Impact of endothelin A receptor antagonist selectivity in chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.

Impact of endothelin A receptor antagonist selectivity in chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.
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DOI:
10.3109/10641950902777739
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发表时间:
2010
影响因子:
1.5
通讯作者:
Thaete LG
Thaete LG
中科院分区:
医学4区
文献类型:
--
作者:
Neerhof MG;Synowiec S;Khan S;Thaete LG

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内皮素受体 A (ETA) 拮抗作用在第 1 天和第 4 天改善胎儿和胎盘的生长以及胎盘灌注,但在 7 天输注一氧化氮合酶 (NOS) 抑制剂的第 7 天没有改善。我们的目的是评估 ETA 拮抗剂选择性程度对慢性 NOS 抑制第 7 天子宫胎盘灌注和胎儿生长的意义。从妊娠第 14 天开始,用 NOS 抑制剂硝基-L-精氨酸甲酯(L-NAME,2.5 mg/kg/h)联合或不联合使用以下一种 ETA 拮抗剂或其各自的载体治疗定时妊娠大鼠 7 天:A-127722(对 ETA 的选择性是 ETB 的 2,000 倍)、FR139317(对 ETA 选择性的 8,000 倍),或 ABT-546(28,000 倍 ETA 选择性)。在治疗第 7 天(妊娠第 21 天)评估子宫和胎盘灌注以及胎儿和胎盘重量。 L-NAME 给药导致子宫和胎盘灌注以及胎儿和胎盘生长显着减少。在 NOS 抑制的情况下,无论所用拮抗剂的选择性程度如何,ETA 拮抗剂在输注 7 天后都不会改善子宫或胎盘灌注或胎儿生长。无论受体选择性程度如何,ETA 拮抗作用在慢性 NOS 抑制的第 7 天都不会改善胎儿生长或子宫胎盘灌注。
Endothelin receptor A (ETA) antagonism improves fetal and placental growth and placental perfusion on days 1 and 4, but not day 7 of a 7-day infusion of a nitric oxide synthase (NOS) inhibitor. Our purpose was to evaluate the significance of the degree of ETA antagonist selectivity on uteroplacental perfusion and fetal growth on day 7 of chronic NOS inhibition. Timed-pregnant rats were treated with the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg/h) with and without one of the following ETA antagonists or their respective vehicles for 7 days beginning on day 14 of gestation: A-127722 (2,000-fold selective for ETA over ETB), FR139317 (8,000-fold ETA-selective), or ABT-546 (28,000-fold ETA-selective). Uterine and placental perfusion, as well as fetal and placental weight, was evaluated at the 7th day of treatment (gestation day 21). L-NAME administration resulted in a significant reduction in uterine and placental perfusion as well as fetal and placental growth. In the setting of NOS inhibition, ETA antagonism did not improve uterine or placental perfusion or fetal growth after 7 days of infusion irrespective of the degree of selectivity of the antagonist used. ETA antagonism, irrespective of the degree of receptor selectivity, does not improve fetal growth or uteroplacental perfusion on day 7 of chronic NOS inhibition.
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