Inhibition of epoxy-eicosanoid degradation improves the tocolytic effects of indomethacin in the uterus from pregnant women

The incidence of preterm birth is an increasing problem. Indomethacin, a non-specific cyclooxygenase inhibitor, has been largely used as tocolytic in the treatment of preterm labor. The aim of the present study was to assess a putative synergistic tocolytic effect between the inhibition of the production of prostanoids and stabilization of epoxides fatty acids, particularly arachidonate on spontaneous uterine contractile activity. The experimental work was performed on uterine biopsies from consenting women undergoing elective cesarean delivery at term. Isometric tension measurements were performed on fresh human myometrial strips. Contractile activities have been monitored upon individual and combined treatments of indomethacin, DDMS, an inhibitor of hydroxy-eicosanoids production and AUDA, an inhibitor of epoxy-eicosanoids degradation. Interestingly, a significant and consistent synergic effect was observed when indomethacin and AUDA were simultaneously added, raising the possibility of a combined clinical use of cyclooxygenase and sEH inhibitors in attempt to treat preterm labor.

► We clearly demonstrate a decrease in the mean amplitude, time to peak, and time to 90% of relaxation upon inhibition of prostanoid production and EET degradation.
► We quantify a synergistic tocolytic effects after addition of cyclooxygenase inhibitor and soluble epoxide hydrolase.
► We measure significant additive tocolytic effects upon inhibition of both prostanoid and hydroxy-eicosanoids production.
► The combined used of indomethacin and a soluble epoxide hydrolase inhibitor could be relevant in the treatment of preterm labor.