Role of reactive oxygen species in hypertension produced by reduced uterine perfusion in pregnant rats.

BACKGROUND: Although recent studies indicate preeclampsia (PE) is associated with increased oxidative stress, the role of reactive oxygen species in the hypertension associated with PE remains unclear. We sought to test the hypothesis that placental ischemia increases oxidative stress which in turn, contributes to hypertension. METHODS: Reduction in uterine perfusion pressure (RUPP) was induced by placing silver clips on the abdominal aorta and the ovarian arteries on day 14 of pregnancy. On day 20 of pregnancy, mean arterial pressure (MAP) was measured and oxidative stress was assessed in renal and placental tissues whereas systemic administration of tempol, a superoxide dismutase (SOD) mimetic, was used to evaluate the contribution of reactive oxygen species on RUPP-induced hypertension. RESULTS: MAP (120 +/- 2 mm Hg vs.106 +/- 3 mm Hg), placental levels of 8-isoprostane (1.9 +/- 0.4 ng/g tissue vs. 0.8 +/- 0.1 ng/g tissue), and malondialdehyde (MDA) (6.9 +/- 0.6 micromol/g tissue vs. 3.9 +/- 0.4 micromol/g tissue) were increased, whereas renal cortical SOD activity was decreased in RUPP rats (1.2 +/- 0.1 units/mg protein vs. 1.6 +/- 0.1 units/mg protein) at day 20 of gestation (20 dG) compared to controls. Chronic treatment with tempol attenuated the hypertension (RUPP + tempol 112 +/- 2 mm Hg vs. RUPP, 120 +/- 2 mm Hg) associated with RUPP, whereas tempol had no effect on MAP (NP, 106 +/- 3 vs. NP + tempol, 108 +/- 2) in control rats. CONCLUSION: The results of this study indicate that placental ischemia decreases innate antioxidant activity resulting in elevated oxidative stress which appears to play a role in mediating hypertension associated with chronic RUPP in pregnant rats.

Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats.

We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31-50; RNASTAAS2, position 21-40; RNASTAAS3, position 143-162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 microg/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 +/- 6 mmHg (after SCR2) to 106 +/- 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, -31 mmHg; RNASTAAS3, -16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (-15 to -41 mmHg) was comparable to the effects of captopril (100 mg x kg(-1) x day(-1) for 3 days: -32 mmHg) and an AT(1) receptor antagonist (L-158809, 1.5 mg x kg(-1) x day(-1) for 3 days: -36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR.