Developmental changes in prostaglandin E2 receptor subtypes in porcine ductus arteriosus: Possible contribution in altered responsiveness to prostaglandin E2

Abstract

Background - Prostaglandin E2 (PGE2) is important in ductus arteriosus (DA) patency, but the types of functional PGE2 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 PGE2. Methods and Results - We determined PGE2 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 EP2, EP3, and EP4 receptors equivalently, but not EP1. In neonatal DA, EP1, EP3, and EP4 were undetectable, whereas EP2 density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE2 and 11-deoxy PGE1 (EP2/EP3/EP4 agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP2 agonist) caused similar cAMP increases in both; EP3 and EP4 ligands (M and B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE1 and 16,16-dimethyl PGE2 in dilating DA in vivo. Conclusions - The data reveal fewer PGE2 receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE2 in newborn. Because EP2 receptors seem to mediate the effects of PGE2 on the newborn DA, one may propose that a selective EP2 agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.