Department of Cell Physiology, The Jikei University School of Medicine.
Circ J. 2018 Dec 25;83(1):209-216. doi: 10.1253/circj.CJ-18-0761. Epub 2018 Nov 10.
Patent ductus arteriosus (PDA) is common in premature infants. Cyclooxygenase inhibitors such as indomethacin, which inhibit prostaglandin E(PGE) synthesis, are currently the sole treatments for patients with PDA. Their efficacy are, however, frequently limited, and adverse effects are problematic. Because the PGE-specific receptor EP4 selectively expresses in rat ductus arteriosus (DA), it is hypothesized that EP4 inhibition would promote DA closure with fewer side-effects.
A new chemical compound EP4 antagonist, RQ-15986 (renamed from CJ-042794), was used. Whether RQ-15986 selectively contracted the DA was examined by measuring the isometric tension of rat DA ex vivo at embryonic day 19 (e19) and e21. RQ-15986 at a dose of 10mol/L increased the isometric tension of the DA up to 44.8±6.2% and 69.1±12.9% to the maximal KCl-induced tension at e19 and e21 respectively. The effect of RQ-15986 on rat DA in vivo was also tested by using a rapid whole-body freezing method. RQ-15986 inhibited PGE-induced DA dilatation in neonatal rats. Furthermore, RQ-15986 contracted the DA in a dose-dependent manner, and the constriction was greater at e21 than at e19. Moreover, RQ-15986 did not contract the aorta or the marginal artery of the colon.
EP4 inhibition contracts rat DA with fewer side-effects. EP4 inhibition is a promising alternative strategy to treat patients with PDA.
动脉导管未闭（PDA）在早产儿中很常见。环氧化酶抑制剂，如抑制前列腺素 E（PGE）合成的吲哚美辛，是目前治疗 PDA 患者的唯一方法。然而，它们的疗效常常受到限制，且存在不良反应问题。因为 PGE 特异性受体 EP4 选择性地在大鼠动脉导管（DA）中表达，因此假设 EP4 抑制将以较少的副作用促进 DA 闭合。
使用了一种新的化学化合物 EP4 拮抗剂，RQ-15986（重新命名为 CJ-042794）。通过测量胚胎第 19 天（e19）和第 21 天（e21）大鼠 DA 的离体等长张力，来检查 RQ-15986 是否选择性地收缩 DA。RQ-15986 剂量为 10mol/L 时，可使 DA 的等长张力分别增加至最大 KCl 诱导张力的 44.8±6.2%和 69.1±12.9%。还使用快速全身冷冻法测试了 RQ-15986 对大鼠体内 DA 的作用。RQ-15986 抑制 PGE 诱导的新生大鼠 DA 扩张。此外，RQ-15986 以剂量依赖性方式收缩 DA，且在 e21 时的收缩程度大于 e19 时。此外，RQ-15986 不会收缩主动脉或结肠边缘动脉。
EP4 抑制以较少的副作用收缩大鼠 DA。EP4 抑制是治疗 PDA 患者的一种有前途的替代策略。
