The authors evaluate the expression of endothelin-1 (ET-1) and its receptors in the uterus and placenta during maternal nitric oxide synthase (NOS) inhibition. Timed-pregnant rats received L-NAME (2.5 mg/kg/h) or saline from day 14 to 21 of gestation. Uterine and placental tissues collected on day 21 were assayed for preproET-1, ET A , and ET B mRNA expression; localization and expression of ET-1 and receptor proteins; and receptor activity. NOS inhibition did not affect preproET-1 mRNA expression in the placenta or uterus. ET A expression decreased in the uterine free wall, but no other changes in receptor mRNA expression were observed in the uterus or placenta. ET-1 and receptor proteins were unchanged. Placental ET A and ET B receptor binding decreased. Uterine ET A receptor binding decreased in the placental bed. ET-1, a prominent mediator during NOS inhibition, is not of uterine or placental origin. Reduced receptor binding activity is the primary means by which these tissues regulate their response to ET-1 in the setting of NOS inhibition.
KeywordsEndothelin; nitric oxide; placenta; pregnancy; uterus; rat Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known and is part of a family of peptides that includes 3 isoforms, ET-1, ET-2, and ET-3. The endothelins are produced mainly by endothelial or epithelial cells and act primarily as paracrine mediators. Their predominant effect is vasoconstriction, although they also affect cell proliferation, differentiation, and migration, as well as chemokinesis and apoptosis. 1,2 Endothelin mediates its effects via 2 types of receptors in mammalian species. The ET A receptor, which has a high affinity for ET-1, is located on smooth muscle cells and is responsible principally for the vasoconstrictive and proliferative effects of ET-1. The ET B receptor, which has an equal affinity for all 3 isoforms, is located on endothelial cells and is responsible for a vasodilatory effect mediated primarily by nitric oxide. 3 It also functions as a clearance receptor to remove excess ET from the circulation. 4Nitric oxide is a potent vasodilator that also has a role in the regulation of production of other vasoactive mediators. In the human fetoplacental circulation, nitric oxide contributes to the maintenance of low vascular tone not only by its direct vasodilatory effects but also by attenuation of ET-1 production. 5 Chronic inhibition of nitric oxide synthase (NOS) reduces regional perfusion, which is secondary not only to the lack of nitric oxide production but also