Cyclooxygenase-2 (COX-2) Plays a Significant Role in Regulating the Fetal Ductus Asteriosus In Vivo and In Vitro

Abstract 406 Developmental Pharmacology: Drug Effects on Neonatal Angiogenesis and Vascular Function Platform, Monday, 5/3

Selective COX-2 inhibitors may be safer than nonspecific COX-1/COX-2 inhibitors, like indomethacin, for use during pregnancy if they have fewer effects on the fetus. We recently found that the fetal lamb ductus arteriosus (DA) expresses both COX-1 and COX-2 and that a selective COX-2 inhibitor (NS398) produced ductus constriction in vitro. We studied late-gestation fetal sheep to evaluate the effects of a novel, highly selective COX-2 inhibitor, celecoxib (which has successfully completed Phase III clinical trials) for its effects on the DA in vitro and in vivo. The therapeutic concentrations of celecoxib needed for treatment of osteoarthritis and rheumatoid arthritis are approximately 0.6 µg/ml; celecoxib will also inhibit COX-1, but at 10-fold higher concentrations. Celecoxib produced modest constriction of the fetal DA in vitro (EC₅₀ = 0.17 ± 0.15 µg/ml; maximal tension (at 2 µg/ml) = 20 ± 12% of K⁺-induced tension; n = 9). In comparison, the maximal tension induced by indomethacin (2 µg/ml) was 45 ± 17% of K⁺-induced tension (n = 11). For the in vivo experiments, fetuses were operated on 48 h prior to the study. We continuously infused the COX inhibitors into the fetal superior vena cava for 5 h and measured their effects on 1) pulmonary (PA) and aortic (Ao) blood pressures (P) and 2) DA flow (Q) (using an ultrasonic flow transducer). We then calculated DA resistance: R_ductus = [(P_PA - P_Ao)/Q_duct]. (Table)

Table 1 No caption available

These data suggest that COX-2 has a constitutive role in maintaining fetal DA patency both in vivo and in vitro. At this time, caution should be used when recommending COX-2 inhibitors, like celecoxib, for use in pregnant women.

(Funded in part by Searle Laboratories.)