Roles of endogenous nitric oxide synthase inhibitors and endothelin-1 for regulating myometrial contractions during gestation in the rat

Abstract

This study investigated the roles of endogenous nitric oxide synthase (NOS) inhibitors and endothelin-1 (ET-1) for regulating myometrial contractions during gestation in the rat. Basal and stimulated cyclic GMP production with L-arginine as a NOS substrate or sodium nitroprusside (SNP) as a NO donor were significantly enhanced at the middle of gestation (14th day), while these were greatly decreased at term (22nd day), suggesting the accelerated NO production and/or up-regulation of guanylate cyclase at the middle of gestation. NOS within the myometrium was mainly Ca2+dependent and partly Ca2+independent and remained unaffected by aminoguanidine as an inhibitor of inducible NOS in non-pregnant and gestational myometrium. NOS activity per se and endothelial NOS (eNOS) protein expression remained unchanged at the middle and term gestation. Neuronal NOS (nNOS) and inducible NOS (iNOS) proteins were undetectable. SNP at a high concentration of 100 μmol/l failed to modify the spontaneous and ET-1-induced rhythmic contractions in non-pregnant and gestational myometrium. Contents of NG-monomethyl-L-arginine (L-NMMA) plus asymmetric NG,NG-dimethyl-L-arginine (ADMA) as endogenous NOS inhibitors and ET-1 within the myometrium were significantly decreased at 14th and 20th days of gestation, whereas these were significantly increased at term gestation (22nd day) and after delivery. There was a significant and positive correlation between endogenous NOS inhibitor content and ET-1. ET-1 within the myometrium was significantly increased with a concomitant decrease in cyclic GMP production after the intraperitoneal application of authentic L-NMMA for 2 weeks, suggesting that the impaired NO production with endogenous NOS inhibitors would result in increased ET-1 content. These results suggest that endogenous NOS inhibitors such as L-NMMA and ADMA play an important role for regulating NO production in rat myometrium. The impaired NO production due to accumulated endogenous NOS inhibitors possibly results in increased ET-1 content within the myometrium, thereby increasing myometrial contractions at term gestation and after delivery. © European Society of Human Reproduction and Embryology 2004; all rights reserved.