LEFT HEART FUNCTION AND INTRACELLULAR CALCIUM AND SODIUM

左心功能与细胞内钙和钠

• 批准号: 2228892
• 负责人: DANIEL BURKHOFF
• 金额: $ 5.48万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2228892
• 关键词: biomechanics; blood volume; calcium channel; calcium indicator; disease /disorder model; dogs; heart contraction; heart function; intracardiac pressure; intracardiac volume; isolation perfusion; laboratory rat; myocardium disorder; nuclear magnetic resonance spectroscopy; oxygen consumption; ryanodine; sodium channel

Knowledge of the fundamental laws which govern the dynamics of ventricular contraction is of primary importance for advancing understanding of heart function in health and disease. Ventricular pump function is now commonly characterized in terms of various indices derived from analysis of pressure-volume loops measured under different loading conditions such as the end-systolic pressure-volume relationship or preload recruitable stroke work. Such approaches are, in the end, unrelated to basic principles of muscle mechanics. On the other hand, it is unknown whether many of the fundamental concepts of cardiac muscle contraction derived from observations made in isolated superfused muscle preparations pertain to the more physiologic conditions of intact muscles in the wall of the ventricle. Thus, there are a number of major conceptual and experimental gaps between how we think about muscle mechanics and how we think about ventricular mechanics. It is the long term objective of this research project to bridge many of these gaps by testing whether certain fundamental observations made in muscle pertain to the intact heart and testing the feasibility of a new theory of ventricular dynamics that is based upon those observations and a biochemical scheme relating calcium transients to ventricular performance over a broad range of loading condiitons and inotropic states. Studies will be performed in isolated cross perfused canine hearts in which aequorin has been macroinjected into epicardial cells. This combination of techniques will be used to study the load dependence of the calcium transient over a broad range of loading conditions as well as to test whether the load dependence of the ventricular pressure waveform can be accounted for the calcium transient and the new theory mentioned above. The validity of several of the assumptions of the theory will be tested in Langendorf rat hearts exposed to ryanodine which will permit study of the calcium and load dependence of tetanic ventricular pressure generation. One group of studies will test a new hypothesis relating to the impact of ventricular stretch on intracellular sodium and its possible links to load dependent changes in intracellular calcium. Finally, studies will be performed in cardiomyopathic hearts in which the damage to the heart is ischemic in nature, a model believed to be relevant to several forms of human heart disease. When interpreted within the framework of the new theories it is hypothesized that the results will provide new insights into mechanisms of contractile dysfunction in this form of cardiomyopathy.

了解控制心室动态的基本定律 收缩对于促进对心脏的理解至关重要 健康和疾病的功能。 现在通常是心室泵功能 以分析得出的各种指数来表征 在不同的加载条件下测量的压力卷环，例如 终端2骨压力 - 体积关系或预紧的可募集的中风 工作。 最终，这种方法与 肌肉力学。 另一方面，未知是否有许多 心肌收缩的基本概念 用孤立的超级肌肉制剂进行的观察与 心室壁中完整肌肉完整的生理条件。 因此，之间存在许多主要的概念和实验差距 我们如何看待肌肉力学以及我们如何看待心室 力学。 这是该研究项目的长期目标 通过测试某些基本 在肌肉中进行的观察与完整的心脏有关并测试 基于心室动力学的新理论的可行性 这些观察结果和生化方案，将钙瞬变与 在广泛的装载管道上的心室性能和 肌力状态。 研究将在孤立的交叉灌注中进行 犬心在其中大量注射到心外膜中 细胞。 这种技术组合将用于研究负载 钙瞬态在广泛的负载范围内的依赖性 条件以及测试是否依赖负载 心室压力波形可以考虑到钙瞬态 以及上面提到的新理论。 几个的有效性 该理论的假设将在langendorf大鼠心脏中进行测试 ryanodine将允许研究钙和负载依赖性 四室心压产生。 一组研究将测试 与心室伸展的影响有关的新假设 细胞内钠及其与负载相关变化的可能联系 细胞内钙。 最后，将在 心肌病的心脏对心脏的损害是缺血性的 大自然，一种被认为与几种形式的人心相关的模型 疾病。 在新理论的框架内解释时 假设结果将为机制提供新的见解 这种形式的心肌病形式的收缩功能障碍。