Role of prostaglandin E₂ and its receptors in the process of ductus arteriosus maturation and functional closure in the rabbit

1. Patent ductus arteriosus (PDA) is a common congenital heart defect in premature infants. The present study was designed to determine the role of the prostaglandin (PG) E₂ pathway in the process of ductus arteriosus (DA) maturation and functional closure. 2. Changes in PGE₂ pathway-related enzymes and receptors in DA in preterm and term rabbits were examined at both the mRNA and protein levels. In addition, responses of DA rings to Po₂ and PGE₂ were determined. 3. Circulating PGE ₂ levels remained high until 2 h after birth. High levels of the EP₄ receptor were found in preterm DA. These tissues were sensitive to PGE₂, which caused vessel dilation, but were insensitive to increased Po₂. In contrast, DA tissues from term rabbits exhibited an immediate contractile response to increased Po₂ and PGE₂ treatment resulted in vasoconstriction, which was associated with increased EP₃ and decreased EP₄ receptor expression in term DA. 4. In conclusion, the preterm PDA is maintained by high levels of PGE₂, which mainly binds to the EP₄ receptor under conditions of hypoxia. In contrast, in the term DA, in which levels of the EP₃ receptor are higher than in preterm DA, exposure to PGE₂ resulted in vasoconstriction under normoxic conditions. These findings suggest that blocking the EP₄ receptor may represent a more selective treatment for the preterm PDA, whereas activating the EP₃ receptor may be more suitable for the treatment of the term PDA.