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.

Resveratrol attenuates oxidative stress and prevents steatosis and hypertension in obese rats programmed by early weaning.

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

Oxidative stress programming in a rat model of postnatal early overnutrition--role of insulin resistance.

Postnatal early overfeeding (EO) is related to later development of overweight and other metabolic disorders. As oxidative stress is implicated in most human diseases, as obesity and diabetes, we decided to study some parameters related to oxidative stress and insulin signaling in liver from EO animals in adult life. To induce EO, litter size was reduced to three pups per litter (SL: small litter) and groups with normal litter size (NL:10 pups per litter) were used as control. After weaning, rats had free access to standard diet and water. Body weight and food intake were monitored daily and offspring were killed at 180 days-old. Significant differences had P<.05 or less. As expected, SL rats had hyperphagia, higher body weight and higher visceral fat mass at weaning and adulthood. In liver, postnatal EO programmed for lower catalase (-42%), superoxide dismutase (-45%) and glutathione peroxidase (-65%) activities. The evaluation of liver injury in adult SL group showed lower nitrite content (-10%), higher liver and plasma malondialdehyde content (+25% and 1.1-fold increase, respectively). No changes of total protein bound carbonyl or Cu/Zn superoxide dismutase protein expression in liver were detected between the groups. Regarding insulin signaling pathway in liver, SL offspring showed lower IRß (-66%), IRS1 (-50%), phospho-IRS1 (-73%), PI3-K (-30%) and Akt1 (-58%). Indeed, morphological analysis showed that SL rats presented focal areas of inflammatory cell infiltrate and lipid drops in their cytoplasm characterizing a microsteatosis. Thus, we evidenced that postnatal EO can program the oxidative stress in liver, maybe contributing for impairment of the insulin signaling.

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.