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 Nω-nitro-L-arginine methyl ester (L-NAME) or saline and with one of three ET receptor antagonists or vehicle. The antagonists included A-182086 (nonselective) 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 the 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 inhibitio, ETA-selective antagonism improved fetal and placental growth, whereas antagonism of both ETA and ETB receptors did not. Endothelin contributes to NOS inhibition-induced growth restriction acting throughthe ETA receptor.
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