CARDIAC PROTECTION BY ADENOSINE IN ISCHEMIA

描述：这项提案的主要目标是测试 缺血引起腺苷生成增加的假说 关键心肌ATP流量的适应性变化，随后恢复 平衡能量，延缓不可逆性心肌损伤的发生。 努力集中在这个反馈系统的两个方面：确定 腺苷保护作用的动力学及机制 缺血，并明确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 假设先前确定的心肌保护作用 腺苷的发展速度慢于ATP的耗竭，达到临界水平 在急性全脑缺血期间；(2)确定其机制。 腺苷在低灌注期的保护作用；(3)检测 假说心肌腺苷的增加在 血液灌流不足不仅仅是由ATP分解引起的，而是有 α受体刺激对腺苷产生的放大作用 通过释放储存的去甲肾上腺素和(4)检验假设 腺苷α受体扩增的机制 低灌注时的产生与腺苷/三磷酸腺苷中的一种有关 助熔剂。具体地说，后一个目标将确定腺苷是否 由于(A)胞外产量增加，产量被放大。 腺苷，(B)胞浆5‘核苷酸酶的激活或抑制 或(C)改变了腺苷的膜转运。 实验计划将开发已证明的实用性和可行性 高能磷酸盐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、示踪剂动力学技术和综合数学 系统模型。重点是对目标ATP的识别 连接腺苷受体和细胞外信号转运蛋白的细胞通路的通量 目标。腺苷生产的肾上腺素能放大作用的研究 将探索ATP依赖和独立的机制以及 开发分析模型，以最大限度地利用 多指示剂稀释法和酶法测定 阻滞剂用于评估胞浆中的腺苷浓度。评选结果 研究将是指导治疗尝试的关键 腺苷在心肌保护作用中的优势 缺血症。他们将阐明心肌梗塞之间的关系 能量学和腺苷可能发挥其最关键的作用作为局部 幽默剂。

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.