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Endothelin-1 (ET-1) is synthesized within the wall of the ductus arteriosus and is a potent constrictor of the ductus arteriosus in vitro. However, the role of endogenous ET-1 in the closure of the ductus arteriosus at birth remains unclear. The vasoconstricting effects of ET-1 are mediated through activation of the ETA receptor. Therefore, we studied the effects of a selective ETA receptor antagonist (PD 156707), or its vehicle, on ductus arteriosus closure in 13 late-gestation fetal lambs during the first 5 hours after birth. We also studied the effects of ETA receptor blockade on ductus arteriosus constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY83583 (a soluble guanylate cyclase inhibitor), in vitro (n=9). In vehicle-treated lambsin vivo, the ductus arteriosus constricted during the 5 hour study period after birth: ductus arteriosus resistance increased (from 0.007±0.01 to 3.406±4.15 mmHg/ml per min/kg,P<0.05); the pressure gradient across the ductus arteriosus increased (from 1.4±2.1 to 25.2±9.4 mmHg, P<0.05); and ductus arteriosus blood flow decreased (from 193.5±48.0 to 19.3±14.3 ml/kg per min, P<0.05). In vitro, the ductus arteriosus was constricted by exposure to 30% oxygen (23%±14 net active tension (NAT), P<0.05), indomethacin(5×10-6M) (22%±5 NAT, P<0.05), LY83583(10-5M) (24%±10 NAT, P<0.05), and ET-1(10-7M) (19±4% NAT, P<0.05). Although PD 156707 blocked both the in vivo and in vitro effects of exogenous ET-1, it had no effect on postnatal ductus constriction nor onin vitro ductus contractile responses to oxygen, indomethacin, or LY83583. This study suggests that endogenous ET-1 does not play an important role in closure of the ductus arteriosus at birth.

Endothelin Receptor Blockade Does Not Alter Closure of the Ductus Arteriosus• 332