Influence of ET(B) receptor antagonism on pregnancy outcome in rats

To determine the effect of endothelin-B (ET(B))-selective receptor antagonism on pregnancy outcome in normal rats.

ET(B) receptor antagonist (A-192621; 5.0, 10.0, and 15.0 mg/kg per day) or vehicle was infused subcutaneously for 7 days by osmotic pump. Infusion was begun on day 14 of a 22-day gestation. Nonpregnant animals were treated similarly, and blood pressure (BP) responses and plasma antagonist levels were compared to those in pregnant animals. Mean arterial pressure (MAP) was measured on days 1, 4, and 7 of the infusion. Plasma ET(B) antagonist levels were measured on day 7 of infusion. On gestational day 21, fetal and placental weights and viability were evaluated at hysterotomy. Data were analyzed by analysis of variance and are presented as mean +/- standard error of the mean.

Fetal and placental weights were significantly lower at doses of 10 and 15 mg/kg per day of the ET(B) antagonist compared with vehicle-treated controls (P <.001); these effects were less severe at 15 than at 10 mg/kg per day despite a fourfold higher plasma level of antagonist. Mean arterial pressure was significantly higher at 10 and 15 mg/kg per day compared with controls, but only on infusion day 1 (P <.05). In contrast, MAPs for nonpregnant rats were elevated throughout the infusion at all doses of the ET(B) antagonist (P <.05).

ET(B) receptor antagonism inhibited fetal growth and increased maternal MAP in a dose-dependent manner, although the effect on BP was not sustained in pregnant animals. ET(B) receptor antagonism is detrimental to pregnancy outcome in the rat.