title: Progesterone supplementation attenuates hypertension and the autoantibody to the angiotensin II type I receptor in response to elevated interleukin-6 during pregnancy.
abstract: OBJECTIVE
  Preeclampsia is a multisystem disorder recognized as hypertension with proteinuria developing >20 weeks' gestation. Preeclampsia is associated with chronic immune activation characterized by increased T and B lymphocytes, cytokines, and antibodies activating the angiotensin II type I receptor (AT1-AA). Hypertension in response to elevated interleukin (IL)-6 during pregnancy occurs with increased renin activity and AT1-AA, and reduced kidney function.
  
  
  METHODS
  We aim to determine whether 17-alpha-hydroxyprogesterone caproate (17-OHPC), progesterone, improved inflammatory pathways during elevated IL-6 in pregnant rats. IL-6 (5 ng/d) was infused via miniosmotic pumps into normal pregnant (NP) rats beginning on day 14 of gestation and 17-OHPC (3.32 mg/kg) was diluted in normal saline and injected on day 18. Blood pressure (mean arterial pressure [MAP]) determination and serum collection were performed on day 19 of gestation.
  
  
  RESULTS
  MAP in NP was 100 ± 3 mm Hg, which increased with IL-6 to 112 ± 4 mm Hg (P < .05). Pregnant rats given 17-OHPC alone had a MAP of 99 ± 3 mm Hg and MAP increased to 103 ± 2 mm Hg in IL-6+17-OHPC. AT1-AA was 1.2 ± 0.5 bpm in NP rats, increased to 17 ± 9 bpm with IL-6 infusion but administration of 17-OHPC significantly blunted AT1-AA to 4 ± 0.8 bpm in NP+IL-6+17-OHPC. Total circulating nitrate/nitrite was significantly decreased and placental Ser(1177)-phosporylated-eNOS/eNOS was lowered with IL-6 infusion. Supplementation of 17-OHPC significantly improved placental Ser(1177)-phosporylated-eNOS/eNOS however, circulating nitrate/nitrite was unchanged with 17-OHPC supplementation.
  
  
  CONCLUSIONS
  This study illustrates that 17-OHPC attenuated hypertension, decreased AT1-AA activity, and improved placental nitric oxide in response to elevated IL-6 during pregnancy and could lend hope to a new potential therapeutic for preeclampsia.
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Lorena M
authors.initials: LM
authors.lastname: Amaral
authors.affiliation: Division of Maternal-Fetal Medicine, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Luissa
authors.initials: L
authors.lastname: Kiprono
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Denise C
authors.initials: DC
authors.lastname: Cornelius
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Carrie
authors.initials: C
authors.lastname: Shoemaker
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS.
authors.forename: Janae
authors.initials: J
authors.lastname: Moseley
authors.affiliation: Experimental and Clinical Research Center and Max Delbrück Center for Molecular Medicine, Helios Clinic, Berlin, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.affiliation: Division of Maternal-Fetal Medicine, University of Mississippi Medical Center, Jackson, MS.
authors.forename: James N
authors.initials: JN
authors.lastname: Martin
authors.affiliation: Experimental and Clinical Research Center and Max Delbrück Center for Molecular Medicine, Helios Clinic, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS. Electronic address: bblamarca@umc.edu.
authors.forename: Babbette
authors.initials: B
authors.lastname: LaMarca
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000008:administration & dosage*; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D015850:Interleukin-6 / Q000008:administration & dosage*; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy / Q000097:blood; D011372:Progestins / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D011372:Progestins; D044140:Receptor, Angiotensin, Type 1; D019326:17-alpha-Hydroxyprogesterone; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: cytokines; hypertension; inflammation; nitric oxide; pregnancy; progesterone; renin angiotensin system