Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2005-07, Vol.46 (1), p.82-86
• Main Authors: LAMARCA, B. Babbette D, COCKRELL, Kathy, SULLIVAN, Elizabeth, BENNETT, William, GRANGER, Joey P
• Format: Article
• Language: English
• Subjects: Animals; Aorta - metabolism; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure - drug effects; Cardiology. Vascular system; Endothelin A Receptor Antagonists; Endothelin-1 - genetics; Endothelins - blood; Endothelins - metabolism; Experimental diseases; Female; Hypertension - chemically induced; Hypertension - etiology; Kidney - metabolism; Medical sciences; Placenta - metabolism; Pregnancy; Pregnancy Complications, Cardiovascular - chemically induced; Pregnancy Complications, Cardiovascular - etiology; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000169152.59854.36

Hypertension during preeclampsia is associated with an increase in plasma levels of tumor necrosis factor (TNF)-alpha, a cytokine known to contribute to endothelial dysfunction. Recently, our laboratory reported that a 2-fold increase in plasma TNF-alpha produces hypertension in pregnant rats. Endothelin is also elevated in preeclampsia and endothelin synthesis is enhanced by TNF-alpha. The purpose of this study was to determine the role of endothlelin in mediating TNF-alpha-induced hypertension in pregnant rats. To achieve this goal, TNF-alpha (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-alpha into pregnant rats increased plasma concentration of TNF-alpha (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-alpha in pregnant rats (105+/-1 versus 97+/-2 mm Hg). In sharp contrast, the ETA receptor antagonist had no effect on arterial pressure in normal pregnant rats (97+/-2 versus 101+/-2 mm Hg). Moreover, chronic infusion of TNF-alpha 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-alpha-induced hypertension in pregnant rats.