Elsevier

Regulatory Peptides

Volume 128, Issue 3, 30 June 2005, Pages 247-252
Regulatory Peptides

Protective effect of the inhibition of the renin–angiotensin system on aging

https://doi.org/10.1016/j.regpep.2004.12.027Get rights and content

Abstract

Experimental studies indicate that chronic long-term inhibition of the renin–angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system and in the kidney of the normal mouse and rat. In this review, all the information available on this subject provided by several studies performed by our research group during the last years is been described. Treatment was initiated either after weaning or at 12 months of age that is about half the normal life span of the rat. A converting enzyme inhibitor: enalapril or an angiotensin II type 1 (AT1) receptor blocker: losartan were used to inhibit the RAS. Cognitive behaviour, emotionality, and locomotor activity were also determined at 10 and 18 months of age in treated since weaning and untreated control rats to elucidate the participation of angiotensin II in memory disfunction. A similar observation was obtained in animals treated from 12 to 18 months of age. Results have demonstrated a significant protective effect on the function and the structure of the cardiovascular system, the kidney and the brain in all the treated animals. Damage observed at 12 months of age was not very significant, but treatment stop further deterioration that was evident in untreated animals. The similarity of the results detected with either enalapril or losartan treatment, clearly indicates that most of the effects are exerted through AT1 receptors. Analysis of the nitric oxide and antioxidant enzymes systems suggest that the protective effect is related to an antioxidant action of the RAS inhibitors and a reduced formation of reactive oxygen species. AngII inhibition might produce changes in the mechanisms of oxidative stress specially at the mitochondrial level. Prevention of mitochondrial decrease and/or damage would be related with the delay of the normal aging process.

Introduction

The renin–angiotensin system (RAS) through its active agent Angiotensin II (AngII) has a large variety of physiological actions that includes arterial blood pressure regulation, sodium and water homeostasis, stimulation of other endocrine systems, etc. Some of the actions are exerted as an endocrine system. Over the past few decades, a large amount of information has uncovered a multitude of deleterious cardiovascular and renal effects attributed to excess AngII. This peptide is now known to act as a paracrine, autocrine and intracrine factor, whose mechanisms of action range from excitation or injury of whole organs to influence on cellular growth and function, alterations of intracellular signaling pathways and promotion of extracellular matrix changes.

The RAS contributes to the pathogenesis of several human diseases, including hypertension, congestive heart failure, coronary artery disease and diabetic nephropathy. Angiotensin converting enzyme inhibitors (ACEI) and AngII nonpeptide type 1 receptor (AT1) blockers are used in the treatment of these diseases. Aging and hypertension are associated with an increased incidence of coronary and cerebrovascular disease and renal failure. Most of the cardiovascular complications are related to alterations in vascular structure and function. The marked enhancement of age-related vascular complications in hypertension suggests an important interaction between the two processes [1]. Several reports have demonstrated that the cardiovascular changes observed during aging are similar to those due to high blood pressure (BP) overload with respect to biochemical, mechanical and electro-physiological properties of the cardiovascular system [2], [3]. In rats, both hypertension and age [2] produce an increase in absolute and relative left ventricular weight and myocardial fibrosis [4]. On the other hand, structure and function of the arterial wall also show similar modifications in hypertension and aging. The main vascular structural alteration is enhanced stiffness [5] related to increased media thickness due to smooth muscle cell hypertrophy/hyperplasia and collagen accumulation [6]. Endothelial and smooth muscle disfunction with aging and hypertension has been described in rat aorta [7]. The similarities between aging and hypertension added to the fact that increased BP is usually observed in aged humans and rats, suggest the possibility that hypertension could be a form of accelerated aging. In this sense, some reports have indicated that hypotensive agents like ACEI and AT1 blocking agents could lower BP in normotensive, normoreninemic animals [6], [8]. Nonetheless, other authors did not report any hypotensive effect even during chronic treatment with the above mentioned pharmacological agents [9]. ACEI could be even more effective in the elderly based on the favorable effects on cardiovascular fibrosis detected in experimental studies [10]. Because the pharmacological effects of the ACEI are due to more than one mechanism, mainly inhibition of AngII formation and blockade of bradykinin metabolism, it was necessary to confirm that these actions are related to blockade of AngII formation either in the plasma or in the involved tissues. Comparison of the effect of enalapril with an AngII receptor blocker, which specifically impedes the binding of AngII to the AT1 receptor, has helped to clarify this matter.

The progressive development of glomerulosclerosis is a well-known phenomenon that occurs in the aging kidney and in a variety of experimental models of renal injury. In the remnant kidney model, Hostetter and colleagues [11] had demonstrated that ACEI and angiotensin II antagonists can attenuate glomerulosclerosis. In a previous report it was shown that enalapril, administered to mice during 24 months, significantly decreases both mesangial expansion and glomerulosclerosis and it also attenuates the loss of glomeruli normally associated with aging [12]. The mechanisms involved in these protective effects of enalapril are not well established. In other models, the decrease of intraglomerular pressure by ACEI, as well as by AngII antagonists, accounts for the attenuation of glomerular injury [13]. Other report has shown that chronic ACEI treatment during the whole life span of the rat reduced proteinuria and albumin accumulation in podocytes, delayed the progression of glomerulosclerosis and prevented the age-related hypertrophy of the mesangial domain of the glomeruli [14].

Changes in behaviour due to advanced age have been studied in the rat, older animals show a decreased performance in memory acquisition and retention tests and significantly lower locomotion activity. In general, cognitive performance as well as noncognitive behaviour are altered in senescent rats. Age related spatial memory deficits are correlated with septohippocampal cholinergic system degeneration [15], [16], [17]. Recent reports have examined whether changes in nitric oxide (NO) production in the brain may be involved in aging-associated brain disfunction [18], [19]. The presence of a separate RAS in mammalian brain has been reported [20]. Binding sites for AngII have been identified in various brain regions including cortex, hippocampus and midbrain [21]. The function of AngII in the central nervous system is synaptic and specifically involves the interaction of the polypeptide with neurotransmitters such as acetylcholine, catecholamines, serotonin and other peptides [22], [23]. However, AngII action on the learning function is rather controversial. In this sense, some studies have reported disruption of passive avoidance retention by AngII infusion in the central nervous system [24]; moreover, AngII administered in the hippocampal area, through an AT1 receptor-mediated effect, inhibits the induction of long term potentiation [25], [26], a relatively long-lasting form of neural plasticity proposed as a model of spatial learning and memory [27], [28]. On the contrary, some studies have demonstrated that acute administration of AngII in the central nervous system improves the learning ability in rats [29], [30]. Nonetheless, a recent report, performed in aged normotensive Dahl rats [31] has shown that long-term inhibition of the renin–angiotensin system improved cognitive function in the aged, normotensive rats. Memory function was tested with a passive avoidance task. The improvement was associated with significant preservation of neuronal cells and capillary densities in the hippocampal area. These data indicate that AngII inhibition maintains cognitive function in the aged rat through protection of vascular vessels and neuronal cells responsible for memory function. The effect seems to be mediated through AT1 receptors.

During the last five years we have investigated the deleterious effects due to aging on target organs in the normal male Wistar rat. Simultaneously, we have analyzed the protective effect of chronic AngII inhibition either with an ACEI (enalapril) or with an AT1 receptor blocker (losartan), given since weaning or at 12 months of age, on these alterations. In the present article a review of the results obtained in the cardiovascular system and the kidney and the evaluation of behavioural parameters vinculated with the neuronal preservation of the brain will be described.

Section snippets

Cardiovascular system

Previous studies have shown that, in the normal adult rat, treatment with enalapril during three weeks decreased blood pressure (BP) and the ventricular weight/body weight ratio [32]. Treatment with either enalapril or losartan during 6 months impaired the BP increase observed in normal rats, indicating that the involvement of the RAS in the regulation of BP in normal conditions is more important than previously believed. Both treatments induced a reduction in the cardiac DNA and collagen

Renal damage

Based on previous information, present experiments were designed to further elucidate the role played by the RAS on the alterations due to aging in the kidney of the normal rat. In the first set of experiments, enalapril and losartan were given in a similar dose and, even though they had the same hypotensive effect on BP, losartan was not able to prevent renal damage in 18 months old rats [40]. The following studies were performed with a larger dose of losartan. After 6 months of treatment,

Behavioural parameters

Based on previous and controversial information about the effect of AngII on learning and behaviour, chronic inhibition of the RAS since weaning with either enalapril or losartan was analyzed in the normal rat. Trying to use the most physiological conditions, testing was performed in an 8 arm maze made of crystal clear acrylic. Animals were continuously trained during 40 days. Criterion for acquisition of either reference or working memory was established as making only one mistake in 5

Conclusions

These studies have demonstrated that chronic long-term inhibition of the RAS induces a significant protective effect on the deleterious process of aging on the cardiovascular system, the kidney and the brain. Protection was determined through functional and structural analysis. Increased activity of NOS in the aortic endothelium, in cardiac and kidney mitochondria, as well as preliminary results in the brain could indicate a reduction in the mechanisms of oxidative stress even at the

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