ACE Inhibition And Physical Performance In Aged Rats
Christy Shawn Carter, Instructor
Aging And Geriatricuniversity Of Florida
Grant 5R01AG024526-04 from National Institute On Aging, IRG: ZRG1
Abstract: 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 INTERVENTIONSPAS-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
Keywords: animal old age, body physical activity, enalapril, losartan, nonhuman therapy evaluation adipose tissue, blood pressure, body composition, insulin sensitivity /resistance, longitudinal animal study, muscle function, striated muscle glucose tolerance test, laboratory rat, statistics /biometry
Project start date: 2005-09-15
Project end date: 2010-07-31
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ACE Inhibition And Physical Performance In Aged Rats
Christy Shawn Carter, Instructor
University Of Florida 219 Grinter Hall Gainesville, Fl 326115500
Grant 5R01AG024526-03 from National Institute On Aging, IRG: ZRG1
Abstract: 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 INTERVENTIONSPAS-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.
Keywords: animal old age, body physical activity, enalapril, losartan, nonhuman therapy evaluation, adipose tissue, blood pressure, body composition, insulin sensitivity /resistance, longitudinal animal study, muscle function, striated muscle, glucose tolerance test, laboratory rat, statistics /biometry
Project start date: 2005-09-15
Project end date: 2010-07-31
5R01AG024526-03 (2007): $288165
5R01AG024526-02 (2006): $297756
Grants awarded to Christy Shawn Carter
ACE Inhibition And Physical Performance In Aged Rats
Christy Shawn Carter, Instructor
Aging And Geriatricuniversity Of Florida
Grant 5R01AG024526-04 from National Institute On Aging, IRG: ZRG1
Abstract: 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 INTERVENTIONSPAS-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
Keywords: animal old age, body physical activity, enalapril, losartan, nonhuman therapy evaluation adipose tissue, blood pressure, body composition, insulin sensitivity /resistance, longitudinal animal study, muscle function, striated muscle glucose tolerance test, laboratory rat, statistics /biometry
Project start date: 2005-09-15
Project end date: 2010-07-31
1R01AG024526-01A1 (2005): $315060
NEUROBIOLOGY OF COGNITIVE DEVELOPMENT--LATENT INHIBITION
Christy Shawn Carter, Instructor
University Of North Carolina Chapel Hill Office Of Sponsored Research Chapel Hill, Nc 27599
Grant 5F31MH011292-03 from National Institute Of Mental Health, IRG: CFN
Abstract: This proposal is designed to examine the biological bases of a developmental change in latent inhibition (LI) of the classically conditioned eyelid response. Previous data from our lab suggests that conditioning emerges gradually between postnatal day 17 (PND17) and PND24 (Stanton, Freeman, and Skelton, 1992; Freeman, Spencer, Skelton, and Stanton, 1993). Recent work in infants in our lab makes it possible to look at not only the behavioral and the neurological development of eyelid conditioning in the rat which is known to be dependent on the cerebellum but to further extend this analysis to other brain structures, such as the hippocampus, and what their role might be in the modulation of higher order forms of learning, such as (LI), within this late developing learning system. In order to address these issues preliminary studies of LI have been carried out in our lab to begin to establish the ontogeny of this behavior. We have shown that while 20-day-old pups do not show latent inhibition, 24-and 32-day-old rats do. We propose to perform selective medial septal lesions and afterwards test pups on LI to see if this behavior is disrupted. The ontogeny of this behavior may reflect a developmental interaction between the hippocampus and cerebellum.
Keywords: cognition, conditioning, developmental neurobiology, hippocampus, learning, stimulus /response, behavioral /social science research tag
5F31MH011292-03 (1998): $14748
5F31MH011292-02 (1997): $14496
ACE Inhibition And Physical Performance In Aged Rats
Christy Shawn Carter, Instructor
Aging And Geriatricuniversity Of Florida
219 Grinter Hall
gainesville, Fl 326115500
Grant 3R01AG024526-03S1 from National Institute On Aging, IRG: ZRG1
Project start date: 2005-09-15
Project end date: 2010-07-31