Exercise, muscle nutritive blood flow and eNOS in aging

描述（由申请人提供）：心血管疾病是美国的主要死亡原因，60岁以后心血管疾病的发病率迅速增加。心血管疾病的一个主要危险因素是高血压，在老年人中也会增加患病率。一氧化氮（NO）诱导的血管舒张随着年龄的增长而减少，导致血压升高和肢体血流量减少，特别是鉴于老年个体中肌肉交感神经张力增加。NO的产生受损也与外周血管疾病、胰岛素抵抗和2型糖尿病有关。然而，有一些证据表明，运动训练改善了NO诱导的肢体血流反应在休息。运动对一氧化氮生成的关键酶内皮型一氧化氮合酶（eNOS）含量的影响在人体肌肉中还没有研究。我们假设，有eNOS表达减少和增加肌肉交感神经张力在老年人，导致减少一氧化氮依赖性骨骼肌营养血流量和肌肉代谢的改变，此外，这些年龄相关的NO介导的变化可以抵消，或逆转，耐力运动训练。我们将调查24名（20-30岁）久坐不动的人（男性和女性），以及24名久坐不动的老年人（60-70岁）（男性和女性）在久坐不动的状态下，以及经过一天和七天的耐力运动训练。其中10名久坐不动的老年人也将在额外的7周耐力训练后进行研究。将进行肌肉活检以测量eNOS含量，并在静息条件下使用微透析监测营养性骨骼肌血流。这些研究将确定耐力运动是否改善了静息时骨骼肌中一氧化氮依赖性营养血流量，并将确定这种改善是否与骨骼肌活检样本中eNOS的增加相关。还将研究肌肉交感神经张力、内皮素和前列环素对NO依赖性血管舒张的介导作用。这些研究的长期目标是：1）确定老年男性和女性中一氧化氮依赖性血管舒张功能降低的机制，2）找到逆转老年男性和女性血管舒张功能下降的实用方法，从而降低该人群中心血管相关疾病的发病率。

DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of death in the United States, with the incidence of cardiovascular disease increasing rapidly after 60 years of age. A primary risk factor for cardiovascular disease is hypertension, which also increases in prevalence in older individuals. Nitric oxide (NO) induced vasodilatation is reduced with age, resulting in increased blood pressure and reduced limb blood flow, particularly in light of the increased muscle sympathetic tone in older individuals. Impaired production of NO is also associated with peripheral vascular disease, insulin resistance, and Type 2 diabetes. However, there is some evidence that exercise training improves NO induced limb blood flow response at rest. The effect of exercise on the content of endothelial nitric oxide synthase (eNOS), the key enzyme in NO production, has not been investigated in muscle in vivo in humans. We hypothesize that there are reductions in eNOS expression and increases in muscle sympathetic tone in older individuals, resulting in reduced nitric oxide dependent skeletal muscle nutritive blood flow and alterations in muscle metabolism; furthermore, these age-associated NO-mediated changes can be counteracted, or reversed, by endurance exercise training. We will investigate 24 (20-30 yr) sedentary individuals (men and women), as well as 24 sedentary older (60-70 yr) individuals (men and women) in the sedentary state, as well as after one day and seven days of endurance exercise training. Ten of these sedentary older individuals will also be studied after an additional seven weeks of endurance training. A muscle biopsy will be taken to measure eNOS content, and nutritive skeletal muscle blood flow will be monitored using microdialysis under resting conditions. These investigations will determine if endurance exercise improves nitric oxide dependent nutritive blood flow in skeletal muscle at rest, and will determine if this improvement is associated with increases in eNOS in skeletal muscle biopsy samples. The mediation of NO-dependent vasodilation by muscle sympathetic tone, endothelin, and prostacyclin will also be investigated. The long-term objectives of these investigations are: 1) to identify mechanisms responsible for a reduced nitric oxide-dependent vasodilatation in older men and women and 2) to find practical means of reversing vasodilator decrements in older men and women, thereby reducing the incidence of cardiovascular-related diseases in this population.