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（逐字化申请中）：治疗的进展 缺血性心脏病和心肌梗死至关重要 了解冠状动脉抗性中发生的病理变化 循环，控制血流的血管床。这是一个建议 研究在控制中发生的机制 缺氧期间冠状动脉流动和氧气在一氧化氮中的作用 代谢。研究的目标是冠状动脉抵抗力，或 微血管，循环。该研究的主要主题是a）定义 一氧化氮的机制（NO）调节血管张力的调节，以响应低 使用体内模型的氧气压力，b）了解机制 对NO和前列腺素的相互调节，反过来影响 调节和保存冠状动脉流动，c）阐明 氧气张力会改变NO的机制和前列腺素的控制 流动介导的血管症。第一个目标将建立生理变化 在体内缺氧期间发生的情况以及一氧化氮在介导的作用 这些变化。该研究将利用基于体内导管的猪 允许选择性灌注冠状动脉的模型 与选定的部分压力平衡的体外充氧血液 氧气，将允许研究缺氧对冠状动脉的影响 血管抗性和流速。机制的详细研究 将基于NO和Prostacyclin的生理介导的变化 生产以及NO和NO和 前反馈抑制前列腺素将在培养的细胞中进行 模型。实验还旨在提高我们对 最近没有发现积极的反馈机制。确定的实验 流动过程中对缺氧的细胞反应将使用允许培养的模型 脉冲流条件下的内皮。分子基础的研究 为了适应缺氧，将主要采用西部和北印迹。 NO和前列腺素合成的药理学拮抗剂将用于 发现控制微血管音调的机制。有了这种方法，它是 研究可能会产生重要的新见解 负责控制微血管张力和冠状动脉血液的机制 缺氧期间的流量和灌注不足的周期，例如在 缺血，再灌注和急性心肌梗塞。