Differential effects of endothelin A and B receptor antagonism on fetal growth in normal and nitric oxide-deficient rats

OBJECTIVE: To determine the role of endothelin (ET) in fetal and placental growth in rats with and without long-term nitric oxide synthase (NOS) inhibition. METHODS: Pregnant rats were treated with N-omega-nitro-L-arginine methyl ester (L-NAME) or saline and with one of three ET receptor antagonists or vehicle. The antagonists included A-182086 (no-selective) as well as A-127722 and FR-139317 (both ETA selective). Treatment was begun on day 14 of gestation. On gestational day 21, a hysterotomy was done. Litter size was recorded, and viability and fetal and placental weights were determined. Results were analyzed by analysis of variance or by a Kruskal-Wallis nonparametric analysis. RESULTS: In the absence of L-NAME, fetal and placental weights were not affected by ETA-selective antagonism but were significantly decreased by nonselective receptor antagonism (P < .001 and P < .05 for fetal and placental weights, respectively). Infusion of L-NAME resulted in fetal and placental growth restriction (P < .001). In the setting of L-NAME infusion, fetal and placental weights were increased by ETA-selective antagonists (P < .01) but not by the nonselective antagonist, compared with weights from animals treated with L-NAME alone. There were more fetal deaths with L-NAME treatment (P < .05), but their occurrence was not significantly affected by any of the ET receptor antagonists. CONCLUSIONS: Endothelin-A antagonism alone did not affect fetal or placental growth, whereas combined ETA plus ETB antagonism produced fetal and placental growth restriction. In the setting of long-term NOS inhibition, ETA-selective antagonism improved fetal and placental growth, whereas antagonism of both ETA and ETB receptor did not. Endothelin contributes to NOS inhibition-induced growth restriction acting through the ETA receptor. Copyright (C) 2001 by the Society for Gynecologic Investigation.