Human Reproduction, Vol. 14, No. 2, 542-552,
February 1999
© 1999 European Society of Human Reproduction and Embryology
Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat*
1 Research Laboratories of Schering AG, Müllerstr 170–178, 13342 Berlin, 2 Institute of Anatomy, Medical School, University of Essen, Germany, 3 University of Texas Medical Branch, Galveston, USA
Successful pregnancy is strictly dependent on the trophoblast-decidual interaction and on an adequate blood supply to the implantation sites. Nitric oxide (NO) has been shown to play an important role during advanced gestation, although its role during early pregnancy is unclear. The aim of the present study in rats was to evaluate whether NO plays a role during the preimplantation [days 1–4 post coitum (p.c.)] and peri-implantation (days 6–8 p.c.) phases of pregnancy. The rats were treated with the non-specific nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME), and the iNOS inhibitor aminoguanidine in the presence and absence of low-dose antiprogestin, onapristone, and evaluated on days 9 p.c. and 19 p.c., respectively. Before implantation, the treatments alone (L-NAME, aminoguanidine, onapristone) had little effect on pregnancy outcome. Conversely, aminoguanidine plus onapristone treatment completely prevented pregnancy, whereas L-NAME plus onapristone reduced the pregnancy rate to approximately 50%. In addition, both treatments drastically reduced decidualization. Oviductal flushing experiments revealed arrest of embryo development at around the 8-cell stage after aminoguanidine plus onapristone treatment on days 1–4 p.c. Similarly, treatment during the peri-implantation period with L-NAME, aminoguanidine, and onapristone each had only marginal effects on pregnancy. However, a combination of L-NAME and onapristone, and aminoguanidine plus onapristone prevented pregnancy in 71% and 42% of dams, respectively, as determined on day 19 p.c. These treatments also markedly inhibited the decidualization process. This study demonstrates synergistic effects of NOS inhibitors and an antiprogestin in preventing pregnancy. NOS, particularly the cytokine- and progesterone-inducible iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting pregnancy.
Key words: antiprogestin/embryo development/implantation/nitric oxide/progesterone
*This work was presented in part at the 44th and 45th Annual Meetings of the Society for Gynecological Investigation in San Diego, California (March, 1997), and in Atlanta, Georgia, USA (March, 1998), respectively.
4 To whom correspondence should be addressed
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