Nitric oxide/cyclic guanosine 3,5 monophosphate response to cyclooxygenase (COX)-2 inhibition in a rabbit model of RU486-induced preterm birth

Abstract

RESPONSE TO CYCLOOXYGENASE (COX)-2 INHIBITION IN A RABBIT MODEL OF RU486-INDUCED PRETERM BIRTH DAVID GORENBERG, KAY BEHARRY, AAMIR AKMAL, KENJI NISHIHARA, JOSHUA WALTZMAN, TAMEROU ASRAT, University of California, Irvine, Obstetrics and Gynecology, Orange, CA University of California, Irvine, Pediatrics, Orange, CA Long Beach Memorial Medical Center, Obstetrics and Gynecology, Long Beach, CA OBJECTIVE: Nitric oxide (NO) may maintain uterine quiescence during pregnancy. The onset of labor is associated with an increase in cyclooxygenase (COX)-2 activity. We investigated whether COX-2 inhibition in a rabbit model of RU486-induced preterm pregnancy loss would influence the NO/cGMP signaling mechanisms in the uterus and cervix. STUDY DESIGN: 3 groups of pregnant rabbits (n = 8/group) were induced with a single 50-mg IM dose of RU486 at 22 days’ gestation. 60, 90, or 120 mg/ kg/day of celecoxib (Cel) or vehicle (Veh) was administered orally and daily until delivery. Gestational age-matched controls (n = 6/group) were induced with 100% ethanol IM and were administered equivalent oral doses of Cel or Veh. Serum levels of NOmetabolites, NOx and cGMP, were determined prior to induction and following delivery. Uterine and cervical levels were determined at delivery. RESULTS: A prolongation of gestation was seen among rabbits induced with RU486 that received celecoxib vs vehicle (78.9 vs 57.4 hrs). Uterine NO levels were elevated in all ETOH groups compared to their age-matched RU486 groups (P < 0.05 to P < 0.0001). No differences in cervical NO levels were noted. In contrast, cervical cGMP levels were elevated in all ETOH groups compared to the RU486 groups (P < 0.05), with no change in uterine cGMP levels. Treatment with Cel induced greater serum NO production (mmol/L) with significance achieved in the Cel 120 group (368.3 ± 59.3) vs Veh (117.0 ± 22.3, P < 0.01). This response was abolished in the RU486-treated group receiving a similar dose of 120 mg/kg/day (53.2 ± 6.2, P < 0.0001). Cel treatment had no significant effect on serum cGMP levels. CONCLUSION: These data demonstrate an association between COX-2 and NO/cGMP signaling system. COX-2 inhibition appears to induce NO synthesis, which may further promote uterine quiescence. This effect is abolished with progesterone antagonism, suggesting an interaction between COX-2 and progesterone receptor.