Chronic blockade of nitric oxide-synthase and endothelin receptors during pregnancy in the rat: effect on pregnancy outcome.

OBJECTIVES: To investigate the effects of endothelin-1 (ET-1) receptor antagonism and/or chronic blockade of nitric oxide (NO) production on pregnancy outcome in the rat.

METHODS: Pregnant or nonpregnant Wistar rats were either treated orally for up to 18 days with the NO-synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME), the ETA-/ETB-receptor antagonist bosentan (Roche Basel, Switzerland) or both, or received no treatment (controls). Blood pressure, body weight, and drug intake were measured at regular intervals. Pregnancy outcome and proteinurea were also determined. Analysis of variance and paired Student t test were used for statistical analysis.

RESULTS: Chronic L-NAME treatment increased systolic blood pressure by 69 and 64 mmHg in pregnant and virgin rats respectively (P < .05). Bosentan-blunted, L-NAME-induced hypertension at the beginning (P < .05), but not at the end of the treatment period in all rats examined. N omega-nitro-L-arginine methyl ester-treatment in pregnancy reduced the number of living fetuses at term (P < .05) and caused proteinurea (P < .05). Bosentan tended to reverse the effects of L-NAME on fetus number and proteinurea, but both effects failed to reach statistical significance.

CONCLUSIONS: The effects of chronic, NO-synthase-blockade on blood pressure in gravid rats can be reversed only temporarily by ETA-/ETB-antagonism, suggesting an involvement of endothelin-1 in the early phase of the L-NAME-induced, preeclampsia-like syndrome during pregnancy, although at later stages other mechanisms may come into play.