Major Role for Cyclooxygenase (COX)-1 in the Control of Ductus Arteriosus(DA) Tone in Fetal Sheep • 116

Non-specific COX inhibitors, such as indomethacin, can cause premature closure of the DA. Currently, selective COX-2 inhibitors are being considered for maternal conditions such as in inflammation and premature labor. It would thus be important to characterize the type of COX present in DA of the fetus and establish its role in DA patency in vitro as well as in vivo. The expression and the functional significance of COX-1 and COX-2 in DA of fetal sheep (125-137 days gestation (≅90%)) delivered by cesarean section was studied. Fetal DA contained both COX-1 and COX-2 proteins (Western blot). COX-1 was found on endothelial and smooth muscle cells, whereas COX-2 was expressed only on endothelial cells (immunohistochemistry). PGE₂ synthesis by endothelialized DA (intact or homogenized) was similarly reduced by the selective COX-1 blocker valerylsalicylate and by COX-2 inhibitors NS-398 and DuP697, suggesting equivalent contribution of COX-1 and COX-2 in the synthesis of PGE₂; but in de-endothelialized DA ≥80% of PGE₂ synthesis arose from COX-1. Selective and non-selective COX blockers caused comparable constriction of isolated DA. However, in contrast to indomethacin (3 mg/kg), DuP697 (5 mg/kg) did not cause DA constriction(echo-Doppler) of exteriorized non-respiring fetal sheep with intact placental circulation, albeit DuP697 reduced DA levels of PGE₂ but not those of plasma. Hence, although the DA of the fetal sheep expresses COX-2 (as well as COX-1) which contributes to intrinsic tone of this vessel, circulating levels of prostaglandins arising from COX-1 predominate in governing ductal patency in vivo. COX-2 inhibitors may thus be preferable to non-selective COX inhibitors in women during pregnancy.