REGULATION OF METABOLISM IN OXYGEN DEFICIENT HEARTS

心肌缺血时不可逆的细胞损伤机制 将在分离的灌流大鼠心脏中进行研究。初步数据 说明高水平的细胞内糖原分解产物 加速从可逆破坏到不可逆转破坏的转变 与组织高能磷酸盐的变化无关。假设是为了 检测的是糖酵解产物(乳酸、NADH、H+、 等)对冠脉流量和氧化代谢减少的反应 引发一系列的二次反应，最终导致 对组织造成不可逆转的损害。拟议的工作将决定 糖酵解产物组织水平的时间关系 缺血与缺血心脏收缩功能的丧失 随后在好氧条件下再灌流。积累 缺血时的糖酵解产物会因先前的糖原而发生变化。 耗竭、维持不同速度的缺血冠脉血流 缺氧灌流液和糖酵解抑制剂的使用。建议进行研究以 允许识别负责的产品(S)。世俗的 不可逆性损伤的发生与出现的关系 线粒体、肌膜和肌浆网的改变 功能将被确定在暴露于广泛的 糖酵解产物的胞间浓度有助于表征 糖酵解产物引起细胞损伤的机制。这个 这些产品的浓度将一起或单独变化。 糖酵解的抑制剂将被开发出来，试图提供 对缺血心肌的长期保护作用。

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.