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Differential Effects of Endothelin A and B Receptor Antagonism on Fetal Growth in Normal and Nitric Oxide-Deficient Rats

Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Northwestern University Medical School, Evanston Northwestern Healthcare, Evanston, Illinois; Evanston Northwestern Healthcare, 2650 Ridge Avenue, Suite 1600 WH, Evanston, IL 60201

Mark G. Neerhof, DO

Richard K. Silver, MD

Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Northwestern University Medical School, Evanston Northwestern Healthcare, Evanston, Illinois

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-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 ET_A 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 ET_A-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 ET_A-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 ET_A plus ET_B antagonism produced fetal and placental growth restriction. In the setting of long-term NOS inhibitio, ET_A-selective antagonism improved fetal and placental growth, whereas antagonism of both ET_A and ET_B receptors did not. Endothelin contributes to NOS inhibition-induced growth restriction acting throughthe ET_A receptor.

Key Words: Intrauterine growth restriction • endothelin receptor antagonism • nitric oxide synthase inhibition • N-nitro-L-arginine methyl ester (L-NAME) • rat

Journal of the Society for Gynecologic Investigation, Vol. 8, No. 1, 18-23 (2001)
DOI: 10.1177/107155760100800103


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