OXYGEN TENSION AND ENDOTHELIUM-DEPENDENT VASODILATION

氧张力和内皮依赖性血管舒张

• 批准号: 3471725
• 负责人: Roger A Johns
• 金额: $ 9.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3471725
• 关键词: adult respiratory distress syndrome; cell bank /registry; cyclic GMP; laboratory rabbit; muscle relaxing factor; oxygen tension; pulmonary circulation; pulmonary hypertension; vascular endothelium; vascular smooth muscle; vasodilation

The role of the endothelium has taken on increasing significance in vascular pharmacology and physiology in the past several years with the discovery that numerous endogenous and exogenous vasodilators exert their action on vascular smooth muscle by releasing from the endothelium a substance termed endothelium- dependent relaxing factor (EDRF). The production of EDRF is calcium dependent; it has a short biologic half-life; and its relaxing action on vascular smooth muscle correlates with an increase in muscle cyclic GMP concentration. Several studies have implicated the importance of oxygen tension in the stability of the relaxation responses induced by EDRF. The proposed research plan will investigate the inhibition of endothelium dependent relaxation by hypoxia. The oxygen sensitivity of these responses could be due to an effect on factor production, to the stability of EDRF once produced, to the reactivity of the vascular smooth muscle where it acts, or to some combination of these events. An experimental system will be used which allows transfer of EDRF from cultured pulmonary artery endothelial cells to one of three bioassays: relaxation of a de-endothelialized vascular ring, increase in cyclic GMP levels in cultured-vascular smooth muscle, or activation of guanylate cyclase. Separate manipulation of the oxygen tensions of the endothelial cells, of EDRF in solution, and of the bioassay preparations will allow us to investigate the sites and mechanisms of oxygen interactions with EDRF. The effects of varying oxygen tensions on the increase in endothelial cell cytoplasmic calcium concentration which normally accompanies EDRF release also will be determined. In addition to providing further insight into the nature of EDRF, these studies will increase our understanding of the potential role of EDRF in the normal and diseased pulmonary circulation including regulation of basal tone, hypoxic pulmonary vasoconstriction, pulmonary hypertension, and adult respiratory distress syndrome.

血管内皮细胞的作用越来越重要。 近年来在血管药理学和生理学方面的研究 随着众多内源性和外源性的发现 血管扩张剂通过以下途径对血管平滑肌起作用 从内皮细胞释放一种叫做内皮的物质- 依赖松弛因子(EDRF)。EDRF的生产是 钙依赖；它的生物半衰期短；它的 血管平滑肌的松弛作用与 增加肌肉中环状GMP浓度。几项研究 已经暗示了氧气张力在稳定性中的重要性 EDRF诱导的松弛反应。 拟议的研究计划将调查对 缺氧引起的内皮依赖性松弛。氧气 这些反应的敏感性可能是由于对因素的影响 生产，到EDRF的稳定性，一旦生产，到 它作用的血管平滑肌的反应性，或 这些事件的某种组合。一个实验性的系统将会 允许从培养的肺组织中转移EDRF 动脉内皮细胞对三种生物测定之一：松弛 去内皮化血管环，环型GMP水平增加 培养的血管平滑肌，或鸟苷的激活 循环酶。不同的氧张力操控 内皮细胞，EDRF的溶液，和生物测定 准备工作将使我们能够调查地点和机制 氧与EDRF的相互作用。不同氧气对人体的影响 血管内皮细胞胞浆钙升高的紧张性 通常伴随EDRF释放的浓度也将 要下定决心。 除了提供对EDRF性质的进一步洞察之外， 这些研究将增加我们对潜在作用的理解 EDRF在正常和病变肺循环中的表达 包括调节基础音、缺氧性肺 血管收缩、肺动脉高压和成人呼吸 窘迫综合症。