Long-term AT<sub>1</sub>receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats

Gilliam-Davis, Shea; Payne, Valerie; Каспер, С.; Tommasi, Ellen N.; Robbins, Michael E.; Diz, Debra I.

doi:10.1152/ajpheart.00457.2007

Cited by 43 publications

(46 citation statements)

References 57 publications

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“…Little is known about the regulation of the local RAS, specifically, the levels of Ang II and Ang-(1-7), within each tissue during aging. There may be an overt elevation of components of the system, as reported for Ang II in the heart during aging [19], consistent with observations on the intrarenal RAS [14,[16][17][18]. In experimental models, increases in gene expression of angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 (AT 1 ) and Ang II type 2 (AT 2 ) receptors have been identified in hearts from senescent rats, independent of circulating RAS [22,23].…”

Section: Brain Ras Baroreflex and Autonomic Dysfunction During Agingsupporting

confidence: 86%

“…Long-term RAS blockade extends the lifespan and improves or prevents the age-related decline in cardiovascular and metabolic function in hypertensive rats as might be expected, but treatment of normotensive rats attenuates the age-related decline in cognitive function, the increase in bodyweight gain and decline in mitochondrial function, and preserves renal function [10][11][12][13][14][15][16]. Numerous studies, however, report a decrease in the plasma RAS components with increased age [17][18][19], which raises issues regarding whether RAS blockade of a variety of local tissue RAS (brain, kidney, heart, pancreas, adipose and adrenal) contributes to the improvements observed [20,21].…”

Section: Brain Ras Baroreflex and Autonomic Dysfunction During Agingmentioning

confidence: 94%

“…In experimental models, increases in gene expression of angiotensinogen, angiotensin-converting enzyme (ACE), Ang II type 1 (AT 1 ) and Ang II type 2 (AT 2 ) receptors have been identified in hearts from senescent rats, independent of circulating RAS [22,23]. Blockade of the RAS by either ACE inhibition or AT 1 -receptor blockers prevents the increase in urinary Ang II in several studies [14,16]. However, these treatments not only reduce the levels or actions of Ang II, but also cause an associated elevation in the levels or actions of Ang-(1-7), another active component of the RAS that has actions that oppose those of Ang II.…”

mentioning

confidence: 99%

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Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

2008

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This article discusses evidence that impairments in control of autonomic outflow mediated by the brain renin-angiotensin system (RAS) contribute to the decline in baroreceptor reflex function and the development of insulin resistance that accompany hypertension and excess salt intake, especially during aging. Imbalances in the regulation of the sympathetic and parasympathetic limbs of the autonomic nervous system observed in older subjects underlie changes in heart-rate variability and play a role in the regulation of overall cardiac function. Age-related alterations in autonomic nervous system function may also explain the age-associated alterations in metabolism. Reduced heart-rate variability is linked to increased mortality in patients with cardiovascular disorders and, coupled with information that is known about local changes in the cardiac and brain RAS during aging, the evidence reveals potential mechanisms for the protective effects of systemic blockade of the RAS against agerelated changes that impact the heart. Executive summary-• Disturbances in the brain renin-angiotensin system as a result of aging or conditions of excess salt contribute to imbalances in autonomic nervous system function leading to impairments in baroreceptor reflex control of heart rate and energy metabolism.• Cardiac structural and functional abnormalities, both systolic and diastolic, may result as a component of their etiology, the age-related hypertension and accompanying baroreflex, insulin resistance or bodyweight changes that are secondary to the impaired autonomic function resulting from alterations in the brain renin-angiotensin system.• Reductions in Ang-(1-7) in tissues such as brain or heart during the aging process or other conditions such as excess salt intake, rather than frank increases in Ang II, appear to contribute to pathophysiologic changes in cardiac structure and function. [1,2]. Importantly, dietary salt excess has been shown to be an invariable determinant of the age-related changes in blood pressure and endorgan damage in many clinical and experimental studies. A large body of epidemiological and experimental evidence demonstrates a significant association between high salt intake and blood pressure as well as a rise in systolic and diastolic blood pressure with aging [3][4][5]. While these changes are presumed to be a major reason for the altered diastolic compliance of the senescent heart, age-related increases in arterial stiffness can further lead to vascularventricular uncoupling [6,7], which, when taken together, predispose to diastolic heart failure (DHF). Stimuli for this cardiovascular remodeling associated with aging and diastolic heart disease include hypertension, increases in bodyweight gain, insulin resistance and renal dysfunction [8]. A common feature associated with the conditions of excess salt or advanced age is impairment of the baroreceptor reflexes for control of heart rate. Reduced heart-rate variability accompanies the imbalance in the sympathetic and parasympathetic nervo...

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Section: Brain Ras Baroreflex and Autonomic Dysfunction During Agingsupporting

confidence: 86%

Section: Brain Ras Baroreflex and Autonomic Dysfunction During Agingmentioning

confidence: 94%

mentioning

confidence: 99%

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Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

2008

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“…37 It has also been noted that rats treated long term with an AT-1 receptor antagonist have increased urinary volume and increased water intake. 38 Thus, the increase in water intake may be secondary to increased urine loss as opposed to a primary hyperdipsia mediated by the action of angiotensin in the brain.…”

Section: Discussionmentioning

confidence: 99%

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

et al. 2008

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Objective: There is emerging evidence that angiotensin stimulates adipocyte differentiation and lipogenesis. This study tested the hypothesis that inhibition of angiotensin II by treatment with an angiotensin-converting enzyme inhibitor, perindopril, would reduce fat mass in rats. Design: After a 12-day baseline, rats were divided into two groups: one was untreated and the other received perindopril (1.2 mg kg À1 per day) in drinking water for 26 days. Subjects: In total, 16 male Sprague-Dawley rats aged 10 weeks at the start of the study. Measurements: Plasma leptin was measured in samples collected at baseline, half-way through and at the end of treatment. Body weight, food and water intake were measured daily throughout the experiment. Body fat mass, bone and lean mass were determined by dual energy X-ray absorptiometry (DEXA) at the end of the treatment period. Results: Daily food intake was the same in both groups throughout the study. By the end of treatment, animals receiving perindopril showed a modest reduction in weight gain relative to the untreated animals (62.4 ± 5.0 g vs 73.0 ± 4.0 g; Po0.05). DEXA analysis showed that body composition was greatly altered and the perindopril-treated group had 26% less body fat mass than the untreated group (61.0 ± 5.2 g vs 44.4 ± 4.2 g; Po0.01). The reduction in body fat mass was correlated with reductions in the weight of both the epididymal and retroperitoneal fat pads (Po0.001). Similarly, plasma leptin was reduced by perindopril treatment (4.64 ± 0.56 ng ml À1 ) compared to the untreated group (8.27 ± 1.03 ng ml À1 ; Po0.001). In contrast, there were no differences in lean or bone mass between the two groups. Conclusion: Oral treatment with perindopril selectively reduced body fat mass without influencing daily food intake. In contrast, there were no differences in lean or bone mass between the two groups.

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“…29,30 The Fischer 344 X Brown Norway rat expresses greater longevity than Fischer 344 animals with rescue from many of their age-related deficits, including the decline in renal function. 31,32 In an attempt to rule out elevated SBP during aging as a contributor to activation of the intrarenal RAS, we studied male Fischer 344 rats between 3 and 15 months of age 33 ( Figure 3A). As expected, SBP did not increase and is actually lower in older than in younger rats.…”

Section: Intrarenal Ras Regulation In Animals Without Age-related Hypmentioning

confidence: 99%

Lewis K. Dahl Memorial Lecture

Diz

2008

Hypertension

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identified many of the relationships that underlie our current thinking and focus of research on hypertension. Among the first to establish the interactions between salt and hypertension, the realization that genetic factors played a major role in how the kidney responded to salt loads 1 led to development of the genetically predisposed Dahl salt-sensitive rat. His research, although not specifically directed toward aging, recognized that the effects of high-salt diets were not necessarily immediate. In fact, he suggested that at least one third of the life span was required for salt-induced changes in systolic blood pressure (SBP).I am very grateful for the honor of presenting the Dahl lectureship on work, which, over the past several years, has had aging as the focus. The emphasis has been on the autonomic nervous system, as influenced by the renin-angiotensin system (RAS), specifically, the balance between angiotensin (Ang) II and Ang-(1-7) and the contributions of brain cardiovascular areas to the constellation of changes occurring with advancing age. The overall message derived is that, although the brain RAS plays a major role in all of the age-related changes in cardiovascular and metabolic function, neither the SBP nor the metabolic changes appear to be initiating factors in the activation of the intrarenal RAS or the decline in kidney function during aging ( Figure 1). Differential Regulation of the Circulating and Intrarenal RAS During AgingComponents of the classical circulating RAS, in particular, renin release from the juxtaglomerular cells of the kidney, undergo a decline in older animals. This includes reductions in renal tissue renin mRNA, juxtaglomerular cell renin content, responsiveness of renin release to various challenges, and plasma renin and angiotensin (Ang) II. [2][3][4][5][6][7][8][9] The renal vasoconstrictor responses to exogenously administered Ang II are increased in older animals, 6 perhaps resulting from the reductions in the circulating system. In striking contrast, however, kidney Ang II content increases in older animals. 6This latter finding is not surprising, because all of the components of the RAS are synthesized locally within the kidney, 10 -12 and local production of Ang peptides is regulated independent of the circulating system. 11,13-16 Thus, whereas the juxtaglomerular cell renin and its release into the circulation are considered representative of the circulating/hormonal RAS, renal tissue content, tubular fluid, or urinary RAS components are considered representative of the intrarenal RAS.The concept of differential regulation of the circulating and intrarenal or other tissue RAS is not new.12 One possibility for these differences relate to the increase in SBP. An increase in arterial pressure during aging may lead to a baromediated reduction in renin release from the kidney, contributing to the decline in the circulating RAS. In contrast, for the intrarenal system, there is evidence that the regulation of tubular renin may be opposite to or at least different fro...

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Long-term AT₁receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats

Cited by 43 publications

References 57 publications

Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

Lewis K. Dahl Memorial Lecture

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Long-term AT1receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats

Cited by 43 publications

References 57 publications

Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

Aging and the Brain Renin–Angiotensin System: Relevance to Age-Related Decline in Cardiac Function

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

Lewis K. Dahl Memorial Lecture

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Long-term AT₁receptor blockade improves metabolic function and provides renoprotection in Fischer-344 rats