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 arteries us (D A) patency, but the types of functional PGE, receptors (EP) in the developi ng 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 PGE2 receptor subtypes by competition bin ding and immunoblot studies on the DA of fetal (approximate to 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 hou rs old) DA patency in vivo. Fetal pig DA expressed EP2, EP3, and EP4 recept ors equivalently, but not EP1. in neonatal DA, EP1, EP3, and EP4 were undet ectable, whereas EP2 density was similar in fetus and newborn. Prostaglandi n-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE(2) and 11-deoxy PGE(1) (EP2/EP3/EP4 agonist) produced more cAMP in fetus than newb orn, but butaprost (selective EP2 agonist) caused similar cAMP increases in both; EP3 and EP4 ligands (M&B28767 and AH23848B, respectively) affected c AMP production only in fetus, After birth, administration of butaprost alon e was as effective as 11-deoxy PGE, and 16,16-dimethyl PGE, 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 responsive ness of the DA to PGE(2) in newborn. Because EP2 receptors seem to mediate the effects of PGE(2) on the newborn DA, one may propose that a selective E P2 agonist may be preferred as a pharmacological agent to maintain DA paten cy in infants with certain congenital heart diseases.