title: Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1.
abstract: 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.
authors.affiliation: 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
authors.forename: Babbette
authors.initials: B
authors.lastname: LaMarca
authors.forename: Marc
authors.initials: M
authors.lastname: Parrish
authors.forename: Lillian Fournier
authors.initials: LF
authors.lastname: Ray
authors.forename: Sydney R
authors.initials: SR
authors.lastname: Murphy
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Roberts
authors.forename: Porter
authors.initials: P
authors.lastname: Glover
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Katrin
authors.initials: K
authors.lastname: Wenzel
authors.forename: Kathy
authors.initials: K
authors.lastname: Cockrell
authors.forename: James N
authors.initials: JN
authors.lastname: Martin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: 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*
chemical_list: D001323:Autoantibodies; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044140:Receptor, Angiotensin, Type 1; D000077868:Atrasentan
references.citation: J Soc Gynecol Investig. 2006 Feb;13(2):79-86
references.pmid: 16443499
references.citation: Hypertension. 2008 Dec;52(6):1161-7
references.pmid: 18981324
references.citation: Am J Reprod Immunol. 1997 Mar;37(3):240-9
references.pmid: 9127646
references.citation: Hypertension. 2008 Apr;51(4):982-8
references.pmid: 18259004
references.citation: Hypertension. 2005 Dec;46(6):1275-9
references.pmid: 16260641
references.citation: Hypertension. 2007 Aug;50(2):269-75
references.pmid: 17576854
references.citation: Hypertension. 2003 Mar;41(3):437-45
references.pmid: 12623940
references.citation: Hypertension. 1998 May;31(5):1065-9
references.pmid: 9576115
references.citation: Circulation. 2000 May 23;101(20):2382-7
references.pmid: 10821814
references.citation: Nat Med. 2008 Aug;14(8):855-62
references.pmid: 18660815
references.citation: Autoimmun Rev. 2005 Jan;4(1):61-5
references.pmid: 15652781
references.citation: Am J Hypertens. 2007 Nov;20(11):1216-21
references.pmid: 17954370
references.citation: Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H923-4
references.pmid: 16467462
references.citation: Hypertension. 2008 Dec;52(6):1168-72
references.pmid: 18852381
references.citation: Circulation. 2003 Apr 1;107(12):1632-9
references.pmid: 12668498
references.citation: J Hypertens. 2008 Aug;26(8):1629-35
references.pmid: 18622242
references.citation: Hypertension. 2005 Apr;45(4):742-6
references.pmid: 15699466
references.citation: N Engl J Med. 2005 Feb 10;352(6):558-69
references.pmid: 15703421
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R29-45
references.pmid: 12069928
references.citation: J Clin Endocrinol Metab. 1997 May;82(5):1582-8
references.pmid: 9141553
references.citation: Hypertension. 2006 Mar;47(3):615-8
references.pmid: 16391174
references.citation: Placenta. 2002 May;23(5):359-72
references.pmid: 12061851
references.citation: Hypertension. 2005 Jul;46(1):82-6
references.pmid: 15928030