Role of Endothelin in Mediating Tumor Necrosis Factor-Induced Hypertension in Pregnant Rats

Abstract

Hypertension during preeclampsia is associated with an increase in plasma levels of tumor necrosis factor (TNF)-α, a cytokine known to contribute to endothelial dysfunction. Recently, our laboratory reported that a 2-fold increase in plasma TNF-α produces hypertension in pregnant rats. Endothelin is also elevated in preeclampsia and endothelin synthesis is enhanced by TNF-α. The purpose of this study was to determine the role of endothlelin in mediating TNF-α–induced hypertension in pregnant rats. To achieve this goal, TNF-α (50 ng/d for 5 days) was infused into control pregnant rats and pregnant rats treated with an endothelin receptor A antagonist, ABT 627 (5 mg/kg per day for 5 days). At day 19 of gestation, arterial pressure was measured and aorta, kidneys, and placentas were harvested. Infusion of TNF-α into pregnant rats increased plasma concentration of TNF-α (13.5±0.8 to 28.0±3.7 pg/mL) and arterial pressure (101±2 to 122±1 mm Hg). The increase in arterial pressure was associated with an increase in preproendothelin mRNA expression in placenta, aorta, and kidneys measured by real-time polymerase chain reaction (PCR). Pretreatment with the endothelin receptor A antagonist completely abolished the blood pressure response to TNF-α in pregnant rats (105±1 versus 97±2 mm Hg). In sharp contrast, the ET A receptor antagonist had no effect on arterial pressure in normal pregnant rats (97±2 versus 101±2 mm Hg). Moreover, chronic infusion of TNF-α had no significant effect on arterial pressure or renal preproendothelin levels in virgin rats. These results suggest an important role for endothelin in mediating TNF-α–induced hypertension in pregnant rats.