Endocrine Abstracts (2006) 12 P112

Functional pharmacology of prostaglandin EP agonists in isolated human myometrium from term pregnant donors

DP Fischer1, D Farrar2, P O’Donovan2, J Senior1, DF Woodward3 & KM Marshall1

1University of Bradford, Bradford, West Yorkshire, United Kingdom; 2Bradford Royal Infirmary, Bradford, West Yorkshire, United Kingdom; 3Allergan Inc, Irvine, California, United States.

Prostaglandin (PG) E2 acts through its receptors (EP1–4) to influence uterine contractility during gestation and parturition. The aim of the present study was to identify functional EP receptor targets in isolated myometrium from term pregnant, non-labouring donors by use of specific and novel EP agonists.

Biopsies of human myometrium were obtained at elective caesarean section from consenting term pregnant women, not in labour (38–40 weeks gestation; n=22). Myometrial strips were mounted longitudinally in immersion baths under physiological conditions and left to equilibrate for at least 90 minutes. Vehicle and concentration-effect curves (10−10 M to 10−5 M) for PGE2, EP2 agonists (butaprost, CP533536), EP4 agonists (AGN201734, PDA124, AGN211330) and EP1/EP3 agonists (ONO-D1-004 and sulprostone) were added to individual organ baths and every 30-minute agonist or vehicle application was measured as area under the curve. Data were expressed as a percentage of the final contraction induced by hypotonic shock and analysed using two-way ANOVA with post-hoc Bonferroni’s test.

PGE2 and AGN201734 exhibited biphasic responses in isolated myometrium, initially inhibiting spontaneous contractions compared to time-matched vehicles (P<0.05) with some excitation evoked at 10−5 M. EP2 receptor agonists attenuated myogenic activity in a monophasic concentration-dependent manner (P<0.001), whilst the other EP4 mimetics produced no response. Although sulprostone appeared to enhance the contractile frequency and amplitude, EP1 and EP3 agonists did not significantly alter myogenic responses to vehicle.

The predominant utero-relaxant effect of PGE2 in isolated lower myometrium suggests that inhibitory receptors supersede contractile EP receptor function at term pregnancy. EP2 agonists were most potent in mediating uterine quiescence; this indicates a crucial role for myometrial EP2 receptors in pregnancy maintenance and parturition.

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