Developmental Changes in Prostaglandin E 2 Receptor Subtypes in Porcine Ductus Arteriosus

Abstract

Background —Prostaglandin E 2 (PGE 2 ) is important in ductus arteriosus (DA) patency, but the types of functional PGE 2 receptors (EP) in the developing DA are not known. We postulated that age-dependent alterations in EP and/or their subtypes may possibly contribute to the reduced responsiveness of the newborn DA to PGE 2 . Methods and Results —We determined PGE 2 receptor subtypes by competition binding and immunoblot studies on the DA of fetal (≈75% and 90% gestation) and newborn (<45 minutes old) pigs. We studied the effects of EP receptor stimulation on cAMP signaling in vitro and on term newborn (<3 hours old) DA patency in vivo. Fetal pig DA expressed EP 2 , EP 3 , and EP 4 receptors equivalently, but not EP 1 . In neonatal DA, EP 1 , EP 3 , and EP 4 were undetectable, whereas EP 2 density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE 2 and 11-deoxy PGE 1 (EP 2 /EP 3 /EP 4 agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP 2 agonist) caused similar cAMP increases in both; EP 3 and EP 4 ligands (M&B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE 1 and 16,16-dimethyl PGE 2 in dilating DA in vivo. Conclusions —The data reveal fewer PGE 2 receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE 2 in newborn. Because EP 2 receptors seem to mediate the effects of PGE 2 on the newborn DA, one may propose that a selective EP 2 agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.