Cyclooxygenase isoforms and prostaglandin E 2 receptors in the ductus arteriosus

Abstract

Background: A patent ductus arteriosus (DA) promotes fetal development. However, the DA must close immediately after birth. Prostaglandin E 2 (PGE 2) is the most important factor in the regulation of DA tone during fetal development. This eicosanoid is generated through the activities of cyclooxygenases-1 (COX-1) and -2 (COX-2) and mediates its effects by interacting with G protein-coupled E-prostanoid (EP) receptors EP 1, EP 2, EP 3, and EP 4. Objective: This article summarizes the role of COX-1 and -2 and PGE 2 receptors in fetal and neonatal DA tone. Methods: A MEDLINE search was performed of the English-language literature, using the terms ductus arteriosus, PGE 2, and lamb. Results: The DA is less responsive to PGE 2 in neonates than in fetuses. EP receptor subtypes 2 to 4 are expressed equivalently in fetal DA. Stimulation of all 3 receptor subtypes relaxes the DA. In the DA of newborns delivered at full term, EP 2 remains unchanged, EP 4 decreases, and changes in EP 3 expression are equivocal. The DA is less responsive to PGE 2 in newborns than in fetuses. The EP 4 receptor may represent a possible therapeutic target for regulating DA tone in premature newborns. An EP 2 agonist might be useful for maintaining DA patency in neonates and children with certain congenital heart diseases. Conclusions: COX-1 is the predominant isoenzyme in fetal DA, whereas COX-2 is upregulated in the DA immediately following birth. More research on patent DA and the role of preterm labor versus cesarean delivery is needed, as well as comparisons of the efficacy of selective EP-receptor targeting and enzymatic inhibition of COX and PGE 2 synthetases.