M HAMLYN
• 金额: $ 29.7万
• 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/6953685
• 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中钠钾泵（Na泵）的活性。强心苷 (CG) 是植物源性类固醇，长期以来因其在医学和基础科学中的用途而得到认可。人们普遍认为，CG 与钠泵的结合会抑制钠离子和钾离子的主动转运。然而，虽然 CG 都以钠泵为目标，但其作用结果在不同细胞类型之间存在显着差异 - 当 CG 浓度低于治疗水平时，会发生深刻的生理作用。此外，Na泵是异质的——由四种已知亚型组成。亿万年来，其中三种亚型保留了以非凡的特异性和高亲和力结合 CG 的能力。给人的印象是，Na 泵除了在离子运输中发挥作用外，还充当一种或多种内源性 CG 的生理受体。事实上，大量证据表明，箭毒的类似物哇巴因是动物和人类循环中普遍存在的成分。内源性“哇巴因”(EO) 与醛固酮一起影响心血管和电解质稳态。循环 EO 的不适当升高与常见的原发性高血压有关。尽管该系统具有重要性和新颖性，但内源性“哇巴因”的起源仍然不确定。肾上腺皮质已多次被认为是 EO 的主要来源，但其生物合成途径并未描述。该提案研究了肾上腺的代谢，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。该方法是多方面的。它涉及对经典类固醇中间体作为 EO 生物合成的可能燃料的研究，以及对标记化合物的命运的研究，以探讨与已知类固醇生物合成途径可能的相似性和差异。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第一个从肾上腺中鉴定出的具有生理意义的新类固醇。它对生命科学和医学的影响既广泛又深远，并将成为高血压和心力衰竭的全新治疗方式的基础。