EFFECTS OF HYPOXIA ON THE CORONARY MICROCIRCULATION

缺氧对冠状动脉微循环的影响

• 批准号: 6389256
• 负责人: BARBARA O MEYRICK
• 金额: $ 26.51万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389256
• 关键词: coronary artery; coronary vasodilator; eicosanoid metabolism; heart circulation; heart pharmacology; microcirculation; myocardial infarction; myocardial ischemia /hypoxia; nitric oxide; northern blottings; oscillatory blood flow; oxygen tension; perfusion; prostacyclins; swine; tissue /cell culture; vascular resistance; vasomotion; western blottings

DESCRIPTION (Verbatim from the application): Advances in the treatment of ischemic heart disease and myocardial infarction are critically dependent upon knowledge of pathological changes that occur in the coronary resistance circulation, the vascular bed that governs blood flow. This is a proposal for research into the mechanisms underlying changes that occur in the control of coronary blood flow during hypoxia and the role of oxygen in nitric oxide metabolism. The target of the research is the coronary resistance, or microvascular, circulation. The principal theme of the research is to a) define mechanisms of nitric oxide (NO) regulation of vascular tone in response to low partial pressures of oxygen using an in vivo model, b) to understand mechanisms of reciprocal regulation of NO and prostanoids which, in turn, impact upon regulation and preservation of coronary blood flow, and c) to elucidate the mechanisms whereby oxygen tension alters NO and prostanoid control of flow-mediated vasomotion. The first aim will establish physiological changes that occur during hypoxia in vivo and the role of nitric oxide in mediating those changes. The research will utilize an in vivo catheter-based porcine model that allows selective perfusion of coronary arteries with extracorporeally oxygenated blood equilibrated with selected partial pressures of oxygen and will allow research into the effect of hypoxia on coronary vascular resistance and flow velocity. The detailed research into mechanisms will build upon the physiological mediated changes in NO and prostacyclin production as well as the mechanisms of reciprocal regulation of NO and prostanoids by negative feedback inhibition will be done in a cultured cell model. Experiments are also designed to increase our understanding of a recently discovered NO positive feedback mechanism. Experiments determining the cellular response to hypoxia during flow will use a model allowing culture of endothelium under pulsatile flow conditions. Research into the molecular basis for adaptations to hypoxia will primarily employ Western and Northern blots. Pharmacologic antagonists of NO and prostanoid synthesis will be used to discover mechanisms controlling microvascular tone. With this approach, it is likely that the research will yield important new insights into the complex mechanisms responsible for the control of microvascular tone and coronary blood flow during hypoxia and periods of hypoperfusion, such as occurs during ischemia, reperfusion, and acute myocardial infarction.

描述（申请中的逐字记录）：治疗的进展 缺血性心脏病和心肌梗塞严重依赖于 了解冠状动脉阻力发生的病理变化 循环，控制血液流动的血管床。这是一项针对 研究控制发生变化的机制 缺氧时冠脉血流及氧对一氧化氮的作用 代谢。研究的目标是冠状动脉阻力，或 微血管，循环。研究的主题是 a) 定义 一氧化氮（NO）调节血管紧张度以响应低水平的机制 使用体内模型测量氧分压，b) 了解机制 NO 和前列腺素的相互调节，进而影响 冠状动脉血流的调节和保存，以及 c) 阐明 氧张力改变 NO 和前列腺素控制的机制 血流介导的血管舒缩。第一个目标是建立生理变化 体内缺氧时发生的变化以及一氧化氮的介导作用 那些变化。该研究将利用猪体内的导管 允许选择性灌注冠状动脉的模型 与选定的分压平衡的体外充氧血液 氧气，并将允许研究缺氧对冠状动脉的影响 血管阻力和流速。机制的详细研究 将建立在 NO 和前列环素的生理介导变化的基础上 NO 的产生以及相互调节的机制 通过负反馈抑制的前列腺素类药物将在培养细胞中完成 模型。实验还旨在加深我们对 最近发现没有正反馈机制。实验确定 流动过程中细胞对缺氧的反应将使用允许培养的模型 脉动流条件下的内皮细胞。分子基础研究 为了适应缺氧，将主要使用蛋白质印迹和北方印迹。 NO 和前列腺素合成的药理学拮抗剂将用于 发现控制微血管张力的机制。通过这种方法， 这项研究很可能会对复杂的问题产生重要的新见解 负责控制微血管张力和冠状动脉血液的机制 缺氧和低灌注期间的血流，例如发生在 缺血、再灌注和急性心肌梗死。