Synergistic role of nitric oxide and progesterone during the establishmentof pregnancy in the rat

Successful pregnancy is strictly dependent on the trophoblast-decidual inte raction and on an adequate blood supply to the implantation sites. Nitric o xide (NO) has been shown to play an important role during advanced gestatio n, although its role during early pregnancy is unclear. The aim of the pres ent study in rats was to evaluate whether NO plays a role during the preimp lantation [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 N-G-nitro-L-arginine methyl ester (L-NAME), and the iNOS inhibitor aminoguanidine in the presence and absence of low-do se antiprogestin, onapristone, and evaluated on days 9 p,c. and 19 p,c,, re spectively. Before implantation, the treatments alone (L-NAME, aminoguanidi ne, onapristone) had little effect on pregnancy outcome. Conversely, aminog uanidine plus onapristone treatment completely prevented pregnancy, whereas L-NAME plus onapristone reduced the pregnancy rate to approximately 50%, I n addition, both treatments drastically reduced decidualization, Oviductal pushing experiments revealed arrest of embryo development at around the 8-c ell stage after aminoguanidine plus onapristone treatment on days 1-4 p,c. Similarly treatment during the peri-implantation period with L-NAME, aminog uanidine, and onapristone each had only marginal effects on pregnancy. Howe ver, a combination of L-NAME and onapristone, and aminoguanidine plus onapr istone prevented pregnancy in 71% and 42% of darns, respectively, as determ ined on day 19 p,c. These treatments also markedly inhibited the decidualiz ation process. This study demonstrates synergistic effects of NOS inhibitor s and an antiprogestin in preventing pregnancy. NOS, particularly the cytok ine- and progesterone-inducible iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting pregnancy.