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.

Experimental studies indicate that angiotensin II (ANG II) through its type 1 receptor (AT1) 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 AT1 receptor blocker (AT1RB). A control group remained untreated; treatment was initiated 2 wk after weaning. A CEI, enalapril (10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), or an AT 1RB, losartan (30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), 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. losartan; enalapril; heart; aorta; life span THE NATURAL PROCESS OF AGING is related to a progressive modification, and ultimately, a loss of organ function. These alterations are common to all species. In general, there is a correlation between the structural and functional changes associated with aging. In mammals, degenerative processes such as arteriosclerosis, the development of senile plaques in the brain, and the replacement of functional parenchyma by fibroconnective tissue in a variety of organs are considered manifestations of aging (19,41).Ultrastructurally, a reduction in the number of cellular organelles such as mitochondria is common in the aging process (13,21,36). Lifelong free radical production could play a main role in the reduction of the number and in both structural and functional mitochondria modifications (6,20,38). It has been widely postulated that reactive oxygen species (ROS) are causally involved in the aging process (19,20). In this sense, earlier data (4, 17) have confirmed that nitric oxide synthase (NOS) activity in the aorta and nitric oxide (NO) production diminish with age, whereas chronic long-term administration of angiotensin II (ANG II) inhibitors maintains endothelial NOS activity in old animals. Moreover, the mitochondria from hearts of aged rats chronically treated with ANG II inhibitors were found to have increased NOS activity and decrease...

Abstract-The history of the discovery of the renin-angiotensin system began in 1898 with the studies made by Tigerstedt and Bergman, who reported the pressor effect of renal extracts; they named the renal substance renin based on its origin. In 1934, Harry Goldblatt induced experimental hypertension in dogs by clamping a renal artery. About 1936, simultaneously in the Medical School of the University of Buenos Aires, Argentina, and in the Eli-Lilly Laboratories in Indianapolis, 2 independent groups of researchers, using the Goldblatt technique to produce experimental hypertension, demonstrated renal secretion of a pressor agent similar to renin. In the following years, both teams described the presence of a new compound in the renal vein blood of ischemic kidneys. This agent was extracted from blood with 70% acetone and had a short pressor effect. The final conclusion was that renin acted enzymatically on a plasma protein to produce the new substance. He related hypertrophy to an increased resistance to blood flow in the small vessels due to the altered condition of the blood. In 1868, George Johnson, 2 reporting studies on nephritis, suggested that hyaline-fibroid alterations in the renal vessels were due to an impure condition of the blood, which was also responsible for left ventricular hypertrophy. F.A. Mahomed, 3 using a primitive sphygmograph for the first time, described high blood pressure in 1872. He also linked left ventricular hypertrophy to hypertension due to nephritis and reported the presence of high blood pressure in patients without renal disease. 4,5 Finally, Riva-Rocci, 6 in 1896, described the first indirect sphygmomanometer to measure arterial pressure in humans, and in 1905, Korotkoff 7 defined the sounds that are named after him.The relationship between pathological alterations in the kidney and the development of systemic arterial hypertension had been postulated for many years. In this sense, Franz Volhard 8 suggested the existence of a circulating vasopressor substance. He classified the hypertensive patients: those with slight vascular damage as reds, and those with important vascular lesions-mostly in the kidney, pale skin, and cerebral damage (malignant hypertension)-as white.On the other hand, by the end of the nineteenth century, Tigerstedt, a Finnish professor of physiology working at the Karolinska Institute, and his assistant Bergman 9 analyzed the effect of renal extracts on arterial pressure. They discovered the presence of a pressor compound in the renal tissue of the rabbit, and based on its origin, they named it renin. The pressor activity could be extracted with glycerin, did not dialyze, and was stable at 56°C and was destroyed by boiling. Moreover, they showed that the renal vein blood increased blood pressure when injected into nephrectomized animals. They also detected the potentiation and protraction of the pressor response to renin in the nephrectomized recipient. They explained that the association between renal disease and cardiac hypertrophy was due to the kidney ...

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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.

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