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. 2009 Oct;54(4):905-9.
doi: 10.1161/HYPERTENSIONAHA.109.137935. Epub 2009 Aug 24.

Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1

Babbette LaMarca  1 , 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
Affiliations

Hypertension in response to autoantibodies to the angiotensin II type I receptor (AT1-AA) in pregnant rats: role of endothelin-1

Babbette LaMarca et al. Hypertension. 2009 Oct.

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.

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Figures

Figure 1
Figure 1
AT1-AA increase significantly in response to chronic infusion, indicated by increased beats per minute (bpm) of cultured rat neonatal cardiomyocyte assay. IgG was isolated from serum collected from NP and AT1-AA infused pregnant rats. The AT1-AA was column purified by epitope binding from the collection of IgG and activity tested by activation of AT1 receptors and increased chronotropic activity of cardiomyocytes in culture.
Figure 2
Figure 2
Changes in mean arterial pressure in normal pregnant (NP) rats in response to AT1-AA infusion. (* P<0.001 vs NP rats). Administration of either an ETA receptor antagonist or an AT1 receptor antagonist, losartan, abolished hypertension in response to AT1-AA in pregnant rats. All data are expressed as mean ±SEM.
Figure 3
Figure 3
Fold increase in tissue preproendothelin mRNA/B-actin determined by real time PCR. P values were <0.0073 in cortices (n=6) and < 0.02 in placenta (n=5). No difference was seen in medullary expression of ET-1 among the groups. AT1 receptor blockade significantly decreased preproendothelin in response to AT1-AA induced hypertension in renal cortices (n=6), and placenta (n=6).
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