Indomethacin blocks interleukin 1beta-induced myometrial contractions in pregnant rhesus monkeys.
OBJECTIVE
We sought to determine whether blockade of prostaglandin synthesis with indomethacin prevents interleukin 1beta-induced increases in uterine contractions in a nonhuman primate model.


METHODS
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 1beta 10 microg 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 1beta alone. At timed intervals amniotic fluid was sampled for leukocyte counts and assayed for prostaglandin E(2) and F(2alpha), the inflammatory cytokines interleukin 1beta, 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 1beta infusion alone and in the absence of indomethacin treatment (P <.05). There was no increase in uterine contractility when interleukin 1beta was infused concurrently with indomethacin treatment. Concentrations of amniotic fluid leukocytes and cytokines increased significantly after interleukin 1beta infusion in both the presence and absence of indomethacin. Amniotic fluid prostaglandins E(2) and F(2alpha) were suppressed during indomethacin treatment but rose significantly after interleukin 1beta infusion in the absence of indomethacin. Except for higher interleukin 6, cytokine levels were unaltered by indomethacin.


CONCLUSIONS
After interleukin 1beta 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 1beta infusion in late-gestation rhesus monkeys or that indomethacin has direct tocolytic effects.
Sadowsky
D W
DW
Division of Reproductive Sciences, Oregon Regional Primate Research Center, Oregon Health Sciences University, Beaverton 97006, USA.
Haluska
G J
GJ
Gravett
M G
MG
Witkin
S S
SS
Novy
M J
MJ
D000653:Amniotic Fluid / Q000737:chemistry / Q000166:cytology; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015237:Dinoprost / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000032:analysis / Q000494:pharmacology*; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007958:Leukocyte Count; D008253:Macaca mulatta; D011247:Pregnancy; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014590:Uterine Contraction / Q000187:drug effects*
D016861:Cyclooxygenase Inhibitors; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D015237:Dinoprost; D015232:Dinoprostone; D007213:Indomethacin