STUNNED HEART AND CARDIAC SURGERY--CA++ AND ENERGETICS

电击心脏和心脏手术--CA 和 Energetics

• 批准号: 2222729
• 负责人: Pedro J. del Nido
• 金额: $ 8.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-24 至 1994-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2222729
• 关键词: adenylate kinase; age difference; bioenergetics; calcium metabolism; chelating agents; fluorescent dye /probe; heart contraction; heart pharmacology; high energy compound; laboratory rabbit; mature animal; myocardial ischemia /hypoxia; newborn animals; nuclear magnetic resonance spectroscopy; ouabain; oxygen consumption; phosphates; reperfusion; sarcoplasmic reticulum

Post-ischemic myocardium exhibits a physiologic abnormality which is manifested by delayed recovery of ATP content and contractile function, and increased oxygen consumption per unit work. The mechanism responsible for the contractile dysfunction and for the higher oxygen consumption when stimulated to perform work is not understood. In order to test the hypothesis that post-ischemic cardiac dysfunction in the adult heart is due to impaired cytosolic calcium regulation associated with altered high energy phosphate energetics, we plan to measure free cytosolic calcium in the reperfused beating heart using calcium sensitive fluorescent dyes. 31P NMR spectroscopy will be used to measure high energy phosphate content and allow calculation of the free energy released from ATP hydrolysis. We plan to utilize the differences between newborn and adult hearts with respect to calcium regulation for excitation-contraction coupling in order to determine the cause and precise location of the regulatory defect in the adult. The role of the sarcoplasmic reticulum in post-ischemic contractile dysfunction will e determined by utilizing measurements of the phasic changes in cytosolic calcium concentration during the cardiac cycle. Because of the increased demand for oxygen per unit work in the post- ischemic adult heart, we plan to test the hypothesis that the energetic inefficiency in the "stunned" heart is at least in part due to altered substrate utilization by the myocytes. We plan to analyze the effects of providing substrates that yield a higher ATP production per mole of oxygen consumed (P:O ratio) on post-ischemic energetic efficiency. We expect that by combining substrates that have high P:O ratios with metabolic inhibitors of other substrates, we will be able to correct the abnormality in the oxygen consumption to work relationship. Post-operative myocardial dysfunction leading to significant mortality and morbidity after cardiac surgery or transplantation remains an important clinical problem. Considerable information regarding the mechanisms for the energetic inefficiency and delayed metabolic and functional recovery of the post-ischemic heart should result from this project.

缺血后心肌表现出生理异常 由ATP内容和收缩功能的延迟恢复表现出来， 并增加每单位工作的氧气消耗。 机制 负责收缩功能障碍和较高的氧气 刺激进行工作时的消费尚不清楚。 为了 测试以下假设 成人心脏是由于胞质钙调节受损而引起的 随着高能磷酸能量的改变，我们计划测量自由 使用钙敏感 荧光染料。 31p NMR光谱将用于测量高 能量磷酸盐含量并允许自由能计算 从ATP水解释放。 我们计划利用 关于钙调节的新生儿和成人心 激发接触耦合以确定原因和 成人监管缺陷的精确位置。 角色 缺血后收缩功能障碍中的肌质网将E 通过利用胞质变化的测量来确定 心脏周期期间的钙浓度。 由于对后的每单位氧气需求增加 缺血性成人心脏，我们计划检验以下假设： “震惊”心脏的效率低下至少部分是由于改变 肌细胞利用底物。 我们计划分析效果 提供每摩尔产生更高ATP的底物 氧气消耗（P：O比）在缺血后的能量效率上。 我们 通过将具有较高P：O比的基材与 其他底物的代谢抑制剂，我们将能够纠正 氧气消耗与工作关系的异常。 术后心肌功能障碍导致重大死亡 心脏手术或移植后的发病率仍然 重要的临床问题。 有关 能量无效和代谢延迟的机制 缺血后心脏的功能恢复应从中导致 项目。