ACE Inhibition and Physical Performance in Aged Rats

老年大鼠的 ACE 抑制和体能

• 批准号: 7119024
• 负责人: CHRISTY SHAWN CARTER
• 金额: $ 29.78万
• 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/7119024
• 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）： 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.当前的PA（老年脆弱：病理生理学和干预措施：PAS-03-122）建议对有希望的干预措施进行临床前测试，并有可能阻止与ACEI等脆弱的身体下降。本应用中介绍的初步研究表明，在老年大鼠中使用ACEI会减轻与年龄相关的身体性能下降，并且与总体内脂肪质量的降低有关。鉴于越来越多的证据将脂肪质量和脂肪分布与肌肉功能与身体下降联系起来的证据越来越多，这在脆弱的背景下引起了极大的兴趣。但是，目前尚不清楚ACEI如何促进性能下降，或者ACEI所见的作用是由血管紧张素受体还是其他机制介导的。使用ARB的高血压人员进行的长期临床试验，仅通过对抗AT1受体或ACEI来阻止ANGII的作用，或者ACEI表明，这两种治疗方法都减少了与II型糖尿病相关的脂肪和肌肉代谢异常的发展风险。关于每种干预如何影响这些变化，仍然存在一些争论。这两种途径的改变都有深远的代谢后果，最著名的是在高血压，肥胖和胰岛素抵抗的条件下。在本应用程序中将解决一个主要和两个次要目标：1）确定依那兰氏和氯沙坦与盐水控制治疗对跨男性棕色挪威X F344大鼠寿命的身体性能的影响； 2）确定与年龄相关的变化的时间过程，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受性以及脂肪组织和骨骼肌生理的变化的影响； 3）将这些发现与身体表现下降相关联。这些数据将为表征长期ACEI和ARB处理在逆转这些变化方面的作用而奠定基础，并为计划在人类中计划随机临床试验的初步数据，以预防与年龄相关的身体机能下降。