Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction
Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction
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DOI：
10.1016/j.placenta.2004.06.003
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发表时间：
2005-02-01
期刊：
影响因子：
3.8
通讯作者：
Neerhof, MG
中科院分区：
文献类型：
--
作者：
Thaete, LG;Kushner, DM;Neerhof, MG
血管活性介质一氧化氮和内皮素都在子宫和胎盘血管系统中产生并具有活性。一氧化氮合酶（NOS）的抑制导致胎儿生长受限。内皮素（ET-1）在NOS抑制的情况下上调。我们的目的是确定ET-1对一氧化氮合酶抑制剂处理的妊娠大鼠子宫和胎盘灌注的影响。从妊娠第14天开始，对定时妊娠Sprague-Dawley大鼠给予L-NAME（2.5 mg/kg/h）、联合和不联合A-127722（10 mg/kg/天）或其相应溶剂，持续1、4或7天。通过微球输注测定各器官的血流量。母亲和胎儿血浆硝酸盐/亚硝酸盐（NOx）测定荧光法。子宫和胎盘灌注显着减少NOS抑制和恢复正常的ETA拮抗作用在第一和第4天的输液，但不是在第7天。母体血浆氮氧化物，但不是胎儿血浆氮氧化物，显着减少NOS抑制单独。ETA拮抗剂与NOS抑制剂相结合显著降低了胎儿血浆NOx。提示ET-1是NOS抑制胎儿生长受限模型中子宫和胎盘血流灌注的重要调节因子。我们的研究结果还表明，母体给予L-NAME不会导致L-NAME通过胎盘的显著转运，但加入ETA拮抗剂会导致胎盘灌注增加，使L-NAME更容易进入胎儿室。
The vasoactive mediators nitric oxide and endothelin are both produced in and active in the uterine and placental vasculature. Inhibition of nitric oxide synthase (NOS) results in fetal growth restriction. Endothelin (ET-1) is upregulated in the setting of NOS inhibition. Our purpose was to determine the impact of ET-1 on uterine and placental perfusion in the pregnant rat treated with a NOS inhibitor. Timed-pregnant Sprague-Dawley rats were treated with L-NAME (2.5 mg/kg/h), with and without A-127722 (10 mg/kg/day), or their respective vehicles, for 1, 4, or 7 days beginning on day 14 of gestation. Blood flow to various organs was determined by microsphere infusion. Maternal and fetal plasma nitrate/nitrite (NOx) was determined by fluorometric assay. Uterine and placental perfusion was significantly decreased by NOS inhibition and was restored to normal by ETA antagonism at I and 4 days of infusion but not at 7 days. Maternal plasma NOx, but not fetal plasma NOx, was significantly decreased by NOS inhibition alone. ETA antagonism in combination with NOS inhibition significantly lowered fetal plasma NOx. These results indicate that ET-1 is an important regulator of uterine and placental perfusion in the NOS inhibition model of fetal growth restriction. Our results also suggest that maternal administration Of L-NAME does not result in significant transport of L-NAME across the placenta, but that addition of an ETA antagonist results in increased placental perfusion, allowing L-NAME greater access to the fetal compartment.