ACE Inhibition and Physical Performance in Aged Rats

老年大鼠的 ACE 抑制和体能

• 批准号: 6924467
• 负责人: CHRISTY SHAWN CARTER
• 金额: $ 31.51万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924467
• 关键词: adipose tissue; animal old age; blood pressure; body composition; body physical activity; enalapril; glucose tolerance test; insulin sensitivity /resistance; laboratory rat; longitudinal animal study; losartan; muscle function; nonhuman therapy evaluation; statistics /biometry; striated muscles

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.

描述（由申请人提供）： 我们建议使用与年龄相关的身体衰退的啮齿动物模型来对两种有前景的药物干预措施（血管紧张素转换酶抑制剂（ACEi）和血管紧张素受体阻滞剂（ARE））进行临床前测试，这两种药物干预措施有可能预防与虚弱相关的身体衰退。研究假定在虚弱中发挥重要作用的病理生理变化。目前的 PA（老年衰弱：病理生理学和干预措施：PAS-03-122）建议对有前景的干预措施进行临床前测试，这些干预措施有可能预防与衰弱相关的身体衰退，例如 ACEi。本申请中提出的初步研究表明，老年大鼠使用 ACEi 可以减轻与年龄相关的身体机能下降，并与全身脂肪量的减少相关。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 如何导致运动表现下降，也不清楚 ACEi 的影响是否是由血管紧张素受体或其他机制介导的。使用ARB（仅通过拮抗AT1受体来阻断ANGII的作用）或ACEi对高血压患者进行的长期临床试验表明，这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风险。关于每种干预措施如何影响这些变化仍然存在一些争论。任一途径的改变都会产生深远的代谢后果，尤其是在高血压、肥胖和胰岛素抵抗的情况下。本申请将解决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盐水对照治疗对雄性 Brown挪威 x F344 大鼠整个生命周期部分身体表现的影响； 2) 确定年龄相关变化的时间进程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和骨骼肌生理学变化的影响； 3）将这些发现与身体机能下降联系起来。这些数据将为表征长期 ACEi 和 ARB 治疗在逆转这些变化中的作用奠定基础，并为规划人类随机临床试验以预防与年龄相关的身体功能下降提供初步数据。