title: Endothelin receptor antagonist has limited access to the fetal compartment during chronic maternal administration late in pregnancy.
abstract: OBJECTIVE
  Endothelin receptor A (ET(A)) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ET(A) antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups.
  
  
  METHODS
  Timed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14-21 (term=22 days). The antagonists and their respective doses were ABT-546 (20mg/kg/day) and FR139317 (12 mg/kg/day). On day 21, in six rats per group, maternal and fetal plasma ABT-546 was assayed by HPLC. Five additional rats in each group delivered spontaneously and nursed their pups through postpartum day 7. Viability of newborns, oxygen saturation, litter sizes, and pup weights were recorded on postpartum days 1 and 7.
  
  
  RESULTS
  Fetal antagonist levels reached only 2% of maternal levels (p<0.01). There were no significant differences among groups in length of gestation; litter size; survival, number and weight of live pups at birth and at 7 days postpartum; and tissue oxygen saturation.
  
  
  CONCLUSIONS
  Maternal administration of an ET(A) antagonist, at a dose sufficient to ameliorate FGR, has no adverse impact on survival and growth of neonatal rat pups. ET(A) antagonism, delivered maternally, produces sufficiently low fetal plasma levels of antagonist so as not to present a survival threat to the neonatal pups. The beneficial effects of maternally administered ET(A) antagonism on fetal growth occur in the maternal, not the fetal, compartment.
authors.affiliation: Department of Obstetrics & Gynecology, Evanston Northwestern Healthcare, Evanston, IL, USA. Lthaete@northshore.org
authors.forename: Larry G
authors.initials: LG
authors.lastname: Thaete
authors.forename: Saira
authors.initials: S
authors.lastname: Khan
authors.forename: Sylvia
authors.initials: S
authors.lastname: Synowiec
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Joy
authors.initials: J
authors.lastname: Bauch
authors.forename: Mark G
authors.initials: MG
authors.lastname: Neerhof
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D065130:Endothelin A Receptor Antagonists; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000517:prevention & control; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011256:Pregnancy Outcome; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C467892:ABT 546; D001381:Azepines; D065130:Endothelin A Receptor Antagonists; D007211:Indoles; D011759:Pyrrolidines; C079574:FR 139317