HYPOXIA, ISCHEMIA, AND CALCIUM IN CARDIAC HYPERTROPHY

心脏肥大中的缺氧、缺血和钙

• 批准号: 2227978
• 负责人: JAMES P MORGAN
• 金额: $ 22.97万
• 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/2227978
• 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证实了其积极作用