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Chronic Blockade of Nitric Oxide Synthase and Endothelin Receptors During Pregnancy in the Rat: Effect on Reactivity of the Uterine Artery In Vitro

Christoph F. Küng, PhD

Pierre Moreau, PhD

Hiroyuki Takase, MD

Department of Obstetrics and Gynecology, University Hospital Zürich, Zürich, and Cardiovascular Research, Cardiology, Inselspital/University Hospital, Bern, Switzerland

Thomas F. Lüscher, MD

Department of Obstetrics and Gynecology, University Hospital Zürich, Zürich, and Cardiovascular Research, Cardiology, Inselspital/University Hospital, Bern, Switzerland; 100771.1237{at}compuserve.com

Objective: To investigate the effects of chronic blockade of nitric oxide (NO) production and endothelin (ET-1) receptor antagonism on edothelial and vascular smooth muscle function of the uterine artery in vitro obtained from nonpregnant and pregnant rats.

Methods: Pregnant or nonpregnant Wistar rats wee either treated orally for up to 18 days with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME), the ET_A-/ET_B-receptor antagonist bosentan, or both, or they received no treatment (controls). Absolute contractile force as well as endothelium-dependent and -independent vascular reactivity of uterine arteries were determined in vitro. Isometric tension was recorded. ANOVA and the Mann-Whitney U test were used for statistical analysis.

Results: Pregnancy increased obsolute tension (mN/mm) elicited in uterine arteries by ET-1 (P < .01), serotonin (P < .05), norepinephrine (P < .02), and KCl (P < .0001). Chronic treatment with L-NAME or L-NAME plus bosentan, but not with bosentan alone, reduced contractions to KCl in pregnant and nonpregnant rats (P < .005-.0001), while pregnancy-induced enhancement in tension development remained unchanged in all groups (P < .005). After exposure of uterine arteries to L-NAME in vitro, vascular sensitivity to ET-1 was augmented in uterine arteries of pregnant but not of nonpregnant animals (P < .05).

L-NAME-pretreatmetn 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 arteries to sodium nitroprusside (P < .002), which was abolished by chronically administered L-NAME. Bosentan had no influence on vasodilation in vitro.

Conclusion: Neither endothelin-1 nor nitric oxide seem to contribute to the augmented tension to depolarization and receptor-operated stimulation of vascular smooth muscle cells in rat uterine arteries during pregnancy. In addition, pregnancy is associated with increased NO production in uterine arteries, as evidenced by augmented endothelium-dependent relaxations, increased NO release by endothelin-1, and decreased sensitivity to sodium nitroprusside.

Key Words: Acetylcholine • bosentan • endothelium • endothelin-1 • N-nitro-L-arginine methyl ester (L-NAME) • uterine arteries • rats

Journal of the Society for Gynecologic Investigation, Vol. 5, No. 6, 288-295 (1998)
DOI: 10.1177/107155769800500602


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