Cardiac Glycosides from the Adrenal Gland

来自肾上腺的强心苷

• 批准号: 7271877
• 负责人: JOHN M HAMLYN
• 金额: $ 28.16万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271877
• 关键词: Active Biological Transport; Adrenal Cortex; Adrenal Glands; Affinity; Aldosterone; Anabolism; Animals; Basic Science; Binding; Binding Proteins; Biological; Biological Factors; Biological Sciences; Blood Circulation; Bos taurus; Cardiac Glycosides; Cardiovascular system; Cattle; Cells; Cholesterol; Complement; Disease; Distal; Electrolytes; Elevation; Essential Hypertension; Etiology; Event; Family; Heart failure; Homeostasis; Human; Hypertension; Investigation; Ion Transport; Isomerism; Label; Laboratories; Link; Mammals; Medicine; Membrane; Metabolism; Modality; Na(+)-K(+)-Exchanging ATPase; Nuclear Magnetic Resonance; Ouabain; Outcome; Pathway interactions; Physiological; Plants; Play; Poison; Pregnenolone; Preparation; Progesterone; Protein Isoforms; Proteins; Pump; Role; Route; Side; Sodium; Sodium Chloride; Source; Specificity; Spectrometry; Steroids; Structure; Surface; System; Therapeutic; Tissues; Water; Zona Glomerulosa; analog; base; cell type; concept; impression; novel; novel therapeutics; potassium ion; receptor; steroid hormone

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(申请人提供)：几乎所有的动物细胞都依赖于其表面膜上的钠钾泵(Na泵)的活性。心脏糖苷(CG)是一种植物来源的类固醇，长期以来一直被认为在医学和基础科学中具有实用价值。人们普遍认为，CG与Na泵的结合抑制了钠和钾离子的主动转运。然而，尽管CG都以钠泵为靶点，但它们的作用结果在不同类型的细胞之间差别很大--当CG浓度低于治疗水平时，就会发生深刻的生理作用。此外，钠泵是异质性的--由一系列已知的四种亚型组成。其中三种异构体保留了与CGs结合的能力，具有非凡的特异性和高亲和力。人们的印象是，钠泵除了在离子运输中发挥作用外，还作为一个或多个内源性CG的生理受体发挥作用。事实上，压倒性的证据表明，箭毒的类似物哇巴因是动物和人类血液循环中普遍存在的成分。内源性哇巴因(EO)和醛固酮一起影响心血管和电解质的稳态。循环EO的异常升高与常见的原发性高血压有关。尽管这一系统具有重要性和新颖性，但内源性“哇巴因”的来源仍不确定。肾上腺皮质已多次被认为是EO的主要来源，但其生物合成途径尚未被描述。这项建议研究了肾上腺的新陈代谢，并专门探索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。它包括研究经典的类固醇中间体作为环氧乙烷生物合成的可能燃料，以及研究标记化合物的命运，以探索与已知的类固醇生物合成途径的可能的异同。对EO及其前体的生物活性和结构以及新的结合蛋白的研究将补充这项研究。这项拟议中的研究的成功结果将是革命性的--这是自发现醛固酮以来，第一个从肾上腺中发现的具有重要生理意义的新类固醇。对生命科学和医学的影响是广泛而深刻的，并将构成高血压和心力衰竭的根本性新治疗方式的基础。

项目成果

Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension.

• DOI: 10.1097/hjh.0b013e32833ea821
• 发表时间: 2011-02
• 期刊: Journal of hypertension
• 影响因子: 4.9
• 作者: Manunta P;Hamlyn JM;Simonini M;Messaggio E;Lanzani C;Bracale M;Argiolas G;Casamassima N;Brioni E;Glorioso N;Bianchi G
• 通讯作者: Bianchi G

Endogenous ouabain and cardiomyopathy in dialysis patients.

透析患者的内源性哇巴因和心肌病。

• DOI: 10.1111/j.1365-2796.2007.01883.x
• 发表时间: 2008
• 期刊: Journal of internal medicine
• 影响因子: 11.1
• 作者: Stella,P;Manunta,P;Mallamaci,F;Melandri,M;Spotti,D;Tripepi,G;Hamlyn,JM;Malatino,LS;Bianchi,G;Zoccali,C
• 通讯作者: Zoccali,C

Steroid biosynthesis and renal excretion in human essential hypertension: association with blood pressure and endogenous ouabain.

• DOI: 10.1038/ajh.2009.3
• 发表时间: 2009-04
• 期刊: AMERICAN JOURNAL OF HYPERTENSION
• 影响因子: 3.2
• 作者: Tripodi, Grazia;Citterio, Lorena;Kouznetsova, Tatiana;Lanzani, Chiara;Florio, Monica;Modica, Rossana;Messaggio, Elisabetta;Hamlyn, John M.;Zagato, Laura;Bianchi, Giuseppe;Staessen, Jan A.;Manunta, Paolo
• 通讯作者: Manunta, Paolo