Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus

Abstract

To investigate the potential role of endothelin-1 (ET-1) in fetal vasoregulation, we examined in sheep the hemodynamic effects of infusion of big ET-1 (bET-1; precursor of ET-1) on the systemic and pulmonary circulations in chronically catheterized late-gestation fetuses. Thirteen animals [134 +/- 0.5 (SE) days gestation] received systemic infusions of bET-1 (1.5 or 3.0 micrograms/min for 10 min via the superior vena cava), which increased systemic arterial pressure by 5.0 +/- 1.9 (P < 0.01) and 13.9 +/- 1.8 mmHg (P < 0.01), respectively. Pretreatment with 10 mg of phosphoramidon, an ET-1-converting enzyme inhibitor, blocked the hypertensive response to bET-1. Six animals (136 +/- 1.5 days gestation) received intrapulmonary infusion of bET-1 (3.0 micrograms/min for 10 min via the left pulmonary artery), which increased pulmonary arterial pressure by 18.1 +/- 1.5 mmHg (P < 0.01). Three animals (130 +/- 1.5 days gestation) received phosphoramidon (1 mg/min for 10 min via the left pulmonary artery), which had no observed effect on baseline pulmonary vascular tone. We conclude that bET-1 produces systemic and pulmonary hypertension in the late-gestation fetus. Phosphoramidon inhibits bET-1-induced hypertension, suggesting that the fetus possesses ET-1-converting enzyme activity.