Patent ductus arteriosus (PDA) often occurs in premature infants [1]. At present, the cyclooxygenase inhibitor indomethacin is used to treat patients with PDA by inhibiting prostaglandin E2 synthesis. However, its efficiency is frequently limited [2] and adverse effects are problematic [3]. We have demonstrated that the prostaglandin E2 receptor EP4 specifically expresses in the rat ductus arteriosus (DA) [4]. Therefore, we hypothesized that EP4 inhibition promoted closure of the DA with fewer side effects.

We first examined the effect of the EP4 antagonist RQ-15986 (CJ-042794) on isometric tension of the ex vivo DA at embryonic day 19 (e19) and 21 (e21). RQ-15986 at a dose of 10−4 M significantly increased the isometric tension of the DA up to 57 ± 14% and 78 ± 11% of 120mM KCl contraction at e19 and e21, respectively. The constrictive effect of RQ-15986 was greater on the DA than on the aorta. Second, we tested the effect of RQ-15986 on in vivo DA. RQ-15986 was intraperitoneally injected into fetuses at e19 and e21. We measured the inner diameter of the vessels by a rapid whole-body freezing method. RQ-15986 constricted the DA but not the aorta in a dose-dependent manner. The contraction percentage was greater at e21 than at e19. Finally, RQ-15986 did not constrict the marginal artery of the colon.

We demonstrated that RQ-15986 constricted the DA with fewer side effects. We concluded that EP4 inhibition would be a promising alternative strategy to treat a patient with PDA.