PRECONDITIONING, ISF ADENOSINE, AND CARDIOPROTECTION

拟议研究的广泛，长期目标是阐明 腺苷的心脏保护作用，并提高我们对 缺血预处理过程中发生的细胞事件。 在 拟议的研究，心脏微透析探针将被植入在 提供变化的透壁轮廓 在组织液（ISF）中腺苷，腺苷代谢物， 局部心肌缺血期间和之后的乳酸和去甲肾上腺素 在麻醉的动物身上。微透析探针也将用于评估 动脉和冠状静脉腺苷水平。 保护将是 通过局部心室功能恢复和大小来评价 局部心肌梗死60分钟后的心肌梗死 缺血实验协议将针对两个主要目标： 目标1.确定分级冠状动脉内 腺苷给药和以下变化：1）ISF和冠状静脉 腺苷; 2）心肌保护程度。 目标二。为了确定 缺血预处理诱导的缺血性脑卒中后心肌缺血因子腺苷一过性升高 以及心肌保护程度， 缺血 拟议的实验将评估腺苷对缺血性心脏病的假设。 通过提供支持或反对该概念的直接证据来进行预处理 缺血前ISF中腺苷的浓度 这是心脏的先决条件，并提供心肌保护。 因此，在本发明中， 这些实验对于我们理解戏剧性的 预处理提供的保护可以转化为临床 模态拟议的实验还将确定是否外源性 腺苷减少缺血诱导的去甲肾上腺素释放， 预处理部分通过减少去甲肾上腺素来保护心脏 在随后的长时间缺血期间释放。

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.