Aging, Exercise and Endothelin-1 Vasoconstrictor Tone

衰老、运动和 Endothelin-1 血管收缩剂

• 批准号: 6912714
• 负责人: CHRISTOPHER A DESOUZA
• 金额: $ 34.98万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912714
• 关键词: acetylcholine; aerobic exercise; aging; clinical research; endothelin; human middle age (35-64); human old age (65+); human subject; nitroferricyanide; vascular endothelium; vasoconstriction; vasodilation; young adult human (21-34)

DESCRIPTION (provided by applicant): Impaired vascular vasomotor function plays an essential role in the pathogenesis and prognosis of cardiovascular disease. The endothelium is central to the regulation of vascular tone through the synthesis and release of opposing vasoactive substances, particularly nitric oxide (NO) and endothelin-1 (ET-1). It has been suggested that a disruption in the balance between the opposing effects of these vasoactive substances, favoring constriction, contributes to the age-related decline in vasomotor regulation. To date, however, the vast majority of studies (in humans) have focused on age-associated changes in NO bioavailability, there is currently very little information regarding the effects of aging on ET-1 vasoconstrictor activity and its potential impact on vasomotor function. This represents a critical void in our understanding of the regulation of vascular tone with human aging. Moreover, increased ET-1-dependent vasoconstriction has been linked to the etiology of a number of age-related pathologies including hypertension, vasospasm, heart failure and coronary artery disease. The specific aims of the present proposal will be to determine if : 1) endogenous ET-1 vasoconstrictor activity increases with age in healthy adult humans and, if so, whether the increase is progressive with age from young adulthood and are mediated by both ET-1 receptor subtypes; 2) the vascular vasoconstrictor response to ET-1 is altered with age; 3) increased ET-1 vasoconstrictor activity contributes to the age-related impairment in endothelial vasodilator function observed in healthy, sedentary adult humans; and 4) a program of regular aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary middle-aged and older adults. To address these aims, forearm vascular responses to selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1 will be determined in healthy adult humans (20-79 yr). In addition, the vasodilator response to acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. ET-1 vasoconstrictor activity will also be assessed before and after a 12-week aerobic exercise training program. The proposed study should provide new and clinically useful information regarding the influence of age on the activity of the ET-1 system and its impact on vasomotor regulation as well as the potential benefical effects of exercise in reducing ET-1 vasoconstrictor tone.

描述（由申请人提供）：血管舒缩功能受损在心血管疾病的发病机制和预后中起着重要作用。 内皮细胞通过合成和释放相反的血管活性物质，特别是一氧化氮 (NO) 和内皮素-1 (ET-1) 来调节血管张力。 有人认为，这些血管活性物质的相反作用之间的平衡被破坏，有利于收缩，导致与年龄相关的血管舒缩调节能力下降。 然而，迄今为止，绝大多数研究（在人类中）都集中在与年龄相关的一氧化氮生物利用度的变化上，目前关于衰老对 ET-1 血管收缩活性的影响及其对血管舒缩功能的潜在影响的信息很少。 这代表了我们对血管张力随人类衰老的调节的理解中的一个关键空白。 此外，ET-1依赖性血管收缩的增加与许多与年龄相关的疾病的病因有关，包括高血压、血管痉挛、心力衰竭和冠状动脉疾病。 本提案的具体目标是确定：1​​）内源性 ET-1 血管收缩活性是否随着健康成年人年龄的增长而增加，如果是这样，这种增加是否从青年期起就随着年龄的增长而逐渐增加，并且是由 ET-1 介导的1种受体亚型； 2)血管对ET-1的收缩反应随着年龄的增长而改变； 3) ET-1 血管收缩活性增加导致健康、久坐的成年人中观察到的与年龄相关的内皮血管舒张功能损伤； 4) 定期有氧运动计划可以减少以前久坐的中老年人中 ET-1 介导的血管收缩。 为了实现这些目标，将确定健康成年人（20-79 岁）的前臂血管对选择性和非选择性 ET-1 受体拮抗剂以及外源 ET-1 的反应。 此外，将在存在或不存在 ET-1 受体阻断的情况下测定血管舒张剂对乙酰胆碱和硝普钠的反应。 还将在 12 周有氧运动训练计划之前和之后评估 ET-1 血管收缩活性。 拟议的研究应提供有关年龄对 ET-1 系统活性的影响及其对血管舒缩调节的影响以及运动在降低 ET-1 血管收缩张力方面的潜在有益作用的新的临床有用信息。