Influence of ETB receptor antagonism on pregnancy outcome in rats

Objective: To determine the effect of endothelin-B (ETB)-selective receptor antagonism on pregnancy outcome in normal rats. Methods: ETB receptor antagonist (A-192621; 5.0, 10.0, and 15.0 mg/kg per d ay) or vehicle was infused subcutaneously for 7 days by osmotic pump. Infus ion was begun on day 14 of a 22-day gestation. Nonpregnant animals were tre ated similarly, and blood pressure (BP) responses and plasma antagonist lev els were compared to those in pregnant animals. Mean arterial pressure (MAP ) was measure on days 1,4, and 7 of the infusion. Plasma ETB antagonist lev els were measured on day 7 of infusion. On gestational day 21, fetal and pl acental weights and viability were evaluated at hysterotomy. Data were anal yzed by analysis of variance and are presented as mean +/- standard error o f the mean. Results: Fetal and placental weights were significantly lower at doses of 1 0 and 15 mg/kg per day of the ETB antagonist compared with vehicle-treated controls (P<.001); these effects were less severe at 15 than at 10 mg/kg pe r day despite a four-fold higher plasma level of antagonist. Mean arterial pressure was significantly higher at 10 and 15 mg/kg per day compare with c ontrols, but only on infusion day 1 (P<.05). In contrast, MAPs for nonpregn ant rats were elevated throughout the infusion at all doses of the ETB anta gonist (P<.05). Conclusions: ETB receptor antagonism inhibited fetal growth and increased m aternal MAP in a dose-dependent manner although the effect on BP was not su stained in pregnant animals. ETB receptor antagonism is detrimental to preg nancy outcome in the rat. (J Soc Gynecol Investig 2001; 8:239-44) Copyright (C) 2001 by the Society for Gynecologic Investigation.