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Am J Physiol Regul Integr Comp Physiol 278: R1496-R1505, 2000;
0363-6119/00 $5.00
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Vol. 278, Issue 6, R1496-R1505, June 2000

Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo

Yasushi Takahashi1, Christine Roman1, Sylvain Chemtob3, Mary M. Tse4, Emil Lin4, Michael A. Heymann1,2, and Ronald I. Clyman1,2

1 Cardiovascular Research Institute and Departments of 2 Pediatrics and 4 Pharmacy, University of California, San Francisco, San Francisco, California 94143-0544; and 3 Research Center, Hôpital Sainte-Justine, Montreal, Quebec, Canada H3T IC5

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents; however, they also have adverse fetal effects such as constriction of the fetal ductus arteriosus. Recently, selective COX-2 inhibitors have been used in the management of preterm labor in the hope of avoiding fetal complications. However, both COX-1 and -2 are expressed by cells of the ductus arteriosus. We used fetal lambs (0.88 gestation) to assess the ability of selective COX-2 inhibitors celecoxib and NS398 to affect the ductus arteriosus. Both selective COX-2 inhibitors decreased PGE2 and 6ketoPGF1alpha production in vitro; both inhibitors constricted the isolated ductus in vitro. The nonselective COX-1/COX-2 inhibitor indomethacin produced a further reduction in PG release and an additional increase in ductus tension in vitro. We used a prodrug of celecoxib to achieve 1.4 ± 0.6 µg/ml, mean ± standard deviation, of the active drug in vivo. This concentration of celecoxib produced both an increase in pressure gradient and resistance across the ductus; celecoxib also decreased fetal plasma concentrations of PGE2 and 6ketoPGF1alpha . Indomethacin (0.7 ± 0.2 µg/ml) produced a significantly greater fall in ductus blood flow than celecoxib and tended to have a greater effect on ductus resistence in vivo. We conclude that caution should be used when recommending COX-2 inhibitors for use in pregnant women, because COX-2 appears to play a significant role in maintaining patency of the fetal ductus arteriosus.

cyclooxygenase; cyclooxygenase-1; cyclooxygenase-2; prostaglandin E2; prostaglandin I2; indomethacin; celecoxib


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