title: Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guinea pigs.
abstract: BACKGROUND
  The opposing renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are upregulated in pregnancy and localize in the utero-placental unit. To test their participation as counter-regulators, circulating angiotensin II (AII) was exogenously elevated and the bradykinin B2 receptor (B2R) was antagonized in pregnant guinea-pigs. We hypothesized that disrupting the RAS/KKS balance during the period of maximal trophoblast invasion and placental development would provoke increased blood pressure, defective trophoblast invasion and a preeclampsia-like syndrome.
  
  
  METHODS
  Pregnant guinea-pigs received subcutaneous infusions of AII (200 μg/kg/day), the B2R antagonist Bradyzide (BDZ; 62.5 microg/kg/day), or both (AII + BDZ) from gestational day 20 to 34. Non-pregnant cycling animals were included in a control group (C NP) or received AII + BDZ (AII + BDZ NP) during 14 days. Systolic blood pressure was determined during cycle in C NP, and on the last day of infusion, and 6 and 26 days thereafter in the remaining groups. Twenty six days after the infusions blood and urine were extracted, fetuses, placentas and kidneys were weighed, and trophoblast invasion of spiral arteries was defined in the utero-placental units by immunocytochemistry.
  
  
  RESULTS
  Systolic blood pressure transiently rose in a subgroup of the pregnant females while receiving AII + BDZ infusion, but not in AII + BDZ NP. Plasma creatinine was higher in AII- and BDZ-treated dams, but no proteinuria or hyperuricemia were observed. Kidney weight increased in AII + BDZ-treated pregnant and non-pregnant females. Aborted and dead fetuses were increased in dams that received AII and AII + BDZ. The fetal/placental weight ratio was reduced in litters of AII + BDZ-treated mothers. All groups that received interventions during pregnancy showed reduced replacement of endothelial cells by extravillous trophoblasts in lateral and myometrial spiral arteries.
  
  
  CONCLUSIONS
  The acute effects on fetal viability, and the persistently impaired renal/placental sufficiency and incomplete arterial remodeling implicate the RAS and KKS in the adaptations in pregnancy. The results partially confirm our hypothesis, as a preeclampsia-like syndrome was not induced. We demonstrate the feasibility of characterizing systemic and local modifications in pregnant guinea-pig, supporting its use to study normal placentation and related disorders.
authors.affiliation: Centro de Investigaciones Médicas, Escuela de Medicina, Pontificia Universidad Católica, Santiago, Chile. gvaldes@med.puc.cl.
authors.forename: Gloria
authors.initials: G
authors.lastname: Valdés
authors.forename: Daniela
authors.initials: D
authors.lastname: Schneider
authors.forename: Jenny
authors.initials: J
authors.lastname: Corthorn
authors.forename: Rita
authors.initials: R
authors.lastname: Ortíz
authors.forename: Stephanie
authors.initials: S
authors.lastname: Acuña
authors.forename: Oslando
authors.initials: O
authors.lastname: Padilla
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D006168:Guinea Pigs; D055104:Infusions, Subcutaneous; D016234:Kallikrein-Kinin System / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D010929:Placentation / Q000187:drug effects; D011225:Pre-Eclampsia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D011247:Pregnancy; D011255:Pregnancy Maintenance / Q000187:drug effects; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology; D043782:Receptor, Bradykinin B2 / Q000737:chemistry / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000494:pharmacology; D014599:Uterus / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D011759:Pyrrolidines; D043782:Receptor, Bradykinin B2; D013882:Thiosemicarbazones; C406475:bradyzide; D000804:Angiotensin II