CARDIAC PROTECTION BY ADENOSINE IN ISCHEMIA

腺苷在缺血时的心脏保护作用

• 批准号: 2227716
• 负责人: KEITH KROLL
• 金额: $ 14.21万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2227716
• 关键词: adenosine; adenosine triphosphate; bioenergetics; chemoprevention; glycolysis; heart circulation; high energy compound; indicator dilution test; intracellular; isolation perfusion; laboratory rabbit; membrane transport proteins; myocardial ischemia /hypoxia; nuclear magnetic resonance spectroscopy

DESCRIPTION: The primary objective of this proposal is to test the hypothesis that increases in adenosine production during ischemia cause adaptive changes in key myocardial ATP fluxes which subsequently restore energy balance and delay the onset of irreversible myocardial damage. Effort is focused on two aspects of this feedback system: determining the kinetics and mechanism of the protective effect of adenosine during ischemia, and defining the pathway for adrenergic amplification of adenosine production. Four Specific Aims are proposed: (1) test the hypothesis that the previously established myocardial protective effect of adenosine develops more slowly than ATP depletion to critical levels during acute total ischemia; (2) identify the mechanism of the protective action of adenosine during underperfusion; (3) test the hypothesis that the increase in myocardial adenosine production during underperfusion is not caused by ATP breakdown alone, but that there is amplification of adenosine production due to alpha receptor stimulation through release of stored norepinephrine and (4) test the hypothesis that the mechanism of alpha receptor amplification of adenosine production during underperfusion is related to one of the adenosine/ATP fluxes. Specifically, the latter aim will identify whether adenosine production is amplified due to (a) increased extracellular production of adenosine, (b) activation of cytosolic 5'nucleotidase or inhibition of adenosine kinase or (c) altered membrane transport for adenosine.The experimental plan will exploit the demonstrated utility and feasibility of NMR spectroscopy measurements of high energy phosphate compounds. Key tools include selective transport, receptor and enzyme agonists and antagonists, tracer kinetic technologies and a comprehensive mathematical model of the system.Emphasis is placed on distinguishing the target ATP fluxes from the cellular pathways linking the adenosine receptor and the target. The studies of adrenergic amplification of adenosine production will explore the ATP dependent and independent mechanisms as well as develop an analytical model for maximizing the information yielded from measurements using multiple indicator dilution analysis and enzyme blockers to assess cytosolic adenosine concentrations. Results of the study will be critical for guiding attempts to take therapeutic advantage of the protective effects of adenosine during myocardial ischemia. They will elucidate the relation between myocardial energetics and adenosine may play its most critical role as a local humoral agent.

描述：该提案的主要目的是测试 缺血期间腺苷产生增加的假设 关键心肌ATP通量的自适应变化，随后还原 能量平衡并延迟不可逆的心肌损伤。 努力的重点是此反馈系统的两个方面：确定 腺苷在 缺血，并定义了肾上腺素能扩增的途径 腺苷产生。 提出了四个具体目标：（1）测试 假设先前建立的心肌保护作用 腺苷的发展速度比ATP耗尽到临界水平的速度较慢 在急性总缺血期间； （2）确定 灌注不足期间腺苷的保护作用； （3）测试 假设心肌腺苷在 灌注不足不是仅仅由ATP分解引起的，而是 由于α受体刺激而放大腺苷产生 通过释放存储的去甲肾上腺素，（4）检验假设 腺苷的α受体扩增机理 灌注不足期间的生产与腺苷/ATP之一有关 通量。 具体而言，后一个目标将确定腺苷是否存在 由于（a）细胞外产生增加而放大生产 腺苷，（b）胞质5'N核苷酸酶或抑制作用的激活 腺苷激酶或（c）改变腺苷的膜转运。 实验计划将利用所证明的效用和可行性 高能磷酸化合物的NMR光谱测量。 关键工具包括选择性运输，受体和酶激动剂以及 对手，示踪动力学技术和全面的数学 系统模型。 连接腺苷受体和的细胞途径的通量 目标。 腺苷产生肾上腺素能扩增的研究 将探索依赖ATP和独立的机制 开发一个分析模型，以最大化从 使用多个指标稀释分析和酶的测量 收缩者评估胞质腺苷浓度。 结果 研究对于指导尝试治疗至关重要 心肌期间腺苷的保护作用的优势 缺血。 他们将阐明心肌之间的关系 能量和腺苷可能在本地起作用最关键的作用 体型。