Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1.
Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA-mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA-mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68+/-0.5 to 10.88+/-1.1 chronotropic units (P<0.001). The increased AT1-AA increased MAP from 99+/-1 to 119+/-2 mm Hg (P<0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA-induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ET(A) receptor antagonist. MAP was 100+/-1 mm Hg in AT1-AA+ET(A) antagonist-treated rats versus 98+/-2 mm Hg in ET(A) antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1-dependent mechanism.
LaMarca
Babbette
B
Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA. bblamarca@physiology.umsmed.edu
Parrish
Marc
M
Ray
Lillian Fournier
LF
Murphy
Sydney R
SR
Roberts
Lyndsay
L
Glover
Porter
P
Wallukat
Gerd
G
Wenzel
Katrin
K
Cockrell
Kathy
K
Martin
James N
JN
Ryan
Michael J
MJ
Dechend
Ralf
R
D000818:Animals; D000077868:Atrasentan; D001323:Autoantibodies / Q000009:adverse effects / Q000276:immunology / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000276:immunology* / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology / Q000378:metabolism*
D001323:Autoantibodies; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044140:Receptor, Angiotensin, Type 1; D000077868:Atrasentan
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