Influence of lipopolysaccharide on the uterine contraction inhibitory effects of tocolytic agents in pregnant mice.
The study was undertaken to investigate the influence of lipopolysaccharide (LPS) on the uterine contraction inhibitory effects of tocolytic agents such as ritodrine, magnesium, and diethylamine/nitric oxide (DEA/NO), and on prostaglandin (PG) E2 and nitric oxide (NO) metabolite (NOx) production in pregnant mice at midgestation. Pregnant C57BL mice on day 14 of gestation were sacrificed 6 hours after intraperitoneal injection of LPS (400 mug/kg) or vehicle. Uterine rings were equilibrated in Krebs-Henseleit solution (37 degrees C) bubbled with 20% O (2) and 5% CO (2) (pH ~7.4) for sampling and isometric tension recording. The concentration levels of PGE2 and NOx in the solution were determined. Changes of spontaneous contractile activity in response to cumulative concentrations of ritodrine, magnesium, and the NO donor, DEA/NO, from the baseline were determined. Integral contractile activity over 10 minutes at each concentration was calculated and expressed as percentage change from basal activity. Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by the Dunnett test (significance: P < 0.05). LPS treatment significantly increased the production levels of PGE2 and NOx (from 66.8 +/- 6.7 pg/g tissue to 147.0 +/- 29.0, from 51.0 +/- 5.4 pmol/2 muL/g tissue to 98.0 +/- 16.2, respectively), P < 0.05). Ritodrine, magnesium, and DEA/NO inhibited spontaneous contractions concentration dependently in uterine rings from both LPS-treated and -untreated animals. Treatment with LPS significantly attenuated the maximal inhibition induced by DEA/NO in uterine rings from pregnant mice. LPS significantly suppressed the uterine contraction inhibitory effects of ritodrine at 10 (-8) M concentrations and of magnesium at 4.2 mmol concentration ( P < 0.05). We concluded that the effects of ritodrine and magnesium may be reduced under inflammatory conditions because LPS increases the production levels of PGE2 and NOx, which cause increased spontaneous contractions of the uterine myometrium. Therefore, when uterine contractions are not controlled by tocolytics in pregnant patients with preterm labor associated with inflammation, labor induction or pregnancy termination may become significant options in clinical practice.
Sugawara
Noboru
N
Department of Obstetrics & Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan.
Okawa
Toshiaki
T
Takahashi
Hidenori
H
Sato
Akira
A
Vedernikov
Yuri P
YP
Saade
George R
GR
Garfield
Robert E
RE
D000818:Animals; D015232:Dinoprostone / Q000096:biosynthesis; D004731:Endotoxins / Q000494:pharmacology*; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D011247:Pregnancy; D012312:Ritodrine / Q000494:pharmacology; D015149:Tocolytic Agents / Q000494:pharmacology*; D014590:Uterine Contraction / Q000187:drug effects* / Q000502:physiology*
D004731:Endotoxins; D006834:Hydrazines; D008070:Lipopolysaccharides; D015149:Tocolytic Agents; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D012312:Ritodrine; D008274:Magnesium; D015232:Dinoprostone