Hypertension in response to chronic reductions in uterine perfusion in pregnant rats: effect of tumor necrosis factor-alpha blockade.
Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-alpha (TNF-alpha). This study was designed to determine the role of endogenous TNF-alpha in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-alpha-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102+/-1 mm Hg in normal pregnant (NP) rats to 134+/-3 mm Hg (P<0.05) in RUPP rats. Serum TNF-alpha increased to 40+/-7.6 pg/mL in RUPP rats (n=24) versus 14.8+/-3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF-alpha in RUPP rats (n=20) to 17.2+/-3 pg/mL and mean arterial pressure to 118+/-2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-alpha blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60+/-0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30+/-0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6+/-2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-alpha is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.
LaMarca
Babbette
B
Department of Physiology and Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
Speed
Josh
J
Fournier
Lillian
L
Babcock
Sara A
SA
Berry
Hunter
H
Cockrell
Kathy
K
Granger
Joey P
JP
D000818:Animals; D001724:Birth Weight; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000378:metabolism* / Q000503:physiopathology; D007074:Immunoglobulin G / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000502:physiology; D009929:Organ Size; D010920:Placenta / Q000033:anatomy & histology / Q000502:physiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood* / Q000235:genetics; D014471:Umbilical Veins / Q000166:cytology; D014599:Uterus / Q000098:blood supply* / Q000502:physiology
D019332:Endothelin-1; D007074:Immunoglobulin G; D007155:Immunologic Factors; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept