A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries
A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries
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DOI：
10.1016/j.ejphar.2016.11.057
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发表时间：
2017-01-15
影响因子：
5
通讯作者：
Kuwano, Keiichi
中科院分区：
文献类型：
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作者：
Fuchikami, Chiaki;Murakami, Kohji;Kuwano, Keiichi
Selexipag (NS-304; [2-{4-[（5,6-diphenylpyrazin-2-yl)（异丙基）氨基]butoxy}- n- (methylsulfonyl)乙酰胺]）是一种新型口服非前列腺素类前列环素受体（IP受体）激动剂，最近已被批准用于治疗肺动脉高压（PAH）。我们检测了selexipag、MRE-269和IP受体激动剂的活性代谢物对大鼠、猪和人肺动脉舒张的影响，这些药物目前作为PAH治疗药物可用。所有实验化合物（MRE-269、环氧丙烯醇、伊洛prost、曲prostinil和beraprost钠）均能诱导人肺动脉平滑肌细胞cAMP的形成，并被IP受体拮抗剂（CAY10441和244-（1h -吲哚1-4-基氧甲基）-苯氧羰基氨基]-3-苯基丙酸）抑制。MRE-269诱导大鼠叶外肺动脉内皮不依赖型血管舒张。相比之下，内皮剥皮或添加一氧化氮合酶抑制剂可显著减弱由环氧前列醇、曲前列素和伯拉前列素钠诱导的EPA血管舒张，但对伊洛前列素没有作用。MRE-269对大鼠小叶内肺动脉（SIPA）和EPA的血管舒张作用相同，而其他IP受体激动剂对SIPA的血管舒张作用小于EPA。此外，前列腺素E受体3拮抗剂增强了除MRE-269外所有IP受体激动剂诱导的血管舒张。我们还研究了非啮齿类动物的肺动脉由IP受体激动剂引起的舒张，发现猪和人的血管舒张模式与大鼠制剂相似。这些结果表明，与其他IP受体激动剂相比，MRE-269作为一种选择性IP受体激动剂起作用，从而导致大鼠、猪和人肺动脉的血管松弛。
Selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]) is a novel, orally available non-prostanoid prostacyclin receptor (IP receptor) agonist that has recently been approved for the treatment of pulmonary arterial hypertension (PAH). We examined the effect of the active metabolite of selexipag, MRE-269, and IP receptor agonists that are currently available as PAH therapeutic drugs on the relaxation of rat, porcine and human pulmonary artery. cAMP formation in human pulmonary artery smooth muscle cells was induced by all test compounds (MRE-269, epoprostenol, iloprost, treprostinil and beraprost sodium) and suppressed by IP receptor antagonists (CAY10441 and 244-(1H-indo1-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid). MRE-269 induced endothelium -independent vasodilation of rat extralobar pulmonary artery (EPA). In contrast, endothelial denudation or the addition of a nitric oxide synthase inhibitor markedly attenuated the vasodilation of EPA induced by epoprostenol, treprostinil and beraprost sodium but not iloprost. The vasorelaxant effects of MRE-269 on rat small intralobar pulmonary artery (SIPA) and EPA were the same, while the other IP receptor agonists induced less vasodilation in SIPA than in EPA. Furthermore, a prostaglandin E receptor 3 antagonist enhanced the vasodilation induced by all IP receptor agonists tested except MRE-269. We also investigated the relaxation induced by IP receptor agonists in pulmonary arteries from non-rodent species and found similar vasodilation modes in porcine and human as in rat preparations. These results suggest that MRE-269, in contrast to other IP receptor agonists, works as a selective IP receptor agonist, thus leading to pronounced vasorelaxation of rat, porcine and human pulmonary artery.