Aging, Exercise and Endothelin-1 Vasoconstrictor Tone

描述（由申请人提供）：血管功能受损在心血管疾病的发病机制和预后中起重要作用。 内皮是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）来调节血管张力的中心。 已经表明，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，有助于血管调节的年龄相关性下降。 然而，到目前为止，绝大多数研究（在人类中）都集中在与年龄相关的NO生物利用度的变化，目前很少有关于衰老对ET-1血管收缩活性的影响及其对血管功能的潜在影响的信息。 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，增加的ET-1依赖性血管收缩与许多年龄相关的病理学的病因学有关，包括高血压、血管痉挛、心力衰竭和冠状动脉疾病。 本发明的具体目的是确定：1）内源性ET-1血管收缩活性在健康成年人中是否随年龄增加，如果是，则该增加是否从青年期开始随年龄进行，并由两种ET-1受体亚型介导; 2）血管对ET-1的血管收缩反应随年龄改变; 3）增加的ET-1血管收缩活性有助于在健康的、久坐的成年人中观察到的内皮血管舒张功能的年龄相关性损伤;和4）规律的有氧运动计划减少先前久坐的中年和老年人中的ET-1介导的血管收缩。 为了解决这些问题，前臂血管反应选择性和非选择性ET-1受体拮抗剂以及外源性ET-1将在健康成人（20-79岁）。 此外，将在不存在和存在ET-1受体阻断剂的情况下测定对乙酰胆碱和硝普钠的血管舒张反应。 ET-1血管收缩活性也将在12周有氧运动训练计划前后进行评估。 拟议的研究应提供新的和临床上有用的信息，年龄对ET-1系统的活性和其对血管调节的影响，以及运动在降低ET-1血管收缩张力的潜在有益影响。

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.