The role of oxidative stress in renovascular hypertension.

1. There is mounting evidence that increased oxidative stress and sympathetic nerve activity play important roles in renovascular hypertension. In the present review, we focus on the importance of oxidative stress in two distinct populations of neurons involved with cardiovascular regulation: those of the rostral ventrolateral medulla (RVLM) and those of the paraventricular nucleus of the hypothalamus (PVN) in the maintenance of sympathoexcitation and hypertension in two kidney-one clip (2K1C) hypertensive rats. Furthermore, the role of oxidative stress in the clipped kidney is also discussed. 2. In the studies reviewed in this article, it was found that hypertension and renal sympathoexcitation in 2K1C rats were associated with an increase in Angiotensin II type one receptor (AT(1) ) expression and in oxidative markers within the RVLM, PVN and in the clipped kidneys of 2K1C rats. Furthermore, acute or chronic anti-oxidant treatment decreased blood pressure and sympathetic activity, and improved the baroreflex control of heart rate and renal sympathetic nerve activity in 2K1C rats. Tempol or vitamin C administration in the RVLM, PVN or systemically all reduced blood pressure and renal sympathetic activity. Cardiovascular improvement in response to chronic anti-oxidant treatment was associated with a downregulation of AT(1) receptors, as well as oxidative markers in the central nuclei and clipped kidney. 3. The data discussed in the present review support the idea that an increase in oxidative stress within the RVLM, PVN and in the ischaemic kidney plays a major role in the maintenance of sympathoexcitation and hypertension in 2K1C rats.

Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension.

BACKGROUND: Based on previous data, we hypothesized that an increase of angiotensin II (Ang II)-via the Ang II type 1 (AT-1) receptor-in the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN) of the hypothalamus could activate NAD(P)H oxidase that will produce superoxides resulting in increased sympathetic activity and hypertension. METHODS: The mRNA expression of AT-1 receptors, NAD(P)H oxidase subunits (p47phox and gp91phox), and CuZnSOD were analyzed in the RVLM and PVN of male Wistar rats (Goldblatt hypertension model, 2K-1C). In addition, we administered Tempol 1 and 5 nmol into the RVLM, PVN, or systemically. The mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) were analyzed. RESULTS: The AT-1 mRNA expression and NAD(P)H oxidase subunits was greater in the RVLM and PVN in 2K-1C compared to the control group. Furthermore, the CuZnSOD expression was similar in both groups. Tempol 1 nmol into the RVLM reduced MAP (15 +/- 1%) and RSNA (11 +/- 2%) only in 2K-1C rats. Tempol (5 nmol) in the same region decreased the MAP (12 +/- 4%) and RSNA (20 +/- 7%), respectively, only in 2K-1C. In the PVN, Tempol 5 nmol resulted in a significant fall in the MAP (24 +/- 1%) and in the RSNA (7.9 +/- 2%) only in the 2K-1C. Acute intravenous (IV) infusion of Tempol decreased MAP and RSNA in the 2K-1C but not in the control rats. CONCLUSIONS: The data suggest that the hypertension and sympathoexcitation in 2K-1C rats were associated with an increase in oxidative stress within the RVLM, the PVN and systemically.

Perinatal salt restriction: a new pathway to programming adiposity indices in adult female Wistar rats.

Low birth weight has been associated with increased obesity in adulthood. It has been shown that dietary salt restriction during intrauterine life induces low birth weight and insulin resistance in adult Wistar rats. The present study had a two-fold objective: to evaluate the effects that low salt intake during pregnancy and lactation has on the amount and distribution of adipose tissue; and to determine whether the phenotypic changes in fat mass in this model are associated with alterations in the activity of the renin-angiotensin system. Maternal salt restriction was found to reduce birth weight in male and female offspring. In adulthood, the female offspring of dams fed the low-salt diet presented higher adiposity indices than those seen in the offspring of dams fed a normal-salt diet. This was attributed to the fact that adipose tissue mass (retroperitoneal but not gonadal, mesenteric or inguinal) was greater in those rats than in the offspring of dams fed a normal diet. The adult offspring of dams fed the low-salt diet, compared to those dams fed a normal-salt diet, presented the following: plasma leptin levels higher in males and lower in females; plasma renin activity higher in males but not in females; and no differences in body weight, mean arterial blood pressure or serum angiotensin-converting enzyme activity. Therefore, low salt intake during pregnancy might lead to the programming of obesity in adult female offspring.

Oxidative stress contributes to renovascular hypertension.

BACKGROUND: Oxidative stress is a state in which excess reactive oxygen species (ROS) overwhelm endogenous antioxidant systems. It is known that this state has been involved in the development of hypertension. On the basis of previous data, we hypothesized that overactivity of NAD(P)H oxidase-derived ROS and the lowered activity of CuZnSOD, an endogenous antioxidant within the rostral ventrolateral medulla (RVLM), could contribute to 2K-1C (two-kidney one-clip) hypertension. Moreover, to test the functional significance of whether oxidative stress was involved in the maintenance of sympathetic vasomotor tone and blood pressure in 2K-1C hypertension, we administered Ascorbic Acid (Vit C), an antioxidant, into the RVLM or systemically. METHODS: Experiments were performed in male Wistar rats (6 weeks after renal surgery--Goldblatt hypertension model--2K-1C). The mRNA expression of NAD(P)H oxidase subunits (p47phox and gp91phox) and CuZnSOD were analyzed in the RVLM using real-time PCR technique. The mean arterial blood pressure, heart rate, and renal sympathetic nerve activity were analyzed. Blood samples were collected and measured using thiobarbituric acid-reactive substances (TBARS). RESULTS: The mRNA expression of NAD(P)H oxidase subnits (p47phox and gp91pox) was greater in 2K-1C compared to the control group in the RVLM, and CuZnSOD expression was similar in both groups. In the RVLM, Vit C resulted in a fall in arterial pressure and in the sympathetic activity only in the 2K-1C rats. Thiobarbituric acid-reactive substances (TBARS) were significantly greater in 2K-1C rats and the acute infusion of Vit C significantly decreased arterial pressure and renal sympathetic activity in 2K-1C. CONCLUSIONS: The results support the idea that an increase in oxidative stress within the RVLM and systemically plays a major role in maintaining high arterial blood pressure and sympathetic drive in 2K-1C hypertension.

Sympathetic and renin-angiotensin systems contribute to increased blood pressure in sucrose-fed rats.

BACKGROUND: This study evaluated the effect of chronic sucrose feeding on hemodynamic parameters and renal sympathetic nervous activity. In addition, angiotensin I, II, and 1-7 levels were determined in plasma, heart, kidney, and the epididymal adipose tissue. METHODS: Male Wistar rats were treated for 30 days with 20% sucrose solution (n = 21) or tap water (n = 19) and food ad libitum. Blood pressure, cardiac output, and total peripheral resistance were recorded at the end of the 30-day treatment period. Sympathetic and angiotensinergic systems were evaluated by acute hexamethonium and captopril administration; plasma and tissue (heart, kidney, and epididymal adipose tissue) angiotensins were measured by high-performance liquid chromatography; and angiotensin-converting enzyme activity was determined by continuous fluorescent assay. Plasma renin activity and plasma levels of insulin and leptin were evaluated by radioimmunoassay. RESULTS: Chronic sucrose feeding was associated with increased blood pressure (BP) (129 +/- 1 v 102 +/- 3 mm Hg) and circulating insulin (171%) and leptin (356%) levels when compared with the control group. The sucrose group also showed a 27% higher renal sympathetic nervous activity. The depressor response to hexamethonium was similar in both groups, whereas captopril caused a more pronounced decrease in BP in the sucrose group than in controls (-40 +/- 2 v -11 +/- 2 mm Hg), possibly reflecting the higher plasma renin activity and plasma content of angiotensin II and renal angiotensin II in sucrose rats. CONCLUSIONS: These findings suggest a specific renal renin-angiotensin-sympathetic activation as a potential mechanism for the cardiovascular changes in response to chronic sucrose feeding.

Mecanismos fisiológicos e fisiopatológicos determinantes da atividade vasomotor simpática / Physiological and pathophysiological mechanisms determining the sympathetic vasomotor tone

RESUMO: A atividade vasomotora simpática é um dos determinantes da pressão arterial (PA). Estabelecer quais são os mecanismos geradores dessa atividade é importante para o entendimento de como o sistema cardiovascular opera, tanto em situações fisiológicas como fisiopatológicas. Os principais grupos pré-motores do simpático estão confinados no núcleo paraventricular do hipotálamo (PVN) e região rostoventrolateral bulbar (RVLM). Em diversas situações fisiopatológicas há aumento na atividade vasomotora simpática, em parte conseqüente a maior atividade dos neurônios do PVN e RVLM. Nesta breve revisão, foram discutidos os principais mecanismos de ativação simpática em diferentes modelos experimentais: 1) hipertensão renovascular, 2) hipertensão por baixa massa renal, 3) insuficiência cardíaca, 4) hipertensão por bloqueio do óxido nítrico, 5) obesidade e 6) dimorfismo sexual. As ações de diferentes mediadores sobre o PVN e RVLM podem em longo prazo determinar novos patamares de atividade simpática, modificando os níveis tensionais e dessa forma, contribuir para a progressão da doença cardiovascular.

High- or low-salt diet from weaning to adulthood: effect on body weight, food intake and energy balance in rats.

OBJECTIVE: To get some additional insight on the mechanisms of the effect of salt intake on body weight. DESIGN AND METHODS: Rats were fed a low (LSD), normal (NSD), or high (HSD) salt diet. In a first set, body weight, tail-cuff blood pressure, fasting plasma thyroid-stimulating hormone, triiodothyronine, L-thyroxine, glucose, insulin, and angiotensin II were measured. Angiotensin II content was determined in white and brown adipose tissues. Uncoupling protein 1 expression was measured in brown adipose tissue. In a second set, body weight, food intake, energy balance, and plasma leptin were determined. In a third set of rats, motor activity and body weight were evaluated. RESULTS: Blood pressure increased on HSD. Body weight was similar among groups at weaning, but during adulthood it was lower on HSD and higher on LSD. Food intake, L-thyroxine concentration, uncoupling protein 1 expression and energy expenditure were higher in HSD rats, while non-fasting leptin concentration was lower in these groups compared to NSD and LSD animals. Plasma thyroid-stimulating hormone decreased on both HSD and LSD while plasma glucose and insulin were elevated only on LSD. A decrease in plasma angiotensin II was observed in HSD rats. On LSD, an increase in brown adipose tissue angiotensin II content was associated to decreased uncoupling protein 1 expression and energy expenditure. In this group, a low angiotensin II content in white adipose tissue was also found. Motor activity was not influenced by the dietary salt content. CONCLUSIONS: Chronic alteration in salt intake is associated with changes in body weight, food intake, hormonal profile, and energy expenditure and tissue angiotensin II content.

Perinatal salt restriction: a new pathway to programming insulin resistance and dyslipidemia in adult wistar rats.

Several studies support the hypothesis that chronic diseases in adulthood might be triggered by events that occur during fetal development. This study examined the consequences of perinatal salt intake on blood pressure (BP) and carbohydrate and lipid metabolism in adult offspring of dams on high-salt [HSD; 8% (HSD2) or 4% (HSD1)], normal-salt (NSD; 1.3%), or low-salt (LSD; 0.15% NaCl) diet during pregnancy and lactation. At 12 wk of age, female Wistar rats were matched with adult male rats that were fed NSD. Weekly tail-cuff BP measurements were performed before, during, and after pregnancy. After weaning, the offspring received only NSD and were housed in metabolic cages for 24-h urine collection for sodium and potassium and nitrate and nitrite excretion measurements. At 12 wk of age, intra-arterial mean BP was measured, a euglycemic-hyperinsulinemic clamp was performed, and plasma lipids and nitrate and nitrite concentrations were determined. Tail-cuff BP was higher during pregnancy in HSD2 and HSD1 than in NSD and LSD dams. Mean BP (mm Hg) was also higher in the offspring of HSD2 (110 +/- 5) and HSD1 (107 +/- 5) compared with NSD (100 +/- 2) and LSD (92 +/- 2). Lower glucose uptake and higher plasma cholesterol and triacylglycerols were observed in male offspring from LSD dams (glucose uptake: HSD2 17 +/- 4, HSD1 15 +/- 3, NSD 11 +/- 3, LSD 4 +/- 1 mg . kg(-1) . min(-1); cholesterol: HSD2 62 +/- 6, HSD1 82 +/- 11, NSD 68 +/- 10, LSD 98 +/- 17 mg/dL; triacylglycerols: HSD2 47 +/- 15, HSD1 49 +/- 12, NSD 56 +/- 19, LSD 83 +/- 11 mg/dL). In conclusion, maternal salt intake during pregnancy and lactation has long-term influences on arterial pressure, insulin sensitivity, and plasma lipids of the adult offspring.