Cambios en la función ventricular sistólica y diastólica en un modelo de sobreexpresión cardíaca del receptor AT-1 de angiotensina / Changes in Systolic and Diastolic Function in a Mouse Model Overexpressing Cardiac Angiotensin II AT-1 Receptor

La angiotensina II (Ang II) está involucrada en diferentes procesos fisiopatológicos, particularmente actuando sobre los receptores AT-1 de Ang II (AT1R). El objetivo de este trabajo fue evaluar la función ventricular sistólica y diastólica in vivo e in vitro en ratones con sobreexpresión cardíaca específica del receptor AT-1 de Ang II (AT1R). Un segundo objetivo fue determinar si el bloqueo agudo y crónico del AT1R revierte los cambios en la función ventricular. Se estudiaron ratones divididos en cuatro grupos experimentales. El primer grupo incluyó animales no transgénicos (NTG, n = 10), el segundo grupo ratones transgénicos (TG, n = 7) que sobreexpresan el AT1R solo a nivel cardíaco y el tercero y el cuarto grupos, animales TG tratados con losartán (L) durante 7 días (TG L7, n = 9) y 30 días (TG L30, n = 7), respectivamente. Los ratones TG presentaron hipertrofia ventricular izquierda (HVI). El tratamiento con losartán por 7 días no revirtió la HVI, lo que sí sucede cuando se extiende por 30 días. Los animales TG presentan una disminución significativa de la fracción de acortamiento, desde un valor de 47,1% ± 2,3% hasta 32,3% ± 1,3% (p < 0,05), y de la +dP/dt máx, que se reduce desde un valor de 7.073 ± 674 mm Hg hasta 3.897,5 ± 209,7 mm Hg/seg (p < 0,05). El tratamiento con losartán por 7 y 30 días revierte esta disfunción sistólica. El tiempo de relajación isovolúmica y el t1/2 fueron de 24,1 ± 1,3 mseg y de 5,1 ± 0,5 mseg, respectivamente, en los NTG. Estos índices se incrementaron a 33,1 ± 2,2 mseg y a 8,4 ± 0,4 mseg, respectivamente, en los ratones TG (p < 0,05). Esta alteración de la función diastólica fue revertida por completo con el tratamiento con losartán por 7 y 30 días. El análisis de la función ventricular in vitro con control de variables corroboró los hallazgos realizados in vivo. La sobreexpresión cardíaca de los AT1R induce una disfunción ventricular sistólica y diastólica que es revertida completamente por el bloqueo del AT1R. Este efecto beneficioso es independiente de modificaciones en la masa ventricular izquierda.(AU)

Angiotensin II (Ang II) is involved in various patho-physiological processes through the activation of Ang II AT-1 receptors. The purpose of this study was to assess in vivo and in vitro systolic and diastolic ventricular function in mice overexpressing the cardiac-specific AT-1 receptor (AT1R). A second objective was to deter¡mine whether acute and chronic ATIR blockade revert the changes in ventricular function. Mice were divided into four experimental groups. The first group included non-transgenic animals (NTG, n=10), the second group consisted of transgenic mice (TG, n=7) with cardiac-specific AT1R overexpression and the third and fourth groups were TG animals treated with losartan (L) for 7 (TG L7, n=9) and 30 days (TG L30, n=7), respectively. Transgenic animals exhibited left ventricular hypertrophy (LVH) which was only regressed with losartan treatment for 30 days. They also presented a significant decrease in shortening fraction from 47.1 ± 2.3% to 32.3 ± 1.3% (p max from 7073 ± 674 to 3897.5 ± 209.7 mm Hg/sec (p Isovolumic relaxation time and t1/2 were 24.1 ± 1.3 and 5.1 ± 0.5 ms, respectively, in the NTG group. These indexes increased to 33.1 ± 2.2 and 8.4 ± 0.4 ms, respectively, in TG mice (p In conclusion, cardiac-specific AT1R overexpression induces systolic and diastolic ventricular dysfunction which is completely reversed by AT1R blockade. This beneficial effect is independent of left ventricular mass changes.(AU)

Cambios en la función ventricular sistólica y diastólica en un modelo de sobreexpresión cardíaca del receptor AT-1 de angiotensina / Changes in Systolic and Diastolic Function in a Mouse Model Overexpressing Cardiac Angiotensin II AT-1 Receptor

La angiotensina II (Ang II) está involucrada en diferentes procesos fisiopatológicos, particularmente actuando sobre los receptores AT-1 de Ang II (AT1R). El objetivo de este trabajo fue evaluar la función ventricular sistólica y diastólica in vivo e in vitro en ratones con sobreexpresión cardíaca específica del receptor AT-1 de Ang II (AT1R). Un segundo objetivo fue determinar si el bloqueo agudo y crónico del AT1R revierte los cambios en la función ventricular. Se estudiaron ratones divididos en cuatro grupos experimentales. El primer grupo incluyó animales no transgénicos (NTG, n = 10), el segundo grupo ratones transgénicos (TG, n = 7) que sobreexpresan el AT1R solo a nivel cardíaco y el tercero y el cuarto grupos, animales TG tratados con losartán (L) durante 7 días (TG L7, n = 9) y 30 días (TG L30, n = 7), respectivamente. Los ratones TG presentaron hipertrofia ventricular izquierda (HVI). El tratamiento con losartán por 7 días no revirtió la HVI, lo que sí sucede cuando se extiende por 30 días. Los animales TG presentan una disminución significativa de la fracción de acortamiento, desde un valor de 47,1% ± 2,3% hasta 32,3% ± 1,3% (p < 0,05), y de la +dP/dt máx, que se reduce desde un valor de 7.073 ± 674 mm Hg hasta 3.897,5 ± 209,7 mm Hg/seg (p < 0,05). El tratamiento con losartán por 7 y 30 días revierte esta disfunción sistólica. El tiempo de relajación isovolúmica y el t1/2 fueron de 24,1 ± 1,3 mseg y de 5,1 ± 0,5 mseg, respectivamente, en los NTG. Estos índices se incrementaron a 33,1 ± 2,2 mseg y a 8,4 ± 0,4 mseg, respectivamente, en los ratones TG (p < 0,05). Esta alteración de la función diastólica fue revertida por completo con el tratamiento con losartán por 7 y 30 días. El análisis de la función ventricular in vitro con control de variables corroboró los hallazgos realizados in vivo. La sobreexpresión cardíaca de los AT1R induce una disfunción ventricular sistólica y diastólica que es revertida completamente por el bloqueo del AT1R. Este efecto beneficioso es independiente de modificaciones en la masa ventricular izquierda.

Angiotensin II (Ang II) is involved in various patho-physiological processes through the activation of Ang II AT-1 receptors. The purpose of this study was to assess in vivo and in vitro systolic and diastolic ventricular function in mice overexpressing the cardiac-specific AT-1 receptor (AT1R). A second objective was to deter­mine whether acute and chronic ATIR blockade revert the changes in ventricular function. Mice were divided into four experimental groups. The first group included non-transgenic animals (NTG, n=10), the second group consisted of transgenic mice (TG, n=7) with cardiac-specific AT1R overexpression and the third and fourth groups were TG animals treated with losartan (L) for 7 (TG L7, n=9) and 30 days (TG L30, n=7), respectively. Transgenic animals exhibited left ventricular hypertrophy (LVH) which was only regressed with losartan treatment for 30 days. They also presented a significant decrease in shortening fraction from 47.1 ± 2.3% to 32.3 ± 1.3% (p max from 7073 ± 674 to 3897.5 ± 209.7 mm Hg/sec (p Isovolumic relaxation time and t1/2 were 24.1 ± 1.3 and 5.1 ± 0.5 ms, respectively, in the NTG group. These indexes increased to 33.1 ± 2.2 and 8.4 ± 0.4 ms, respectively, in TG mice (p In conclusion, cardiac-specific AT1R overexpression induces systolic and diastolic ventricular dysfunction which is completely reversed by AT1R blockade. This beneficial effect is independent of left ventricular mass changes.

Effects of moderate and chronic exercise on the nitrergic system and behavioral parameters in rats.

Several reports suggest that nitric oxide (NO) could play a critical role on synaptic plasticity related to physical activity improving learning and memory; thus, physical exercise would have important effects on cerebral health. In order to analyze the long-term effects of chronic moderate physical training on the morphology and activity of nitrergic neurons belonging to the cerebral cortex, hippocampus and striatum, and their relationship with behavioral parameters. Wistar rats were aerobically trained (AT) up to the age of 18months and compared to sedentary controls (SC). At the end of the training protocol behavioral parameters were analyzed in an eight-arms radial maze. Rats were sacrificed by perfusion fixation with 4% paraformaldehyde. Brains were dissected out and coronal sections containing the three mentioned areas were obtained. The neurons expressing nitric oxide synthase (NOS) were stained using the technique of NADPH-diaphorase (NADPH-d) and their morphological and densitometric parameters were quantified by image analysis. Afterwards, the isoforms of NOS were determined by immunofluorescence. Results revealed AT rats learned faster, performed less mistakes and were more successful than SC rats in the maze. The nitrergic neurons of the cerebral cortex were larger and they had an increased number of dendrites. The NADPH-d reactivity in the cortex and striatum was upregulated. Colocalization was significant for the neuronal nitric oxide synthase (nNOS), in both groups. In conclusion, moderate and chronic exercise had a positive effect on cognitive performance and anxiety related behavior. An upregulation of the nitrergic system was detected in AT rats and this fact could be involved in this beneficial action on the aged subjects.

Changes seen in the aging kidney and the effect of blocking the renin-angiotensin system.

BACKGROUND: The objective was to evaluate structural changes of glomeruli during aging and the role of chronic renin-angiotensin system inhibition (RASi) on these changes; starting RASi on Wistar rats at two different moments: the first group after weaning and the second at the midpoint of their lifespan (12 months). METHODS: Thirty rats were divided, after weaning, into three groups of 10: group 1: control (C); group 2 : 30 mg/kg/day losartan (L); group 3 : 10 mg/kg/day enalapril (E). At 18 months, rats were placed in metabolic cages to evaluate proteinuria, then killed. Another group of 24 rats, 12 months old, were divided into three groups of eight: group 1: C; group 2: L; group 3: E. At 18 months the same procedure described above was carried out. Finally, a third group of 20 rats was studied as healthy controls and killed: 10 rats at 7 months and ten at 12 months of age. Tissue samples were collected after sacrifice. To evaluate glomerular fibrotic changes, both focal and periglomerular sclerosis, and mesangial matrix expansion, a scoring scale was established. We also evaluated anti-alpha-SM-actin and anti-collagen-III immunolabeling. Glomerular area was measured using an image analyzer. RESULTS: Proteinuria and serum creatinine increased with age but were reduced in treated animals. Main glomerular changes present in 18-month-old rats were reduced by half in treated animals. Glomerular area showed significant increase with normal aging and all treatment strategies protected against it. CONCLUSION: RAS plays a central role in natural process of renal aging, probably by producing effects influencing the biology of aging, the effects of which can be attenuated by RASi.

Rosuvastatin given during reperfusion decreases infarct size and inhibits matrix metalloproteinase-2 activity in normocholesterolemic and hypercholesterolemic rabbits.

There is evidence that statin treatment before ischemia protects myocardium from ischemia/reperfusion injury. The objective is to determine whether rosuvastatin administered during reperfusion modifies infarct size and the recovery of postischemic ventricular dysfunction in normocholesterolemic and hypercholesterolemic rabbits. In addition, we also evaluated the role of matrix metalloproteinase type 2 (MMP)-2 activation. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In group 2, we added rosuvastatin after 30 minutes of ischemia and from the beginning of reperfusion. In group 3, an MMP inhibitor (doxycycline) was administered during the first 2 minutes of reperfusion. Finally, we repeated these groups but in hypercholesterolemic rabbits (groups 4, 5, and 6). The infarct size was 16.6% +/- 3.9% in group 1 and 25.6% +/- 2.7% in group 4. Rosuvastatin reduced infarct size to 4.5% +/- 1.1% and 6.1% +/- 1.5% in groups 2 and 5, respectively (P < 0.05). Rosuvastatin significantly decreased MMP-2 activity during reperfusion, and doxycycline induced an inhibition of MMP-2 activity and a reduction of infarct size in normocholesterolemic (4.9% +/- 0.9%) and hypercholesterolemic animals (8.3% +/- 1.6%) (P < 0.05). Rosuvastatin reduces infarct size and attenuates MMP-2 activity. These data and the correlation between MMP-2 and infarct size suggest that MMP-2 plays an important role in the mechanisms of cardioprotection afforded by rosuvastatin.

Efecto de la rosuvastatina sobre el infarto experimental en conejos normales e hipercolesterolémicos / Effects of Rosuvastatin on Experimental Infarction on Normal and in Hypercholesterolemic Rabbits

Es conocido que el pretratamiento con rosuvastatina disminuye el tamaño del infarto y mejora la disfunción ventricular. Sin embargo, no existe evidencia experimental que demuestre su efecto cuando se administra durante la reperfusión. El objetivo del presente estudio fue evaluar si la rosuvastatina administrada durante la reperfusión modifica el tamaño del infarto y la recuperación de la función ventricular posisquémica en corazones de conejos normocolesterolémicos e hipercolesterolémicos. Corazones aislados e isovolúmicos de conejo fueron perfundidos según la técnica de Langendorff. En el grupo 1 (G1) se realizó una isquemia global de 30 minutos seguidos por 120 minutos de reperfusión. En el grupo 2 (G2) se administró rosuvastatina (50 µM) durante toda la reperfusión. En los grupos 3 y 4 (G3 y G4) se repitieron los protocolos de G1 y G2, respectivamente, pero en conejos alimentados durante un mes con una dieta rica en colesterol al 1%. El colesterol total antes de iniciar la dieta fue de 59,6 ± 9,3 mg/dl y luego de la alimentación durante 4 semanas con una dieta rica en colesterol se incrementó hasta un valor de 185,4 ± 21,4 (p < 0,05). No hubo diferencias en la recuperación de la presión desarrollada (PDVI) ni en la presión diastólica final del ventrículo izquierdo (PDFVI) en los animales normocolesterolémicos. Sin embargo, en G3 y G4 la administración de rosuvastatina atenuó la disfunción ventricular posisquémica sistólica y diastólica. El tamaño del infarto de G1 y G3 fue de 16,6 ± 2,6 y 25,6 ± 2,7, respectivamente (p < 0,05). La administración de rosuvastatina redujo el tamaño del infarto en G2 y G4 a un valor de 4,5 ± 1,1 y 5,5 ± 1,6 (p < 0,05), respectivamente. La rosuvastatina administrada desde el inicio de la reperfusión disminuye el tamaño del infarto en conejos normales e hipercolesterolémicos y mejora la recuperación de la función ventricular sólo en los animales hipercolesterolémicos.

It is well accepted that previous treatment with rosuvastatin may reduce infarct size and improve ventricular dysfunction. Nevertheless, there is no experimental evidence of this action when administered during reperfusion. The objective of the present study was to assess if the administration of rosuvastatin during reperfusion might modify not only the infarct size but also ventricular function recovery after an ischemic episode in normocholesterolemic and hypercholesterolemic rabbits. Isolated and isovolumetric rabbit hearts were perfused according to Langendorff technique. Rabbits in group 1 (G1) underwent a 30-minute global ischemia followed by a reperfusion lasting for 120 minutes. Rosuvastatin (50 µM) was administered to rabbits in group 2 (G2) throughout the whole reperfusion. Protocols G1 and G2 were repeated in groups 3 and 4 (G3 and G4), respectively, but in rabbits previously fed for a month with a 1% cholesterol-rich diet. Total cholesterol levels were 59.6±9.3 mf/dl before treatment with the diet, and after a cholesterol-rich diet for 4 weeks, cholesterol levels increased to 185.4±21.4 (p<0.05). No differences among recovery in left ventricle developed pressure (LVDP) or in end-diastolic left ventricle pressure (EDLVP) were reported in normocholesterolemic animals. Nevertheless, the administration of rosuvastatin mitigated systolic and diastolic post-ischemic left ventricular dysfunction. Infarct size in G1 and G3 was 16.6±2.6 and 25.6 ± 2.7, respectively (p < 0.05). Administration of rosuvastatin reduced the infarct size in G2 and G4 to 4.5±1.1 y 5.5±1.6 (p<0.05), respectively. The administration of rosuvastatin since the beginning of reperfusion reduces the infarct size in normocholesterolemic and hypercholesterolemic rabbits, and improves ventricular function only in hypercholesterolemic animals.

Protective effect of long-term angiotensin II inhibition.

Experimental studies indicate that angiotensin II (ANG II) through its type 1 receptor (AT(1)) promotes cardiovascular hypertrophy and fibrosis. Therefore, the aim of this study was to analyze whether chronic long-term inhibition of the renin-angiotensin system (RAS) can prevent most of the deleterious effects due to aging in the cardiovascular system of the normal rat. The main objective was to compare two strategies of ANG II blockade: a converting enzyme inhibitor (CEI) and an AT(1) receptor blocker (AT(1)RB). A control group remained untreated; treatment was initiated 2 wk after weaning. A CEI, enalapril (10 mg.kg(-1).day(-1)), or an AT(1)RB, losartan (30 mg.kg(-1).day(-1)), was used to inhibit the RAS. Systolic blood pressure, body weight, and water and food intake were recorded over the whole experimental period. Heart, aorta, and mesenteric artery weight as well as histological analysis of cardiovascular structure were performed at 6 and 18 mo. Twenty animals in each of the three experimental groups were allowed to die spontaneously. The results demonstrated a significant protective effect on the function and structure of the cardiovascular system in all treated animals. Changes observed at 18 mo of age in the hearts and aortas were quite significant, but each treatment completely abolished this deterioration. The similarity between the results detected with either enalapril or losartan treatment clearly indicates that most of the effects are exerted through AT(1) receptors. An outstanding finding was the significant and similar prolongation of life span in both groups of treated animals compared with untreated control animals.

Divergent regulation of circulating and intrarenal renin-angiotensin systems in response to long-term blockade.

BACKGROUND/AIMS: Long-term treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin (Ang) II type I (AT(1)) receptor blockers can improve kidney function and attenuate the progressive decline in kidney function associated with age. In this study in Wistar rats medicated for 22 months, we determined the effects of enalapril (10 mg/kg/day) and losartan (30 mg/kg/day) treatment, in comparison with vehicle (tap water), on renal AngII receptor density and circulating and urinary components of the renin-angiotensin system (RAS). METHODS: Kidney sections were incubated with [(125)I-sarcosine(1)-threonine(8)]AngII (0.6 nM) for Ang receptor density, and Ang peptides were determined using radioimmunoassays. RESULTS: Receptor density was approximately 50% higher in vasa recta, glomeruli, and tubulointerstitium in enalapril-treated rats and lower in vasa recta and glomeruli in losartan-treated relative to vehicle-treated rats. Losartan and enalapril treatment elevated plasma levels of AngI and Ang-(1-7) while AngII increased only in losartan-treated rats. In contrast, both treatments were associated with a reduction in urinary excretion of all three Ang peptides as compared with control rats. CONCLUSION: The reduction in urinary Ang peptides with losartan and enalapril treatment suggests that blockade of intrarenal AngII may be an important mechanism underlying the renoprotection seen with such treatments.

Protective effect of the inhibition of the renin-angiotensin system on aging.

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.

Enriched environment, nitric oxide production and synaptic plasticity prevent the aging-dependent impairment of spatial cognition.

In rodents, neuronal plasticity decreases and spatial learning and working memory deficits increase upon aging. Several authors have shown that rats reared in enriched environments have better cognitive performance in association with increased neuronal plasticity than animals reared in standard environments. We hypothesized that enriched environment could preserve animals from the age-associated neurological impairments, mainly through NO-dependent mechanisms of induction of neuronal plasticity. We present evidence that 27 months old rats from an enriched environment show a better performance in spatial working memory than standard reared rats of the same age. Both mtNOS and cytosolic nNOS activities were found significantly increased (73% and 155%, respectively) in female rats from enriched environment as compared with control animals kept in a standard environment. The enzymatic activity of complex I was 80% increased in rats from enriched environment as compared with control rats. We conclude that an extensively enriched environment prevents old rats from the aging-associated impairment of spatial cognition, synaptic plasticity and nitric oxide production.

Enalapril and losartan attenuate mitochondrial dysfunction in aged rats.

Renin-angiotensin system (RAS) inhibition can attenuate the effects of aging on renal function and structure; however, its effect on mitochondrial aging is unknown. To investigate whether an angiotensin-converting enzyme inhibitor (enalapril) or an angiotensin II receptor blocker (losartan) could mitigate age-associated changes in kidney mitochondria, male Wistar rats (14 mo old) received during 8 mo water containing either enalapril (10 mg/kg/day) (Enal), or losartan (30 mg/kg/day) (Los), or no additions (Old). Four-month-old untreated rats (Young) were also studied. In Old rats mitochondrial respiratory control, ADP/O, nitric oxide synthase activity, and uncoupling protein 2 levels were lower (46, 42, 27, and 76%, respectively), and Mn-SOD activity was higher (70%) than in Young, Enal, and Los rats. In Old rats mitochondrial hydrogen peroxide production was higher than in both Young (197%) and Enal or Los (40%) rats. In Old rats, kidney GSH/GSSG was lower than in both Young (80%) and Enal (57%) or Los (68%) rats. In Old rats electron microscopy showed effacement of microvilli in tubular epithelial cells, ill-defined mitochondrial cristae, lower mitochondrial numbers, and enhanced number of osmiophilic bodies relative to Young, Enal, or Los rats. In conclusion, enalapril and losartan can protect against both age-related mitochondrial dysfunction and ultrastructural alterations, underscoring the role of RAS in the aging process. An association with oxidative stress modulation is suggested.

Long-term angiotensin II inhibition increases mitochondrial nitric oxide synthase and not antioxidant enzyme activities in rat heart.

OBJECTIVE: To provide insight into the subcellular mechanisms involved in the improvement of cardiovascular structure and function by long-term inhibition of the renin-angiotensin system. DESIGN: The activities of antioxidant enzymes and mitochondrial free radical production were determined in the heart of control (C), enalapril-treated (E), and losartan-treated (L) rats to test the hypothesis of increased antioxidant enzyme activities and participation of mitochondria in the effects of chronic treatments with angiotensin II inhibitors. METHODS: At 6 and 18 months of treatment, superoxide dismutases (SOD), Se-glutathione peroxidase, and catalase activities were determined in left ventricle homogenates by spectrophotometric methods and nitric oxide (NO) production in submitochondrial membranes by the oxyhemoglobin oxidation assay. The maximal rate of hydrogen peroxide (H2O2) production by submitochondrial membranes was also evaluated at 18 months by the scopoletin-horseradish peroxidase method. RESULTS: No significant increase was found in the antioxidant enzymes measured. At 6 months, Mn-SOD was actually decreased in E and catalase in both E and L, whereas at 18 months Se-glutathione peroxidase was decreased in L. Production of NO by submitochondrial particles was 64% higher at 6 months in E and 105% higher at 18 months in E and L. Maximal hydrogen peroxide production was lower at 18 months in both groups. CONCLUSIONS: Results do not support the hypothesis of an increase in antioxidant enzyme activity by long-term treatment with angiotensin II inhibitors as previously suggested and point towards a role for the NO produced by mitochondrial nitric oxide synthase (mtNOS) in the protective effect of these drugs.

Advances in our understanding of aging: role of the renin-angiotensin system.

Knowledge about the pathophysiological role of the renin-angiotensin system is constantly improving and its relationship with mechanisms of oxidative stress suggests its possible involvement with the deleterious effects of aging. Recent data opens a new field of investigation in this area.