Studies of pulmonary prostaglandin biosynthetic and catabolic enzymes as factors in ductus arteriosus patency and closure. Evidence for a shift in products with gestational age.

The mechanisms underlying patency of the ductus arteriosus in utero and closure shortly after birth should permit optimal regulation of this important physiologic process. Although many studies indicate that vasodilatory prostaglandins contribute to patency, the contribution of the prostaglandin or prostanoid pathways to the closure mechanism has been less evident. The present studies tested a hypothesis which relates products of the cyclooxygenase pathway to modulation of ductal caliber. We began by defining the prostaglandin biosynthetic and catabolic activities of isolated fetal and neonatal lung as a function of gestational age. Inasmuch as biosynthetic enzymes compete for the same substrate, namely PGH2, the competitiveness of the enzymes was explored by varying endoperoxide concentration. The results indicate that the types and quantities of products formed by lung tissue are dependent markedly on both gestational age and substrate concentration. Cyclooxygenase activity was relatively constant through term, but increased sharply in neonatal lung tissue Although PHG2-PGE2 isomerase activity was high throughout gestation, prostacyclin synthase activity was only moderate and age-invariant after 130 d gestation. Lung thromboxane synthase activity increased markedly at 144 d gestation and in the neonatal lung. Catabolic activity (represented by 15-hydroxyprostaglandin dehydrogenase) was relatively high up to 130 d, became sharply minimal at term but increased in activity rapidly in the neonatal lung. These findings support the concept of a "balance" between dilatory and constrictor products of the cyclooxygenase pathway as one determinant of both patency of the ductus arteriosus and closure at birth or after administration of prostaglandin synthetase inhibitors.