The effects of cervical application of inhibitors of inducible nitric oxide synthase, cyclooxygenase-1, and-cyclooxygenase-2 on delivery in rats

OBJECTIVE: To investigate the effect of cervical application of nonselectiv e and selective inhibitors of nitric oxide synthases-N-nitro-L-arginine met hyl ester, L-N-iminoethyl-lysine, and aminoguanidine-as well as inhibitors of cyclooxygenases-Indomethacin, and nimesulide-on timing of delivery and f etal death and disease in pregnant rats STUDY DESIGN: in a series of experimental protocols, timed-pregnant Sprague -Dawley rats (length of pregnancy, 22 days) were randomly allocated to dail y cervical applications of (1) 0.04 mg (n = 6), 0.4 mg (n = 6), 4 mg (n = 6 ), or 40 mg (n = 6) L-N-iminoethyl-lysine or vehicle (n = 12) on days 19 to 22 of pregnancy; (2) 50 mg aminoguanidine (ri = 6), 150 mg aminoguanidine (n = 6), or vehicle (n = 10) on days 19 to 22 of pregnancy; (3) 3 mg indome thacin (n = 6) or vehicle (n = 6) on days 19 to 22 of pregnancy; (4) 12.5 m g/kg nime-sulide (n = 8), 25 mg/kg nimesulicle (n = 8), 50 mg/kg nimesulide (n = 12), or vehicle (n = 12) on days 19 to 22 of pregnancy and 50 mg/kg n imesulide (n = 23) or vehicle (n = 23) on days 14 to 22 of pregnancy; (5) 5 0 mg/kg nimesulide (n = 10), 50 mg aminoguandine plus 50 mg/kg nimesulide ( n = 10), 50 mg aminoguanidine (n = 10), or vehicle (n = 10) on days 14 to 2 2 of pregnancy. The following variables were evaluated: proportion of anima ls that were delivered on day 23, time to delivery of the first pup (midnig ht on day 22 was considered to be 0 hour), number of stillborn pups, and av erage pup weight of each litter. RESULTS: Unlike L-N-iminoethyl-lysine, aminoguanidine, and Indomethacin, 50 mg/kg nimesulide applied on the cervix dally for 8 days significantly incr eased the proportion of animals that were delivered on day 23 (18 of 23 ver sus 7 of 23; P=.003) and the time to delivery of the first pup by a mean of 10.8 hours (P < .001). Shorter treatment with nimesulide for 4 days increa sed only the time to delivery of the first pup at the 25-mg/kg dosage (P=.0 08), Simultaneous application of aminoguandine and nimesullde significantly (P=.008) prolonged pregnancy to a degree similar to nimesulide alone. The experiment with N-nitro-L-arginine methyl ester was aborted because of seve re maternal side effects. Unlike pups in the L-N-iminoothyl-lysirie, aminog uanidine, and nimesulide groups, significantly more pups in the ndomethacln group died in utero compared with the control group (36.1 % versus 3.1 %; P < .001), and the surviving pups had lower birth weights (P < .001). CONCLUSIONS: In an animal model, nimesulicle was effective in delaying the onset of labor, was well tolerated during pregnancy, and affected cervical ripening directly independent of progesterone withdrawal. Conversely, cervi cal application of nitric oxide synthase and nonselective cyclooxygenase In hibitors do not extend the duration of pregnancy in the dosages studied, an d some are associated with significant adverse effects in the mothers and f etuses.