Autoantibodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor alpha in pregnant rats.
Circulating factors, such as agonistic autoantibodies to the angiotensin II type 1 (AT1) receptor (AT1-AAs), and inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), are suggested to be important links between placental ischemia and hypertension in preeclamptic women. The purpose of this study was to determine the role of placental ischemia and TNF-alpha in stimulating the AT1-AA and the importance of AT1 receptor activation in mediating hypertension during reductions in uterine perfusion pressure (RUPP) and chronic TNF-alpha excess in pregnant rats. Increased mean arterial pressure in RUPP pregnant rats (122+/-1 mm Hg RUPP versus 101+/-1 mm Hg normal pregnant [NP]; P<0.001) was associated with increased circulating TNF-alpha (RUPP 48+/-13 pg/mL versus N 8+/-1 pg/mL; P<0.05) and AT1-AA (RUPP 15.3+/-1.6 U versus NP 0.6+/-0.3 U; P<0.001). Moreover, TNF-alpha-induced hypertension (97+/-2 to 112+/-2 mm Hg; P<0.05) in pregnant rats was associated with AT1-AA production (TNF-alpha rats 9.2+/-2.3 U versus NP rats 1.0+/-0.8 U; P<0.05). To determine the importance of AT1 receptor activation in mediating hypertension in RUPP- and TNF-alpha-treated rats, we administered an AT1 receptor antagonist to RUPP-, TNF-alpha-treated, and NP rats. Blood pressure responses were attenuated in RUPP rats (Delta 32 mm Hg versus Delta 20 mm Hg, NP; P<0.001), as well as in TNF-alpha-treated rats (Delta 10 mm Hg versus Delta 5 mm Hg, NP; P<0.05). Collectively, these data indicate that placental ischemia and TNF-alpha are important stimuli of AT1-AA, and activation of the AT1 receptor appears to, in part, mediate hypertension produced by RUPP and TNF-alpha in pregnant rats.
LaMarca
Babbette
B
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA. jgranger@physiology.umsmed.edu
Wallukat
Gerd
G
Llinas
Mayte
M
Herse
Florian
F
Dechend
Ralf
R
Granger
Joey P
JP
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D007511:Ischemia / Q000276:immunology* / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D010920:Placenta / Q000276:immunology* / Q000503:physiopathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D014599:Uterus / Q000098:blood supply
D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha; D019808:Losartan