ACE Inhibition and Physical Performance in Aged Rats

描述(由申请人提供)： 我们建议使用与年龄相关的体力衰退的啮齿动物模型进行临床前测试，对两种有可能预防虚弱相关的体力衰退的药物干预进行临床前测试，这两种药物是血管紧张素转换酶抑制剂(ACEI)和血管紧张素受体阻滞剂(ARE)，并研究被认为在虚弱中起重要作用的病理生理变化。目前的PA(老年人的虚弱：病理生理学和干预：PAS-03-122)建议对有潜力的干预措施进行临床前测试，以防止ACEI等虚弱相关的身体衰退。在本申请中提出的初步研究表明，在老年大鼠中使用ACEI可以缓解与年龄相关的体能下降，并与总体体脂质量的减少有关。鉴于越来越多的证据将脂肪质量和脂肪分布的差异与肌肉功能和身体衰退联系起来，这在脆弱的背景下是非常有意义的。然而，目前尚不清楚ACEI是如何导致运动能力下降的，也不清楚ACEI的影响是由血管紧张素受体还是其他机制介导的。对高血压患者使用ARB或ACEI的长期临床试验表明，这两种治疗方法都降低了与II型糖尿病相关的脂肪和肌肉代谢异常的风险。ARB只通过拮抗AT1受体来阻断AngII的作用。关于每一次干预如何影响这些变化，仍存在一些争论。任何一种途径的改变都会产生深远的代谢后果，尤其是在高血压、肥胖症和胰岛素抵抗的情况下。这项应用将涉及一个主要目标和两个次要目标：1)确定依那普利和氯沙坦与生理盐水对照治疗对雄性Brown挪威×F344大鼠部分寿命的身体机能的影响；2)确定与年龄相关的变化的时间进程，以及依那普利和氯沙坦对全身胰岛素敏感性和糖耐量的影响，以及脂肪组织和骨骼肌生理学的变化；3)将这些发现与身体机能下降联系起来。这些数据将为确定长期ACEI和ARB治疗在逆转这些变化中的作用奠定基础，并为计划在人体上预防与年龄相关的身体功能下降的随机临床试验提供初步数据。

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.