Endothelin receptor antagonist has limited access to the fetal compartment during chronic maternal administration late in pregnancy

Abstract

AimsEndothelin receptor A (ETA) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ETA antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups. Main methodsTimed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14–21 (term=22days). The antagonists and their respective doses were ABT-546 (20mg/kg/day) and FR139317 (12mg/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. Key findingsFetal 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 7days postpartum; and tissue oxygen saturation. SignificanceMaternal administration of an ETA antagonist, at a dose sufficient to ameliorate FGR, has no adverse impact on survival and growth of neonatal rat pups. ETA 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 ETA antagonism on fetal growth occur in the maternal, not the fetal, compartment.