VASCULAR ENDOTHELIUM ABNORMALITIES IN HEART FAILURE

心力衰竭中的血管内皮异常

• 批准号: 2228185
• 负责人: STUART D KATZ
• 金额: $ 6.23万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2228185
• 关键词: blood flow measurement; congestive heart failure; exercise; human subject; metabolism; nitric oxide; pathology; peripheral blood vessel; rest; vascular endothelium; vasoactive agent; vasomotion

DESCRIPTION: The reduced vasodilatory response to exercise in the peripheral circulation appears to be an important determinant of exercise intolerance in patients with severe congestive heart failure. Increased peripheral vasomotor tone in patients with congestive heart failure at rest and during exercise may be related to abnormalities in vascular endothelium function. Endothelial cell dysfunction appears to be characterized by decreased agonist-induced, endothelium-dependent, nitric oxide-mediated vasodilation and possibly increased release of the endothelium-derived vasoconstricting substance, endothelin-1. Whether abnormalities of vascular endothelial cell dysfunction directly contribute to the abnormal vascular response to exercise in patients with congestive heart failure has not been previously determined. Accordingly, the specific aims of this research proposal are (1) to investigate the role of endothelium-derived vasoactive substances in the pathophysiology of increased peripheral vasomotor tone at rest and during exercise in patients with congestive heart failure; (2) to determine whether abnormalities of nitric oxide metabolism contribute to the pathophysiology of abnormal endothelial regulation of peripheral vasomotor tone at rest and during exercise in patients with heart failure; and (3) to investigate the pathogenesis of vascular endothelial cell dysfunction by assessing changes in endothelial cell regulation of peripheral vasomotor tone and nitric oxide metabolism in response to therapy for heart failure. In a series of interrelated studies, endothelial cell regulation of peripheral vasomotor tone and nitric oxide metabolism will be assessed in patients with congestive heart failure and normal subjects with 3 methods: 1) measuring forearm blood flows (with venous occlusion plethysmography) at rest and in response to rhythmic handgrip exercise before and after administration of graded doses of L-NG- mono-methylarginine (L-NMMA, an inhibitor of nitric oxide synthesis) and bosentan (an endothelin receptor antagonist); 2) determining total body nitric oxide synthesis by measuring 15N-labeled metabolites of nitric oxide after an infusion of 15N-L-arginine (the amino acid metabolic precursor of nitric oxide) at rest and during exercise; and 3) measuring expression and activity of the inducible form of nitric oxide synthase in peripheral mononuclear phagocytes (macrophages) with molecular biology techniques. These three techniques will be applied to investigate endothelial regulation of peripheral vasomotor tone and nitric oxide metabolism before and after chronically increasing peripheral blood flow with a left ventricular assist device, before and after chronic angiotensin converting- enzyme inhibition, and before and after physical training. Increased understanding of the pathophysiologic changes in vascular endothelial cell function in patients with congestive heart failure, will enable more effective use of currently available drug treatments and facilitate the development of new therapeutic strategies. Correction of specific abnormalities in vascular endothelial cell function may serve as a target for future pharmacologic therapy development.

描述：减少了对运动的血管舒张反应 外围循环似乎是重要的决定因素 严重充血性心力衰竭的患者运动不耐受。 充血性心脏患者的外周血管舒张张张力增加 休息和运动过程中的失败可能与异常有关 在血管内皮功能中。 内皮细胞功能障碍 似乎以减少激动剂诱导的特征 内皮依赖性，一氧化氮介导的血管舒张和 可能会增加内皮衍生的释放 血管收缩物质，内皮素-1。是否异常 血管内皮细胞功能障碍直接有助于 充血患者的血管反应异常 心力衰竭尚未确定。因此， 该研究建议的具体目的是（1） 研究内皮衍生的血管活性物质的作用 在增加外周血管肌张力张力的病理生理学中 在充血性心力衰竭的患者中休息和运动期间； （2）确定一氧化氮代谢的异常 有助于异常内皮调节的病理生理学 休息时和运动过程中的外围血管舒适音调 心力衰竭的患者； （3）研究发病机理 血管内皮细胞功能障碍通过评估 外周血管张力和硝酸的内皮细胞调节 氧化代谢响应心力衰竭的治疗。 在一系列相互关联的研究中，内皮细胞调节 将评估外周血管舒缩张力和一氧化氮代谢 充血性心力衰竭和正常受试者的患者 3种方法：1）测量前臂血流（带静脉阻塞 静止图），以响应有节奏的手柄 施用分级剂量的L-NG-的锻炼 单甲基精氨酸（L-NMMA，一氧化氮合成的抑制剂）和 波森坦（内皮素受体拮抗剂）； 2）确定总 人体一氧化氮合成，通过测量15N标记的代谢产物 注入15N-L-精氨酸（氨基酸）后一氧化氮 一氧化氮的代谢前体）在休息和运动过程中； 3）测量可诱导形式的表达和活性 外周单核吞噬细胞中的一氧化氮合酶 （巨噬细胞）用分子生物学技术。这三个 技术将应用于研究的内皮调节 外周血管张力和一氧化氮代谢前后 长左心室长期增加外周血流动 慢性血管紧张素转化之前和之后的辅助装置 - 酶抑制，体育训练之前和之后。 对病理生理变化的了解增加 充血性心脏的血管内皮细胞功能 失败，可以更有效地使用当前可用的 药物治疗并促进新治疗的发展 策略。 纠正血管中特定异常 内皮细胞功能可能是未来的目标 药理疗法开发。