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（由申请人提供）：几乎所有动物细胞都取决于其表面膜中钠钾泵（NA泵）的活性。心脏糖苷（CG）是植物来源的类固醇，以医学和基本科学的效用而闻名。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CGS所有靶向NA泵，但其作用的后果在不同的细胞类型之间存在巨大不同 - 并且严重的生理作用发生，CG浓度低于治疗水平。此外，NA泵是异质的 - 由四个已知同工型的家族组成。其中三种同工型保留了与Eons具有非凡特异性和高亲和力结合CG的能力。印象是NA泵除了在离子转运中的作用外，还充当一个或多个内源性CG的生理受体。确实，压倒性的证据表明，箭毒的类似物ouaabain是动物和人类循环中无处不在的组成部分。内源性的“ ouabain”（EO）与醛固酮一起影响心血管和电解质稳态。循环EO的不当升高与常见的基本高血压有关。尽管该系统的重要性和新颖性，但内源性“ Ouabain”的起源仍然不确定。肾上腺皮质反复被视为EO的主要来源，但未描述生物合成途径。该建议研究了肾上腺的代谢，并专门探讨了牛肾上腺皮质组织和细胞EO生物合成的可能性。该方法是多方面的。它涉及对经典类固醇中间体的研究作为EO生物合成的可能燃料，并研究标记化合物的命运，以探测已知类固醇生物合成途径的可能相似性和差异。该研究将通过对EO及其前体的生物活性和结构以及新型结合蛋白的研究来补充。拟议的研究的成功结果将是革命性的 - 自从发现醛固酮以来，这是从肾上腺中鉴定出的首个新生理意义的类固醇。对生命科学和医学的影响既广泛又深刻，并且将成为高血压和心力衰竭的新型治疗方式的基础。

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