CHRONIC BLOCKADE OF NITRIC-OXIDE SYNTHASE AND ENDOTHELIN RECEPTORS DURING PREGNANCY IN THE RAT - EFFECT ON REACTIVITY OF THE UTERINE ARTERYIN-VITRO

OBJECTIVE: To investigate the effects of chronic blockade of nitric ox ide (NO) production and endothelin (ET-1) receptor antagonism on endot helial and vascular smooth muscle function of the uterine artery in vi tro obtained from nonpregnant and pregnant rats. METHODS: Pregnant or nonpregnant Wistar rats were either treated orally for up to 18 days w ith the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester (L -NAME), the ETA-/ETB-receptor antagonist bosentan, or both, or they re ceived no treatment (controls). Absolute contractile force as well as endothelium-dependent and -independent vascular reactivity of uterine arteries were determined ill vitro. Isometric tension was recorded. AN OVA and the Mann-Whitney U test were used for statistical analysis. RE SULTS: Pregnancy increased absolute tension (nN/mm) elicited in uterin e arteries by ET-1 (P < .01), serotonin (P < .05), norepinephrine (P < .02), and KCl (P < .0001), Chronic treatment with L-NAME or L-NAME pl us bosentan, but not with bosentan alone, reduced contractions to KCl in pregnant and nonpregnant mts (P < .005-.0001), while pregnancy-indu ced enhancement in tension development remained unchanged in all group s (P < .005). After exposure of uterine arteries to L-NAME in vitro, v ascular sensitivity to ET-1 was augmented in uterine arteries of pregn ant brit not of nonpregnant animals (P < .05). L-NAME-pretreatment did not influence the pregnancy-induced increase of vascular sensitivity to acetylcholine but reduced maximal relaxation in nonpregnant animals (P < .05). In addition, pregnancy diminished sensitivity of uterine a rteries to sodium nitroprusside (P < .002), which was abolished by chr onically administered L-NAME. Bosentan had no influence on vasodilatio n in vitro. CONCLUSION: Neither endothelin-1 nor nitric oxide seem to contribute to the augmented tension to depolarization and receptor-ope rated stimulation of vascular smooth muscle cells in rat uterine arter ies during pregnancy. In addition, pregnancy is associated with increa sed NO production in uterine arteries, as evidenced by augmented endot helium-dependent relaxations, increased NO release by endothelin-1, an d decreased sensitivity to sodium nitroprusside. Copyright (C) 1998 by the Society for Gynecologic Investigation.