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导致 关键心肌 ATP 通量的适应性变化随后恢复 能量平衡并延缓不可逆心肌损伤的发生。 该反馈系统的工作重点集中在两个方面：确定 腺苷保护作用的动力学和机制 缺血，并定义肾上腺素能放大的途径 腺苷生产。 提出了四个具体目标：（1）测试 先前建立的心肌保护作用的假设 腺苷的发展速度比 ATP 消耗到临界水平的速度要慢 急性完全缺血期间； (2) 识别机制 腺苷在灌注不足时的保护作用； (3) 测试 假设心肌腺苷产生增加 灌注不足不仅仅是由 ATP 分解引起的，而是存在以下因素： 由于α受体刺激而导致腺苷产生放大 通过释放储存的去甲肾上腺素并（4）检验假设 腺苷α受体放大机制 灌注不足期间的产生与腺苷/ATP 之一有关 通量。 具体来说，后一个目标将确定腺苷是否 由于 (a) 细胞外产量增加，产量被放大 腺苷，(b) 胞质 5' 核苷酸酶的激活或抑制 腺苷激酶或（c）改变腺苷的膜转运。 实验计划将利用已证明的实用性和可行性 高能磷酸盐化合物的核磁共振波谱测量。 关键工具包括选择性转运、受体和酶激动剂以及 拮抗剂、示踪动力学技术和综合数学 系统模型。重点是区分目标 ATP 连接腺苷受体和细胞通路的通量 目标。 肾上腺素能放大腺苷产生的研究 将探索 ATP 依赖和独立机制以及 开发一个分析模型，以最大化从中产生的信息 使用多指示剂稀释分析和酶进行测量 阻滞剂来评估胞质腺苷浓度。 结果 研究对于指导尝试采取治疗措施至关重要 腺苷对心肌保护作用的优势 缺血。 他们将阐明心肌之间的关系 能量学和腺苷可能作为局部药物发挥着最关键的作用 体液剂。