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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery.
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Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery.

机译：推定的新型选择性ETA受体拮抗剂HJP272，1,3,6-三取代-2-羧基-喹啉-4-酮对感染介导的早产的影响。

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摘要

Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%-80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated PTB. In our previous work, we have shown that blockade of ET-1 synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-1 action with 5-50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1 ,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50,70 nmol/L), prevents PTB induced with up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.
机译：早产（PTB）定义为妊娠37周之前发生的任何出生，仅占所有出生的12％，但约占长期神经系统疾病发病率的一半，占围产期死亡率的60％-80％。 PTB的最常见原因是子宫内感染。内皮素-1（ET-1）是一种有效的血管收缩肽，既可以被炎性细胞因子上调，又能够增加肌层平滑肌张力。因此，我们假设ET-1在与感染相关的PTB的情况下是分娩级联反应的重要组成部分。在我们以前的工作中，我们已经表明，通过使用金属蛋白酶抑制剂磷酰胺阻断ET-1的合成可控制早产。在目前的工作中，我们显示了i.p. 5-50 mg / kg时对ET-1的阻断作用。 3-（3-羧基苄基）-1-（（（6-乙基苯并[d] [1,3]二恶唑-5-基）甲基] -6-羟基-4-氧代-1,4-二氢喹啉-2-羧酸（HJP272）是一种推定的新型选择性ETA受体拮抗剂（IC50,70 nmol / L），可预防高达50 mg / kg的ip诱导的PTB小鼠模型中的脂多糖。据我们所知，这是第一个用特定的ETA受体拮抗剂控制与感染相关的PTB的报告。鉴定一种新型的PTB有效疗法可能具有重要的临床意义。

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