REGULATION OF METABOLISM IN OXYGEN DEFICIENT HEARTS

心肌缺血不可逆性细胞损伤的机制 将在离体灌注的大鼠心脏中进行研究。 初步数据 表明糖原分解细胞内产物的高水平 加速从可逆损害到不可逆损害的转变 与组织高能磷酸盐的变化无关。 假设， 糖酵解产物（乳酸盐，NADH，H+， 等等）。对冠状动脉血流和氧化代谢减少的反应 引发了一系列的次级反应， 对组织造成不可逆的损伤 拟议的工作将决定 糖酵解产物的组织水平之间的时间关系 缺血和缺血心脏收缩功能的丧失 随后在有氧条件下再灌注。 积累 缺血期间糖酵解产物将因先前的糖原 消耗，维持不同速率的缺血性冠状动脉血流， 缺氧灌注液和糖酵解抑制剂的使用。 建议开展研究， 允许识别责任产品。 时间 不可逆损伤的发生与 线粒体、肌膜和肌浆网的改变 功能将在暴露于广泛的 糖酵解产物的细胞间浓度，以帮助表征 糖酵解产物引起细胞损伤的机制。 的 这些产物的浓度将一起和单独变化。 糖酵解抑制剂将被开发，试图提供 延长缺血心肌的保护作用。

The mechanism of irreversible cellular damage during myocardial ischemia will be investigated in isolated perfused rat hearts. Preliminary data indicate that high levels of intracellular products of glycogenolysis accelerate the transition from reversible to irreversible damage independent of changes in tissue high energy phosphates. The hypothesis to be tested is that accumulation of glycolytic products (lactate, NADH, H+, etc.) in response to decreased coronary flow and oxidative metabolism initiates a series of secondary reactions that ultimately cause irreversible damage to the tissue. The proposed work will determine the temporal relation between tissue levels of glycolytic products during ischemia and the loss of contractile function in ischemic hearts subsequently reperfused under aerobic conditions. Accumulation of glycolytic products during ischemia will be varied by prior glycogen depletion, maintenance of different rates of ischemic coronary flow with anoxic perfusate and use of glycolytic inhibitors. Studies are proposed to allow identification of the responsible product(s). The temporal relationship between onset of irreversible damage and the appearance of alterations in mitochondrial, sarcolemmal and sarcoplasmic reticular functions will be determined in ischemic tissue exposed to a wide range of intercellular concentrations of glycolytic products to help characterize the mechanisms of glycolytic product induced cellular damage. The concentration of these products will be varied together and individually. Inhibitors of glycolysis will be developed in an attempt to provide prolonged protection to ischemic myocardium.