Role of endothelin in mediating tumor necrosis factor-induced hypertension in pregnant rats.
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.
LaMarca
B Babbette D
BB
Department of Physiology, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
Cockrell
Kathy
K
Sullivan
Elizabeth
E
Bennett
William
W
Granger
Joey P
JP
D000818:Animals; D001011:Aorta / Q000378:metabolism; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D016232:Endothelins / Q000097:blood / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000209:etiology*; D007668:Kidney / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000139:chemically induced / Q000209:etiology*; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011759:Pyrrolidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077868:Atrasentan