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(Hypertension. 2009;54:905.)
© 2009 American Heart Association, Inc.

Original Articles

Hypertension in Response to Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) in Pregnant Rats

Role of Endothelin-1

Babbette LaMarca; Marc Parrish; Lillian Fournier Ray; Sydney R. Murphy; Lyndsay Roberts; Porter Glover; Gerd Wallukat; Katrin Wenzel; Kathy Cockrell; James N. Martin, Jr; Michael J. Ryan; Ralf Dechend

From the Departments of Obstetrics & Gynecology (Division of Maternal-Fetal Medicine) and Physiology, Center for Excellence in Cardiovascular-Renal Research (B.L., M.P., L.F.R., S.R.M., L.R., P.G., K.C., J.N.M., M.J.R.), University of Mississippi Medical Center, Jackson; and the HELIOS Clinic (G.W., K.W., R.D.), Charite, Campus-Buch & Max-Delbrueck Center, Berlin, Germany.

Correspondence to Babbette LaMarca, PhD, Departments of Obstetrics & Gynecology and Physiology, Division of Maternal Fetal Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505. E-mail bblamarca{at}physiology.umsmed.edu

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.

Key Words: preeclampsia • hypertension • kidney • placenta • inflammation