Interaction of nitric oxide (no) and progesterone on preterm delivery in rats. 5

OBJECTIVE: To investigate the effects of (1) the NOS inhibitor L-NAME, and (2) the NO donor nitroglycerin (NG) alone and in combination with the progesterone agonist (R5020, promegestone) on preterm labor induced by antiprogestin {onapristone, ZK) in rats. STUDY DESIGN: Starting on day 17, pregnant rats were treated as follows: Group 1} ZK (3 mg single s.c. injection) or L-NAME (50 mg/day, s.c. infusion) alone or in combination. Group 2) ZK (3 mg single s.c. injection) with or without NG (4 mg/day in s.c. pellets) with or without R5020 (0.1 to 2 mg/day s.c.). Animals were sacrificed at different hours post-treatment (group 1) or on day 21 (group 2). Fetal birth rate was obtained by counting remaining fetuses and placenta attachment sites. RESULTS: Onapristone alone consistently induced preterm birth within 72 hours. L-NAME alone had no effect on parturition, but increased the efficacy of onapristone by shortening the induction-delivery intervals (Fig. A). NG alone had no effect on onapristone-induced preterm birth. On the other hand, R5020 attenuated (0.1 to 1 mg/day) or completely inhibited (2 rng/day) onapristone-induced preterm labor. The inhibitory effect of R5020 was increased with an additional NG treatment (Fig. B). CONCLUSIONS: This study confirms that inhibition of NO production increases the efficacy of antiprogestin to induce labor and delivery. On the other hand, synergistic effects of NG and R5020 are demonstrated. These results support the important role of both progesterone and NO in the maintenance of pregnancy. NO donors in combination with progesterone may provide an effective strategy for the treatment of preterm labor.