ACE Inhibition and Physical Performance in Aged Rats

描述（由申请人提供）： 我们建议使用啮齿动物模型的年龄相关的身体下降进行临床前测试的两个有前途的药理干预措施，有可能阻止脆弱相关的身体下降，血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARE），并研究病理生理变化假设在脆弱中发挥重要作用。当前PA（老年虚弱：病理生理学和干预：PAS-03-122）建议对有前景的干预措施进行临床前试验，这些干预措施有可能预防虚弱相关的身体衰退，如ACEi。本申请中提出的初步研究表明，在老年大鼠中使用ACEi可减弱与年龄相关的体能下降，并与全身脂肪量减少有关。鉴于越来越多的证据将脂肪量和脂肪分布的差异与肌肉功能和身体衰退联系起来，这在虚弱的背景下非常有趣。然而，目前尚不清楚ACEi如何导致性能下降，或者ACEi的作用是否由血管紧张素受体或其他机制介导。使用ARB（仅通过拮抗AT 1受体阻断ANGII的作用）或ACEi对高血压患者进行的长期临床试验表明，两种治疗方法均可降低与II型糖尿病相关的脂肪和肌肉代谢异常的发生风险。对于每种干预措施如何影响这些变化，仍有一些争论。任何一种途径的改变都有深远的代谢后果，最明显的是在高血压、肥胖和胰岛素抵抗的情况下。1）确定依那普利和氯沙坦相对于盐水对照治疗对雄性Brown Norway x F344大鼠的部分寿命中的身体表现的影响; 2）确定年龄的时间进程-相关变化以及依那普利与氯沙坦治疗对全身胰岛素敏感性和葡萄糖耐量以及脂肪组织变化的影响和骨骼肌生理学; 3）将这些发现与身体机能下降联系起来。这些数据将为描述长期ACEi和ARB治疗在逆转这些变化中的作用奠定基础，并为计划人体随机临床试验提供初步数据，以预防与年龄相关的身体功能下降。

DESCRIPTION (provided by applicant): We propose to use a rodent model of age-related physical decline to conduct pre-clinical testing of two promising pharmacologic interventions with the potential to forestall frailty-associated physical decline, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARE) and to study pathophysiologic changes postulated to play important roles in frailty. The current PA (FRAILTY IN OLD AGE: PATHOPHYSIOLOGY AND INTERVENTIONS:PAS-03-122) recommends the preclinical testing of promising interventions with the potential to forestall frailty-associated physical decline such as ACEi. Preliminary studies presented in this application suggest that ACEi use in aged rats attenuates age-related declines in physical performance and is associated with a reduction in total body fat mass. This is of great interest in the context of frailty given the growing body of evidence linking differences in fat mass and fat distribution to muscle function and physical decline. However, it is unclear how ACEi may contribute to declining performance or whether the effects seen with ACEi are mediated by the angiotensin receptor or other mechanisms. Long-term clinical trials in hypertensive persons using either ARBs, which only block the action of ANGII by antagonizing the AT1 receptor, or ACEi have shown that both treatments reduce the risk for the development of metabolic abnormalities in fat and muscle associated with type II diabetes. There is still some debate as to how each intervention affects these changes. Alterations in either pathway have profound metabolic consequences, most notably in conditions of hypertension, obesity and insulin resistance. One primary and two secondary aims will be addressed in this application: 1) Determine the effect of Enalapril and Losartan vs. saline control treatment on physical performance across a portion of the lifespan of male Brown Norway x F344 rats; 2) Determine the time course of age-related changes and the effect of Enalapril vs. Losartan treatment on whole body insulin sensitivity and glucose tolerance and changes in adipose tissue and skeletal muscle physiology; 3) relate these findings to declining physical performance. These data will lay the groundwork for characterizing the role of long-term ACEi and ARB treatment in reversing these changes, as well as provide preliminary data for planning randomized clinical trials in humans for the prevention of the age related decline in physical function.