Aging, Exercise and Endothelin-1 Vasoconstrictor Tone

描述(申请人提供)：血管血管运动功能受损在心血管疾病的发病机制和预后中起着至关重要的作用。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)，对血管张力的调节起着中心作用。有人认为，这些有利于收缩的血管活性物质的相反作用之间的平衡被破坏，导致与年龄相关的血管运动调节的下降。然而，到目前为止，绝大多数研究(在人类中)都集中在NO生物利用度的年龄相关性变化上，目前关于衰老对ET-1血管收缩活性的影响及其对血管运动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上的一个关键空白。此外，ET-1依赖的血管收缩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。本提案的具体目的将是确定：1)在健康成年人中，内源性ET-1血管收缩活性是否随年龄增加而增加，如果是，这种增加是否从青年开始就随年龄递增，并由两种ET-1受体亚型介导；2)对ET-1的血管收缩反应随年龄而改变；3)ET-1血管收缩活性增加导致在健康、久坐的成年人中观察到的内皮血管扩张功能的年龄相关损害；以及4)在先前久坐的中老年人中，定期有氧运动计划减少ET-1介导的血管收缩。为了达到这些目的，将在健康成人(20-79岁)中测定前臂血管对选择性和非选择性ET-1受体拮抗剂以及外源性ET-1的反应。此外，血管扩张剂对乙酰胆碱和硝普钠的反应将在没有和存在ET-1受体阻断的情况下进行测定。在为期12周的有氧运动训练计划之前和之后，还将评估ET-1血管收缩活性。这项拟议的研究将提供有关年龄对ET-1系统活性的影响及其对血管运动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益处的新的临床有用信息。

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.