Tempol, a superoxide dismutase-mimetic drug, prevents chronic ischemic renal injury in two-kidney, one-clip hypertensive rats.

Tempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.

Differential responses of mesenteric arterial bed to vasoactive substances in L-NAME-induced preeclampsia: Role of oxidative stress and endothelial dysfunction.

To investigate the systemic and placental oxidant status as well as vascular function in experimental preeclampsia (PE) induced by nitro-L-arginine methyl ester (L-NAME). Fetal parameters and maternal blood pressure, proteinuria, mesenteric arterial bed (MAB) reactivity, and systemic and placental oxidative stress were compared between four groups: pregnant rats receiving L-NAME (60 mg/kg/day, orally) (P + L-NAME) or vehicle (P) from days 13 to 20 of pregnancy and nonpregnant rats receiving L-NAME (NP + L-NAME) or vehicle (NP) during 7 days. L-NAME administration during pregnancy induced some hallmarks of PE, such as hypertension and proteinuria. The P + L-NAME group presented lower weight gain and placental mass as well as reduced number and weight of live fetuses than P group. The vasodilator effect induced by acetylcholine (ACh) and angiotensin II (Ang II) was lower in the perfused MAB from NP + L-NAME and P + L-NAME than in control groups. Otherwise, the nitroglycerine-induced vasodilation and the phenylephrine- and Ang II-induced vasoconstriction were higher in MAB from NP + L-NAME and P + L-NAME groups than in the respective controls. Systemic and placental oxidative damage, assessed by malondialdehyde and carbonyl levels, was increased and activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced in P + L-NAME and NP + L-NAME groups compared to controls. The present data suggest that the oxidative stress and reduced bioavailability of nitric oxide may contribute to attenuation of vasodilator responses to ACh and Ang II, and hyperreactivity to Ang II in the mesentery of preeclamptic rat, which may contribute to the increased peripheral vascular resistance and BP, as well as intrauterine growth restriction in L-NAME-induced PE.

Euterpe oleracea Mart.-Derived Polyphenols Protect Mice from Diet-Induced Obesity and Fatty Liver by Regulating Hepatic Lipogenesis and Cholesterol Excretion.

The aim of this study was to investigate the effect of a polyphenol-rich Açaí seed extract (ASE, 300 mg/kg-1d-1) on adiposity and hepatic steatosis in mice that were fed a high-fat (HF) diet and its underlying mechanisms based on hepatic lipid metabolism and oxidative stress. Four groups were studied: C57BL/6 mice that were fed with standard diet (10% fat, Control), 10% fat + ASE (ASE), 60% fat (HF), and 60% fat + ASE (HF + ASE) for 12 weeks. We evaluated the food intake, body weight gain, serum glucose and lipid profile, hepatic cholesterol and triacyglycerol (TG), hepatic expression of pAMPK, lipogenic proteins (SREBP-1c, pACC, ACC, HMG-CoA reductase) and cholesterol excretion transporters, ABCG5 and ABCG8. We also evaluated the steatosis in liver sections and oxidative stress. ASE reduced body weight gain, food intake, glucose levels, accumulation of cholesterol and TG in the liver, which was associated with a reduction of hepatic steatosis. The increased expressions of SREBP-1c and HMG-CoA reductase and reduced expressions of pAMPK and pACC/ACC in HF group were antagonized by ASE. The ABCG5 and ABCG8 transporters expressions were increased by the extract. The antioxidant effect of ASE was demonstrated in liver of HF mice by restoration of SOD, CAT and GPx activities and reduction of the increased levels of malondialdehyde and protein carbonylation. In conclusion, ASE substantially reduced the obesity and hepatic steatosis induced by HF diet by reducing lipogenesis, increasing cholesterol excretion and improving oxidative stress in the liver, providing a nutritional resource for prevention of obesity-related adiposity and hepatic steatosis.

Grape skin extract protects against programmed changes in the adult rat offspring caused by maternal high-fat diet during lactation.

Maternal overnutrition during suckling period is associated with increased risk of metabolic disorders in the offspring. We aimed to assess the effect of Vitis vinifera L. grape skin extract (ACH09) on cardiovascular and metabolic disorders in adult male offspring of rats fed a high-fat (HF) diet during lactation. Four groups of female rats were fed: control diet (7% fat), ACH09 (7% fat plus 200 mg kg(-1) d(-1) ACH09 orally), HF (24% fat), and HF+ACH09 (24% fat plus 200 mg kg(-1) d(-1) ACH09 orally) during lactation. After weaning, all male offspring were fed a control diet and sacrificed at 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams and ACH09 prevented the hypertension. Increased adiposity, plasma triglyceride, glucose levels and insulin resistance were observed in offspring from both ages, and those changes were reversed by ACH09. Expression of insulin cascade proteins IRS-1, AKT and GLUT4 in the soleus muscle was reduced in the HF group of both ages and increased by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric arteries antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase in the HF group. In conclusion, the treatment of HF-fed dams during lactation with ACH09 provides protection from later-life hypertension, body weight gain, insulin resistance and oxidative stress. The protective effect ACH09 may involve NO synthesis, antioxidant action and activation of insulin-signaling pathways.

L-arginine-nitric oxide pathway and oxidative stress in plasma and platelets of patients with pre-eclampsia.

Pre-eclampsia (PE), a syndrome of pregnancy-induced hypertension, continues to be a leading cause of maternal and fetal morbidity and mortality. The aim of this study was to investigate whether changes in oxidative status are correlated with alterations in the L-arginine-nitric oxide pathway and platelet aggregation in PE. Plasma and platelets from women with PE (n=24) or normotensive pregnancy (NP, n=27) recruited in the third trimester of gestation were used to measure oxidative damage assessed by protein carbonyl content, antioxidant activities of superoxide dismutase (SOD), catalase (CAT) and nitrite levels. Transport of L-[(3)H]-arginine, as well as the activities of the nitric oxide (NO) synthase (eNOS and inducible NO synthase (iNOS)) and platelet aggregation, were also evaluated. Plasma nitrite levels and the activities of SOD and CAT were reduced in PE (5.2±2.7, 3.4±0.8, 0.3±0.4, respectively, P<0.05) compared with NP (8.7±2.3, 6.7±3.1, 1.0±0.5, respectively), whereas protein carbonyl content and L-arginine levels were not significantly different between PE and NP groups. In platelets, L-arginine transport was reduced in PE (19.2±10.5, P<0.05) compared with NP (62.0±31.1), whereas the NOS activity, eNOS and iNOS expression, nitrite levels and platelet aggregation were unaffected. Protein carbonyl content was increased, and CAT activity was reduced in platelets from PE (0.03±0.02, 0.55±0.30, respectively, P<0.05), compared with NP (0.005±0.005, 1.01±0.36, respectively). The data suggest that a systemic impairment of antioxidant defense mechanisms is associated with decreased plasma nitrite levels, which may contribute to hypertension in PE. Oxidative stress may contribute to the reduced influx of L-arginine in platelets. Compensatory mechanisms may contribute to the maintenance of NO production and its modulatory role on platelet function.

Role of renin-angiotensin system and oxidative status on the maternal cardiovascular regulation in spontaneously hypertensive rats.

BACKGROUND: The purpose of this study was to investigate the contribution of renin-angiotensin system (RAS) and oxidative status on the maternal cardiovascular regulation at the end of pregnancy in normotensive and spontaneously hypertensive rats (SHR). METHODS: Blood pressure (BP), mesenteric arterial bed (MAB) reactivity, mesenteric oxidative damage, protein expression, and antioxidant activities were compared between four groups: SHR (SHR-P) and normotensive Wistar controls (W-P) in the 20th day of pregnancy or age-matched nonpregnant rats (SHR-NP and W-NP). RESULTS: BP in W-P and SHR-P was reduced at the end of pregnancy. The vasodilator effects of angiotensin II (Ang II) and angiotensin 1-7 (Ang-(1-7)) were higher in SHR-P than in other groups. Endothelial nitric oxide synthase (eNOS) expression was increased in W-P and SHR-P compared to nonpregnant groups. Angiotensin-converting enzyme (ACE) and AT(1) receptor expressions were increased in SHR-NP compared to normotensive groups and pregnancy reduced their expressions in SHR. No difference was observed in AT(2) receptor expression among the groups. ACE2 expression was higher in hypertensive than normotensive groups. The levels of thiobarbituric acid-reactive substances (TBARS) were reduced in pregnant compared to nonpregnant groups. Superoxide dismutase (SOD) activity was reduced in SHR-P compared to SHR-NP. However, pregnancy increased catalase (CAT) and glutathione peroxidase (GPx) activities in normotensive rats and SHR, respectively. CONCLUSIONS: The results suggest that the reduction of BP to normal values at the end of pregnancy in SHR may be related to an increased NO production and vasorelaxation to Ang II and Ang-(1-7) associated with decreased expression of vascular ACE and AT(1) receptors and oxidative status.

Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension.

BACKGROUND: Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K-1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS: 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS: Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS: The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects.