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(逐字摘自申请书)：该病的治疗进展 缺血性心脏病和心肌梗死严重依赖于 冠状动脉阻力中发生的病理变化的知识 循环，控制血液流动的血管床。这是一份关于 对控制中发生变化的潜在机制的研究 低氧时冠脉血流量及氧在一氧化氮中的作用 新陈代谢。研究的对象是冠脉阻力，或 微血管，循环。研究的主要主题是：a)确定 一氧化氮(NO)调节血管张力的机制 使用活体模型的氧分压，b)了解机理 对NO和前列腺素的相互调节，进而影响 冠脉血流的调节和保存，以及c)阐明 氧分压改变NO和前列腺素控制的机制 血流介导的血管运动。第一个目标是建立生理变化 体内缺氧过程中的变化及一氧化氮在其中的作用 那些变化。这项研究将利用体内导管为基础的猪 允许冠状动脉选择性灌流的模型 体外氧合血液与选定的分压保持平衡 并将允许研究低氧对冠状动脉的影响 血管阻力和血流速度。对机理的详细研究 将建立在生理调节的NO和前列环素变化的基础上 以及NO和NO的相互调节机制 前列腺素通过负反馈抑制将在培养的细胞中进行 模特。实验的目的也是为了增加我们对 最近发现没有正反馈机制。实验确定了 细胞在流动过程中对缺氧的反应将使用一种允许培养 脉动血流条件下的内皮细胞。关于分子基础的研究 对于低氧的适应，将主要使用Western和Northern杂交。 NO和前列腺素合成的药理拮抗剂将用于 发现控制微血管张力的机制。使用这种方法，它是 很可能，这项研究将对该建筑群产生重要的新见解 微血管张力和冠脉血流控制机制的研究进展 低氧和低灌注期的血流，如在 缺血、再灌注和急性心肌梗死。