Cyclooxygenase- (COX) 2 is the main intrinsic source of prostaglandins (PG) in the ductus arteriosus (DA) of the newborn (NB) but not of the fetus. • 109

Abstract

Non-selective COX inhibitors are the mainstay for treatment of patent DA. COX-1 is the principal source of PG in the systemic circulation of the NB; but inhibition of COX-1 compromises gut and renal function. Selective COX-2 blockers would be effective in closing NB DA provided this enzyme is the principal source of PG in this tissue and intrinsic DA PG contribute more than circulating PG (from COX-1) to ductal tone. We studied the ontogeny of COX-1 and 2 expression in DA, and evaluated its functional significance. DA of NB( 90%, <10% and ≈50% of PG synthesis respectively in the NB DA, pulmonary artery and aorta, arose from COX-2. In contrast to NB, DA of fetal (95% gestation) pig expressed simply COX-1, and was confirmed in sheep and human fetus. Functional significance of predominant COX-2 expression in NB DA was evaluated by measuring contraction of isolated pig DA (bath[O2]=5%) to COX-2 blocker DuP697 (10 μM); DuP697 elicited DA contraction not augmented by non-selective COX blocker ibuprofen (0.1 mM). Finally, administration of DuP697 (5 mg/kg iv, which reduces COX-2 activity but not circulating PGE2 levels) to NB pig (<2½ h old) and fetal sheep (90% gestation) did not affect DA patency (echocardiogram), whereas indomethacin decreased plasma PGE2 levels and closed the DA. Data indicate that the DA of the NB, in contrast to that of the fetus, expresses abundantly more COX-2 than COX-1; but the circulating PGs, mostly from COX-1, exert the major control on DA patency in vivo. Thus COX-2 inhibitors are not an alternative to non-selective COX inhibitors to treat patent DA. On the other hand, because COX-2 is induced in inflamed tissue as well as in fetal membranes during labor, blockers of COX-2 to women during gestation (eg. early tocolysis) may be preferable to non-selective COX inhibitors which may undesirably close fetal DA.