ALTERATIONS OF METABOLISM IN ISCHEMIC MYOCARDIUM

缺血心肌代谢的改变

• 批准号: 3343740
• 负责人: A. JAMES LIEDTKE
• 金额: $ 13.29万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3343740
• 关键词: acetates; acetoacetates; acyl coA; beta hydroxybutyrate; bioenergetics; cardiotonic agents; carnitine; dichloroacetate; enzyme substrate; fatty acid metabolism; glucose metabolism; heart circulation; heart function; myocardial ischemia /hypoxia; oxidative phosphorylation; pyruvates

The objects of these proposals are to establish the limits of metabolic adaptation in ischemic myocardium and to evaluate several interventions designed to improve energy production and/or mechanical function. We have observed previously that the damages of myocardial ischemia result not only from the loss in oxygen delivery, but also from an accumulation of several inhibitory metabolites. Nevertheless, manipulations which either modify or circumvent these products can be affected to stimulate residual oxidative phosphorylation. Studies in working swine hearts are planned to continue these investigations. Emphasis will be specifically directed at determining the effects of substrate enhancement, documenting the influence of agents designed to blunt the effects of fatty acid excess, and further detailing the impact of coronary washout. Alternate substrates which may have specific advantages in providing mitochondria with increased amount of acetyl-CoA and which will be evaluated in the coming grant year include: acetate, beta-hydroxybutyrate and pyruvate with dichloro acetate. Specific agents to be used in modifying fatty acid excess will be the various isomers (L, D and DL) of carnitine. Experiments will be formed to evaluate and determine the magnitude and distribution of the intracellular incorporation of carnitine, the effects of their isomeric stereospecificity, and their potential impact on modifying and hopefully improving energy production in ischemic tissue. Studies to evaluate the impact of coronary washout on preserving metabolic and mechanical functions are also planned. Studies will determine whether washout in ischemia alters vascular redistribution and oxygen content. It is hoped that a critical evaluation of cardiac metabolism and energy production with these several interventions will provide insights to possible future therapeutic options for protecting ischemic myocardium.

这些建议的目的是确定代谢的极限 缺血心肌的适应并评估设计的几种干预措施 改善能量产生和/或机械功能。 我们观察到 以前认为心肌缺血的损害不仅是由于心肌丢失 氧气输送过程中，还来自几种抑制物的积累 代谢物。 然而，修改或规避的操纵 这些产品可能会受到影响，刺激残留的氧化磷酸化。 计划对工作猪心脏进行研究以继续这些调查。 重点将专门针对确定底物的影响 增强，记录旨在减弱效果的药物的影响 脂肪酸过量，并进一步详细说明冠状动脉冲洗的影响。 替代基板在提供方面可能具有特定优势 乙酰辅酶 A 含量增加的线粒体，将在 即将到来的资助年包括：乙酸盐、β-羟基丁酸盐和丙酮酸盐 二氯乙酸酯。 用于调节脂肪酸过量的特定试剂 将是肉碱的各种异构体（L、D 和 DL）。 实验将是 旨在评估和确定影响的大小和分布 肉碱的细胞内掺入及其异构体的影响 立体特异性，以及它们对修饰和希望的潜在影响 改善缺血组织的能量产生。 评估影响的研究 冠状动脉冲洗对保持代谢和机械功能的影响也 计划。 研究将确定缺血的冲刷是否会改变血管 再分布和氧含量。 希望得到严格评价 通过这几种干预措施，心脏代谢和能量产生将 为未来可能的保护缺血的治疗选择提供见解 心肌。