CARDIAC PROTECTION BY ADENOSINE IN ISCHEMIA

描述：本提案的主要目标是测试 假设在缺血期间腺苷产生增加导致 关键心肌ATP流量的适应性变化，随后恢复 能量平衡和延迟不可逆心肌损伤的发生。 努力集中在这个反馈系统的两个方面： 腺苷保护作用的动力学和机制 缺血，并确定肾上腺素能放大的途径， 腺苷产生。 提出了四个具体目标：（1）测试 假设先前确定的心肌保护作用 腺苷的发展比ATP耗竭到临界水平要慢得多 在急性完全缺血;（2）确定的机制， 腺苷在灌注不足时的保护作用;（3）检测腺苷在灌注不足时的保护作用。 假设心肌腺苷产生的增加， 灌注不足不是由ATP分解单独引起的， 由于α受体刺激导致的腺苷产生的放大 通过释放储存的去甲肾上腺素和（4）检验假设 腺苷α受体放大的机制 在灌注不足期间的产生与腺苷/ATP之一有关 剂. 具体来说，后一个目标将确定腺苷是否 由于（a）增加的细胞外生产， （B）激活胞质5 '核苷酸酶或抑制 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效用和可行性 高能量磷酸盐化合物的核磁共振光谱测量。 关键工具包括选择性转运、受体和酶激动剂， 拮抗剂，示踪动力学技术和一个全面的数学 重点是区分目标ATP 连接腺苷受体和腺苷受体的细胞通路的流量 目标 肾上腺素能放大腺苷生成的研究 将探讨ATP依赖和独立的机制，以及 建立一个分析模型，最大限度地利用 使用多指示剂稀释分析和酶 阻断剂以评估胞质腺苷浓度。 结果 研究将是至关重要的指导尝试采取治疗 腺苷在心肌保护作用中的优势 缺血 他们将阐明心肌 能量和腺苷可能发挥其最关键的作用，作为一个局部 体液因子

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.