SUBSTRATE METABOLISM IN ISCHEMIA AND REPERFUSION

本提案的目的是表征基质 在休克和冬眠心肌代谢，并描述了 脂肪酸氧化调节底物之间的关系 在延长的再灌注状态下的能量再合成， 慢性低灌注 拟议的具体目标部分来自工作 在目前的授予间隔，详细介绍了代谢- 急性（35-60分钟）再灌注心肌的功能关联。 它 确定代谢性能部分恢复， 受损 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再合成和能量转移， 郁闷. 总之，这些缺陷可能导致机械损伤。 漂亮 这样的观察现在将扩大到包括再灌注 持续时间较长的条件。 该提案还将利用一个 慢性低灌注心肌冬眠动物模型的建立 在猪身上。 区域缩短的逐渐恶化，局部 反应性充血恢复，存活心肌大量保留 观察了 最大的数据库描述代谢在慢性 危害心肌是临床上由正电子发射引起的 断层扫描，并建议依赖于无氧糖酵解作为主要 满足能源需求。 申请人认为，这一结论 有缺陷的，因为它是可疑的心脏肌肉，即使受损 收缩，可以长期生存在这样微不足道的ATP生产。 到 解决这些争议，详细调查多个基板 利用，能量学和线粒体性能计划在 更长的再灌注时间1）在持续暴露于局部缺血后， 非Q波梗塞，预处理和2）在冬眠的心脏 模型 还计划测试肉毒碱的监管重要性 棕榈酰转移酶（CPT I）作为调节 脂肪酸氧化在延长再灌注和低灌注。 以前的数据表明，肉毒碱转移酶-转位酶序列 在局部缺血中是限速的。 研究将在隔离和 完整的心脏和分离和重建的膜酶系统。 的 这项建议的健康相关性与越来越多地使用 危及生命的冠状动脉患者的临床再灌注方案 动脉疾病 这一提议的结果可能会揭示一些机制， 提高代谢效率，逆转机械功能障碍 与再流和慢性低灌注有关。

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.