SUBSTRATE METABOLISM IN ISCHEMIA AND REPERFUSION

这项提案的目标将是确定底物的特征 顿抑和冬眠心肌的代谢，并描述 氧化底物之间的关系、脂肪酸的调节 长时间再灌流状态下的能量传递和能量再合成 慢性低灌注症。拟议的具体目标部分是从工作中延伸出来的 在目前的授予间隔内进行，其中详细说明了代谢- 急性(35-60分钟)再灌流心肌的功能联系。它 被确定代谢性能部分恢复，部分 受伤了。脂肪酸氧化的正常模式被重新建立 葡萄糖、丙酮酸和乳酸氧化的相互抑制。 相反，线粒体ATP的再合成和能量转移 情绪低落。综上所述，这些缺陷可能会导致机械 令人惊叹。这样的观察现在将扩大到包括再灌流 持续时间较长的情况。该提案还将利用 慢性低灌流诱导冬眠心肌的新动物模型 在猪身上。区域缩短的逐步恶化，部分 反应性充血的恢复和存活心肌的基本保存 都观察到了。描述慢性新陈代谢的最大数据库 受损心肌是临床上因正电子发射而产生的心肌。 体层摄影术，提示依赖无氧糖酵解为主要症状 基板，以满足能源需求。申请人认为，这一结论是 有缺陷的，因为它是可疑的如何心肌，即使与受损 收缩，可以长期生存在如此微不足道的ATP生产上。至 解决这些争议，对多基板进行详细的综述 利用，能量，和有丝分裂的性能被计划在 较长时间的再灌流1)在持续暴露于缺血后， 2)冬眠心脏的非Q波心肌梗死和预适应 模特。它还计划测试肉碱的调节重要性。 棕榈酰基转移酶(CPT I)在调控中的限速控制位点 长时间再灌流和低灌流时的脂肪酸氧化。 先前的数据表明，肉碱转移酶-易位酶序列 在缺血时是限速的。研究将在孤立的和 完整的心脏和分离的和重组的膜-酶系统。这个 这项提议的健康相关性与越来越多的人使用 危及生命的冠心病患者的临床再通方案 动脉疾病。这项提案的结果可能揭示出 提高代谢效率，逆转机械功能障碍 与复流和慢性低血流有关。

The objectives of this proposal will be to characterize substrate metabolism in stunned and hibernating myocardium and describe the relationships among substrates for oxidation, regulation of fatty acid transfer, and energy resynthesis under prolonged states of reperfusion and chronic hypoperfusion. The proposed specific aims in part extend from work conducted in the present granting interval which detailed the metabolic- functional associations in acutely (35-60 min) reperfused heart muscle. It was determined that metabolic performance was in part restored and in part impaired. Normal patterns of fatty acid oxidation were re-established with reciprocal inhibitions of glucose, pyruvate, and lactate oxidations. Conversely, mitochrondrial ATP resynthesis and energy transfer were depressed. Taken together, these defects may contribute to mechanical stunning. Such observations will now be expanded to include reperfusion conditions of longer duration. The proposal also will take advantage of a new animal model of hibernating myocardium induced by chronic hypoperfusion in pigs. A progressive deterioration in regional shortening, partial restoration of reactive hyperemia, and largely preserved viable myocardium were observed. The largest database describing metabolism in chronically jeopardized myocardium is that derived clinically from positron emission tomography and suggests dependence on anaerobic glycolysis as the prime substrate for energy needs. In the applicant's opinion, this conclusion is flawed since it is dubious how heart muscle, even with impaired contraction, could survive long-term on such trivial ATP production. To resolve these controversies, a detailed survey of multiple substrate utilizations, energetics, and mitochrondrial performance is planned over longer periods of reperfusion 1) after sustained exposures to ischemia, non-Q wave infraction, and pre-conditioning and 2) in the hibernating heart model. It is also planned to test the regulatory importance of carnitine palmitoyltransferase (CPT I) as a rate-limiting control site in modulating fatty acid oxidation during prolonged reperfusion and hypoperfusion. Previous data suggested that the carnitine transferase-translocase sequence is rate-limiting in ischemia. Studies will be conducted in isolated and intact hearts and isolated and reconstituted membrane-enzyme systems. The health relatedness of this proposal is linked to the increasing use of clinical reperfusion protocols in patients with life-threatening coronary artery disease. The results of this proposal may reveal mechanisms to improve metabolic efficiency and reverse the mechanical dysfunction associated with reflow and chronic hypoperfusion.