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

Abstract

Objective: We sought to determine whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1β–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 1β 10 μg 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 1β alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostaglandin E2 and F2α, the inflammatory cytokines interleukin 1β, interleukin 6, interleukin 8, tumor necrosis factor α, and interleukin 1 receptor antagonist by specific assays. Results: Uterine activity was increased severalfold from baseline after interleukin 1β infusion alone and in the absence of indomethacin treatment (P <.05). There was no increase in uterine contractility when interleukin 1β was infused concurrently with indomethacin treatment. Concentrations of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1β infusion in both the presence and absence of indomethacin. Amniotic fluid prostaglandins E2 and F2α were suppressed during indomethacin treatment but rose significantly after interleukin 1β infusion in the absence of indomethacin. Except for higher interleukin 6, cytokine levels were unaltered by indomethacin. Conclusions: After interleukin 1β 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 1β infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects. (Am J Obstet Gynecol 2000;183:173-80.)