HYPOXIA, ISCHEMIA, AND CALCIUM IN CARDIAC HYPERTROPHY

心脏肥大中的缺氧、缺血和钙

• 批准号: 2227979
• 负责人: JAMES P MORGAN
• 金额: $ 22.96万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2227979
• 关键词: calcium channel; calcium indicator; cellular pathology; heart circulation; heart contraction; heart failure; heart pharmacology; hypertension; isolation perfusion; laboratory rat; myocardial infarction; myocardial ischemia /hypoxia; reperfusion; sarcolemma; sarcoplasmic reticulum; ventricular hypertrophy

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.

缺氧和缺血的实验研究表明， 细胞内钙（Ca 2 +i）处理变化之间的相关性 和非肥大心脏的心室功能障碍。总 这一建议的目的是测试假设，这些 Ca 2+和功能的异常将因发展而加剧 心肌肥大的症状这将通过五种方式来实现。 具体目的：1）评价缺氧/复氧对大鼠心肌细胞的影响 和低流量或全脑缺血/再灌注对Ca 2 +i，收缩压和 舒张压、冠脉灌注压和心电图 在对照组大鼠心脏中。这些实验将用一种新的 我们已经开发了一些技术来研究定性和定量的 缺血期间Ca 2 +i和功能的变化;即，孤立的， 负载生物发光钙指示剂的冠状动脉灌注心脏 2）我们将描述负责Aequorin的细胞机制。 缺氧/复氧过程中Ca 2 +i的异常调节， 缺血/再灌注的药理学研究的影响 在控制的各个步骤上具有已知动作的干预 兴奋-收缩偶联在肌膜，肌浆网和 肌丝位点。3）我们将测试功能性 钙调节的异常和变化， 缺氧/复氧和低流量或全脑缺血/再灌注 与年龄匹配的心脏相比， 对照将建立五种不同的肥大和/或衰竭大鼠模型。 研究包括：a）心肌梗死伴代偿性肥大; B）自发性高血压; c）主动脉缩窄伴压力超负荷 肥大; d）主动脉瓣关闭不全伴容量超负荷肥大， e）甲状腺功能亢进症。4)我们将确定肥大的程度 存在可以与对缺氧的反应直接相关， 缺血或依赖于心室功能障碍的存在， 临床心力衰竭5)我们将检验这一假设， 异常的Ca 2 +i反应，或逆转肥大的程度 目前，将正常化或防止的影响， 缺氧/复氧和缺血/再灌注。综上所述各项 这些研究应该增强我们对细胞效应的理解， 缺氧缺血对肥厚心肌影响及其与心肌缺血的关系 700万患有缺血性心脏病的美国人中的一个大的亚组， 同时存在心脏肥大。