HYPOXIA, ISCHEMIA, AND CALCIUM IN CARDIAC HYPERTROPHY

对缺氧和缺血的实验研究表明， 细胞内钙(Ca~(2+))处理变化之间的相关性 和非肥厚心脏的心功能不全。这位将军 这项提议的目的是检验这样的假设： 钙离子和功能的异常将因发育而加剧 心肌肥厚的可能性。这将通过五个方面来实现 具体目标：1)我们将评估缺氧/复氧的影响 和低流量或全脑缺血/再灌流的钙离子，收缩和 舒张压、冠脉灌注压与心电图 控制着老鼠的心脏。这些实验将用一种新的 我们为研究定性和定量而开发的技术 缺血时钙离子浓度和功能的变化； 负载生物发光钙指示剂的冠脉灌流心脏 我们将描述细胞机制，这些机制负责 低氧/复氧过程中钙离子i的异常调节 从药理作用研究脑缺血/再灌注 对控制各个步骤采取已知行动的干预措施 肌膜、肌浆网和肌浆网的兴奋收缩偶联 肌丝部位。3)我们将检验这样一种假设 钙离子调节的异常和变化 低氧/复氧与低流量或全脑缺血/再灌注 显著肥厚的心脏比年龄匹配的心脏更严重 控制。五种不同的肥厚和/或衰竭的大鼠模型将 研究内容包括：a)心肌梗死代偿性肥厚； B)自发性高血压；c)压力超负荷的主动脉带 肥厚；d)主动脉瓣关闭不全伴容量超负荷性肥厚 E)甲亢。4)我们将确定肥厚程度是否 目前可以直接与对低氧的反应和 缺血或依赖于存在的心功能障碍和 临床心力衰竭。5)我们将检验这样的假设，即预防 钙离子反应异常，或肥厚程度逆转 这将正常化或防止 缺氧/复氧和缺血/再灌流。这些加在一起， 研究应该加强我们对细胞效应的理解 肥厚心肌的缺氧和缺血及其与动脉粥样硬化的关系 700万患有缺血性心脏病的美国人的大亚群 有共存的心肌肥厚。

Experimental studies of hypoxia and ischemia have demonstrated a positive correlation between alterations in intracellular calcium (Ca2+i) handling and ventricular dysfunction in non-hypertrophied hearts. The general purpose of this proposal is to test the hypothesis that these abnormalities in Ca2+ and function will be exacerbated by the development of myocardial hypertrophy. This will be accomplished by means of five specific aims: 1) We will evaluate the effects of hypoxia/reoxygenation and low-flow or total global ischemia/reperfusion on Ca2+i, systolic and diastolic pressure, coronary perfusion pressure and the electrocardiogram in control rat hearts. These experiments will be accomplished with a new technique we have developed for studying qualitative and quantitative changes in Ca2+i and function during ischemia; i.e., the isolated, coronary perfused heart loaded with the bioluminescent calcium indicator aequorin.2) We will delineate the cellular mechanisms responsible for the abnormal modulation of Ca2+i during hypoxia/reoxygenation and ischemia/reperfusion by studying the effects of pharmacologic interventions with known actions on the various steps controlling excitation-contraction coupling at sarcolemmal, sarcoplasmic reticular and myofilament sites .3) We will test the hypothesis that the functional abnormalities and changes in Ca2+ modulation that develop in response to hypoxia/reoxygenation and low-flow or total global ischemia/reperfusion are more severe in hearts with significant hypertrophy than in age-matched controls. Five different rat models of hypertrophy and/or failure will be studied including, a) myocardial infarction with compensatory hypertrophy; b) spontaneous hypertension; c) aortic banding with pressure-overload hypertrophy; d) aortic insufficiency with volume-overload hypertrophy and e) hyperthyroidism. 4) We will determine whether the degree of hypertrophy present can be directly correlated with the responses to hypoxia and ischemia or is dependent on the presence of ventricular dysfunction and clinical heart failure. 5) We will test the hypothesis that prevention of the abnormal Ca2+i responses, or reversal of the degree of hypertrophy that is present, will normalize or prevent the effects of hypoxia/reoxygenation and ischemia/reperfusion. Taken together, these studies should enhance our understanding of the cellular effects of hypoxia and ischemia on hypertrophied myocardium and be relevant to a large sub-group of the 7 million Americans with ischemic heart disease who have coexistent cardiac hypertrophy.