Role of endothelin in mediating soluble fms-like tyrosine kinase 1-induced hypertension in pregnant rats.
Although soluble fms-like tyrosine kinase 1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor, has been implicated in the pathogenesis of hypertension during preeclampsia, the mechanisms whereby enhanced sFlt-1 production leads to hypertension remain unclear. Both sFlt-1 and endothelin 1 productions are elevated in women with preeclampsia and in placental ischemic animal models of preeclampsia; however, the importance of endothelin 1 and sFlt-1 interactions in the control of blood pressure during pregnancy is unknown. The purpose of this study was to determine the role of endothelin 1 in mediating sFlt-1-induced hypertension in pregnant rats. To achieve this goal, sFlt-1 (3.7 microg/kg per day for 6 days) was infused into normal pregnant rats and pregnant rats treated with a selective endothelin type A receptor antagonist, ABT 627 (5 mg/kg per day for 6 days). Plasma concentration of sFlt-1 increased from 735+/-34 pg/mL in normal pregnant rats to 2498+/-645 pg/mL (P<0.05) with infusion of sFlt-1. Arterial pressure increased from 100+/-1 mm Hg in normal pregnant rats to 122+/-3 mm Hg (P<0.05) in sFlt-1-infused rats. Chronic increases in plasma sFlt-1 in normal pregnant rats increased preproendothelin mRNA expression in the renal cortices by approximately 3-fold. In addition, chronic endothelin type A receptor blockade completely abolished the blood pressure response to sFlt-1 in pregnant rats (104+/-3 versus 100+/-1 mm Hg; P<0.05), whereas the endothelin A receptor antagonist had no effect on arterial pressure in NP rats (105+/-2 versus 100+/-1 mm Hg). In conclusion, this study demonstrates that endothelin 1, via endothelin type A receptor activation, plays an important role in mediating the hypertension in response to excess sFlt-1 during pregnancy.
Murphy
Sydney R
SR
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Miss 39216-4505, USA.
LaMarca
B Babbette D
BB
Cockrell
Kathy
K
Granger
Joey P
JP
D000704:Analysis of Variance; D000818:Animals; D000077868:Atrasentan; D001795:Blood Pressure Determination; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000378:metabolism* / Q000503:physiopathology; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood; D011270:Pregnancy, Animal; D011336:Probability; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011257:Pregnancy Proteins; D011759:Pyrrolidines; D012333:RNA, Messenger; C501164:Flt1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040281:Vascular Endothelial Growth Factor Receptor-1; D000077868:Atrasentan