Indomethacin blocks interleukin 1β-induced myometrial contractions in pregnant rhesus monkeys

OBJECTIVE: We sought to determine whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1 beta-induced increases in uterine contractions in a nonhuman primate model. STUDY DESIGN: Maternal and fetal vascular catheters, intra-amniotic fluid pressure catheters, and fetal electrocardiographic and myometrial electromyographic electrodes were implanted in 11 rhesus monkeys at 124 +/- 2 days' gestation (term, 167 days). After postsurgical stabilization (136 +/- 2 days) indomethacin 50 mg was administered orally twice daily for 5 days (n = 6). On day 3 human recombinant interleukin 1 beta 10 mu g was infused into the amniotic cavity over 2 hours. Five days after the last indomethacin dose the study was repeated without indomethacin treatment. Uterine activity was continuously monitored and quantified as the hourly contraction area (millimeters of mercury seconds per hour) in the experimental group and a control group (n = 5) that received interleukin 1 beta alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostaglandin E-2 and F-2 alpha, the inflammatory cytokines interleukin 1 beta, interleukin 6, interleukin 8, tumor necrosis factor alpha, and interleukin 1 receptor antagonist by specific assays. RESULTS: Uterine activity was increased severalfold from baseline after interleukin 1 beta infusion alone and in the absence of indomethacin treatment (P < .05). There was no increase in uterine contractility when interleukin 1 beta was infused concurrently with indomethacin treatment. Concentrations of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1 beta infusion in both the presence and absence of indomethacin. Amniotic fluid prostaglandins E-2 and F-2 alpha were suppressed during indomethacin treatment but rose significantly after interleukin 1 beta infusion in the absence of indomethacin. Except for higher interleukin 6, cytokine levels were unaltered by indomethacin. CONCLUSIONS: After interleukin 1 beta infusion, indomethacin blocked the development of uterine activity. Amniotic fluid prostaglandins were suppressed by indomethacin treatment, but cytokines and leukocytes were not. These results suggest that prostaglandins or possibly other indomethacin-suppressible compounds stimulate uterine activity after interleukin 1 beta infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects.