Eicosanoids are derived from arachidonic acid (AA) and emerged as a novel class of smooth muscle tone modulators but, to date, no functional study on pregnant human myometrium has been performed. The aim of this study was to explore the pathway of eicosanoids in pregnant women tissues and the effect of exogenous eicosanoids such as epoxyeicosatrienoic acid (EET) on spontaneous uterine contractile activity.
Nine uterine biopsies were performed, from consenting women undergoing elective caesarean sections at term. Isometric tension measurements were performed in vitro on fresh human myometrial strips (n=84) in isolated organ baths. After a 2 hour equilibration period, we assessed the effect of AUDA, DDMS, MS-PPOH, 8,9-EET, 14,15-EET or 20-HETE. Contractile activities were quantified by calculating the area under the curve over 20 minute periods. Proteins from myometrium, decidua, fetal membranes and placenta were extracted and separated on SDS-PAGE prior to Western blot analysis. Statistical analysis included paired t-test with p<0.05 considered significant.
Our data demonstrated the presence of CYP450 2J2 epoxygenase and soluble Epoxyde Hydrolase (sEH), which respectively produces and degrades EET-regioisomers, in all tested tissues. Addition of 1 μM AUDA (p=0.006), which inhibits sEH, had a tocolytic effect, but MS-PPOH, an epoxygenase inhibitor, had no detectable effect. Exogenous 8,9-EET and 14,15-EET (1 to 3 μM) were separately added in the organ bath and significant tocolytic effects on uterine contractile activities were observed. On the other hand, 10 μM DDMS, an ω-hydroxylase inhibitor (p=0.003) which prevents the production of 20-HETE from AA, or 20-HETE (3 μM) (p=0.005) had also tocolytic effects on contractile activities.
Epoxy- and hydroxy-eicosanoids represent new arachidonic acid pathways in pregnant women myometrium and display tocolytic activities. These findings suggest that CYP450 isozymes would represent relevant pharmacological targets under physio-pathological conditions.
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.