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

OBJECTIVE: We sought to determine whether blockade of prostaglandin synthes is with indomethacin prevents interleukin 1 beta-induced increases in uteri ne contractions in a nonhuman primate model. STUDY DESIGN: Maternal and fetal vascular catheters, intra-amniotic fluid p ressure catheters, and fetal electrocardiographic and myometrial electromyo graphic electrodes were implanted in 11 rhesus monkeys at 124 +/- 2 days' g estation (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 th e 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 (mill imeters of mercury seconds per hour) in the experimental group and a contro l group (n = 5) that received interleukin 1 beta alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostagland in E-2 and F-2 alpha, the inflammatory cytokines interleukin 1 beta, interl eukin 6, interleukin 8, tumor necrosis factor alpha, and interleukin 1 rece ptor antagonist by specific assays. RESULTS: Uterine activity was increased severalfold from baseline after int erleukin 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. Concentration s of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1 beta infusion in both the presence and absence of indomethaci n. Amniotic fluid prostaglandins E-2 and F-2 alpha were suppressed during i ndomethacin treatment but rose significantly after interleukin 1 beta infus ion in the absence of indomethacin. Except for higher interleukin 6, cytoki ne levels were unaltered by indomethacin. CONCLUSIONS: After interleukin 1 beta infusion, indomethacin blocked the de velopment of uterine activity. Amniotic fluid prostaglandins were suppresse d by indomethacin treatment, but cytokines and leukocytes were not. These r esults suggest that prostaglandins or possibly other indomethacin-suppressi ble compounds stimulate uterine activity after interleukin 1 beta infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects.