Preterm birth in rats produced by the synergistic action of a nitric oxide inhibitor (NG-nitro-L-arginine methyl ester) and an antiprogestin (onapristone).

Abstract

The aim of this study was to determine whether inhibition of nitric oxide synthesis would affect the action of an antiprogesterone to provoke preterm labor. Pregnant rats were continuously infused with NG-nitro-L-arginine methyl ester starting on day 16 of gestation. On day 17 of gestation groups of animals were injected subcutaneously with a single dose of either 3 or 30 mg/kg onapristone; animals were monitored for preterm labor and delivery for up to 48 hours. Significant findings included the following results. (1) Combined treatment with NG-nitro-L-arginine methyl ester (50 mg per day) and low-dose onapristone (3 mg/kg) produced preterm labor, > 70% of the fetuses were delivered within 27 hours of treatment, whereas < 5% of the fetuses were delivered in the animals receiving either of these compounds alone. (2) NG-nitro-D-arginine methyl ester (50 mg per day) had no effect. (3) inhibition of nitric oxide by NG-nitro-L-arginine methyl ester also significantly increased the efficacy of high-dose onapristone (30 mg/kg) in preterm labor and delivery. Treatment of pregnant rats with a combination of a nitric oxide inhibitor with onapristone significantly potentiated the ability of the antiprogesterone to induce preterm labor. The interaction of nitric oxide and progesterone may be required to maintain pregnancy.