Developmental changes in prostaglandin E(2) receptor subtypes in porcine ductus arteriosus. Possible contribution in altered responsiveness to prostaglandin E(2).

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 ( approximately 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.