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ET A Receptor Antagonism and Estrogen Replacement Prevent Ang II Hypertension in Menopausal Mice
Author(s) -
Pollow Dennis P.,
RomeroAleshire Melissa J.,
Davies John,
NikolichZugich Janko,
Brooks Heddwen L.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.965.14
Subject(s) - medicine , endocrinology , menopause , estrogen , antagonism , estrogen receptor , receptor , hormone replacement therapy (female to male) , blood pressure , breast cancer , cancer , testosterone (patch)
Cardiovascular disease, including hypertension, increases dramatically in women after menopause, however the efficacy of hormone replacement therapy (HRT) in preventing such diseases has produced controversial results. Endothelin receptor antagonists have been tested as anti‐hypertensive agents in clinical trials and may represent a promising alternative to HRT in postmenopausal women. Therefore, we sought to directly compare the anti‐hypertensive capacity of estrogen replacement (17‐b estradiol pellet, 0.1mg) vs. the ET A receptor antagonist ABT‐627 (5mg/kg, i.p., daily) in the VCD mouse model of menopause (4‐vinylcyclohexene diepoxide, VCD). Ang II (800ng/kg/min, 14d) was infused into VCD‐treated menopausal female mice alone (Meno), or with either concurrent 17‐b estradiol replacement (E2) or ET A receptor antagonism (ET A A). Premenopausal mice received sesame oil vehicle with and without subsequent Ang II (Con, Con/Ang). Ang II infusion induced a significant increase in systolic blood pressure in VCD‐treated menopausal mice compared to Ang II infusion in premenopausal mice (Con Δ2 ± 2 mmHg, Con/Ang Δ15 ± 2* mmHg, Meno/Ang Δ37 ± 6* # mmHg, *P<0.05 vs Con, #P<0.05 vs Con/Ang). Both 17‐b estradiol replacement and ET A receptor antagonism prevented the increased blood pressure response in Ang II‐infused menopausal mice (E2 Δ10 ± 6* mmHg, ET A A Δ14 ± 3* mmHg, *P<0.05 vs Meno/Ang). Splenic and renal T cell profiles were assessed via flow cytometry. 17‐b estradiol replacement increased the percentage of Foxp3 + T regulatory cells in the spleen compared to all other groups (Con 17 ± 1%, Con/Ang 18 ± 1%, Meno/Ang 18 ± 1%, E2 23 ± 1%*, ET A A 18 ± 1%, *P<0.05 vs all groups). However, no changes in T cell profiles occurred with any treatment in the kidney. Quantitative real‐time PCR demonstrated that Ang II‐induced expression of whole kidney collagen type IV in VCD‐treated menopausal mice was significantly reduced by ET A receptor antagonism, but not 17‐b estradiol replacement (ET A A 0.68 ± 0.08 fold*, E2 1.25 ± 0.05 fold*, *P<0.05 vs Meno). These data suggest that ET A receptor antagonism may be an effective treatment strategy for preventing hypertension in postmenopausal women. Support or Funding Information American Heart Association Predoctoral Fellowship (DPP), NIH DK073611 (HLB), Sarver Heart Center (DPP), ARCS Foundation (DPP)