PRECONDITIONING, ISF ADENOSINE, AND CARDIOPROTECTION

预适应、ISF 腺苷和心脏保护

• 批准号: 2222643
• 负责人: David G Van Wylen
• 金额: $ 12万
• 依托单位: ST. OLAF COLLEGE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2222643
• 关键词: adenosine; chemoprevention; conditioning; dipyridamole; dogs; heart circulation; heart function; heart metabolism; heart pharmacology; high performance liquid chromatography; histology; interstitial; isolation perfusion; lactates; microdialysis; myocardial infarct sizing; myocardial ischemia /hypoxia; myoglobin; norepinephrine

The broad, long-term aims of the proposed research are to elucidate the cardioprotective actions of adenosine and to enhance our understanding of the cellular events which occur during ischemic preconditioning. In the proposed research, cardiac microdialysis probes will be implanted in the endocardium and epicardium to provide transmural profiles of the changes in interstitial fluid (ISF) levels of adenosine, adenosine metabolites, lactate, and norepinephrine during and after regional myocardial ischemia in anesthetized animals. Microdialysis probes will also be used to assess arterial and coronary venous adenosine levels. Cardioprotection will be evaluated by the recovery of regional ventricular function and by the size of the myocardial infarction following 60 minutes of regional myocardial ischemia. The experimental protocols will address two primary aims: Aim 1. To determine the relationship between graded intracoronary adenosine administration and the changes in: 1) ISF and coronary venous adenosine, and; 2) the degree of myocardiaI protection. Aim 2. To determine the relationship between the magnitude of the transient increase in ISF adenosine induced by ischemic preconditioning and the degree of myocardial protection from subsequent prolonged ischemia. The proposed experiments will assess the adenosine hypothesis for ischemic preconditioning by providing direct evidence for or against the concept that it is the concentration of adenosine in the ISF prior to ischemia that preconditions the heart and affords myocardial protection. As such, these experiments are important to our understanding of how the dramatic protection afforded by preconditioning can be translated into a clinical modality. The proposed experiments will also determine if exogenous adenosine reduces the ischemia-induced norepinephrine release and if preconditioning protects the heart in part by reducing norepinephrine release during a subsequent period of prolonged ischemia.

拟议研究的广泛、长期目标是阐明 腺苷的心脏保护作用和增进我们对 在缺血预适应过程中发生的细胞事件。在 拟议的研究，心脏微透析探头将被植入 心内膜和心外膜提供这些变化的跨壁轮廓 在间质液体(ISF)中腺苷、腺苷代谢物、 局部心肌缺血期间和术后的乳酸和去甲肾上腺素 在麻醉的动物身上。微透析探头也将用于评估 动脉和冠状动脉静脉的腺苷水平。心脏保护将是 通过局部心功能的恢复和大小来评价 局部心肌梗死60分钟后的心肌梗死 缺血症。实验方案将解决两个主要目标： 目的1.确定冠状动脉内分级与冠状动脉病变的关系 腺苷给药及其在以下方面的变化：1)ISF和冠状静脉 腺苷；2)心肌保护程度。 目的2.确定大小与大小的关系 缺血预适应引起胰岛素样生长因子腺苷的一过性升高 以及随后延长对心肌的保护程度 缺血症。 拟议的实验将评估腺苷对脑缺血的假说。 通过提供支持或反对这一概念的直接证据来预先处理 它是缺血前ISF中的腺苷浓度 这对心脏有预调节作用，并提供心肌保护。因此， 这些实验对于我们理解戏剧性的 预适应提供的保护可以转化为临床上的 情态。拟议中的实验还将确定外源基因 腺苷减少缺血诱导的去甲肾上腺素释放 预适应通过减少去甲肾上腺素来保护心脏 在随后长时间的缺血期内释放。