Endocrine Abstracts (2009) 19 P301

Functional pharmacology of prostaglandin E receptors in isolated human myometrium before and after labour-onset

D Fischer1, D Farrar2, P O’Donovan2, D Woodward3 & K Marshall1

1University of Bradford, Bradford, West Yorkshire, UK; 2Bradford Royal Infirmary, Bradford, West Yorkshire, UK; 3Allergan Inc., Irvine,
California, USA.

Prostaglandin (PG) E2 acts through its receptors (EP1–4) to modulate myometrial contractions and cervical ripening at term gestation. Although uterine PGE2 biosynthesis is augmented with labour progression (Durn et al. 2008); functional EP1–4 receptors have yet to be determined. To characterise these receptors in gravid human myometrium, in vitro responses to selective and novel EP agonists were investigated before and after labour-onset.

Lower segment myometrial biopsies were obtained at Caesarean section from consenting term pregnant donors (38–41 weeks), not in labour (n=10) or in spontaneous labour (n=19). The Local Regional Ethics Committees granted approval for this study. To record contractile responses, myometrial strips were mounted under physiological conditions and attached to isometric force transducers. Vehicle and concentration-effect curves [10−10M to 10−5M] were constructed for PGE2, EP2 agonists (butaprost, CP533,536, AH-13205, AGN211330), EP4 agonists (AGN201734, L-902688) and EP1/EP3 agonists (ONO-D1-004, sulprostone). Data were expressed as a percentage of the final contraction induced by hypotonic shock with distilled water and analysed using two-way ANOVA with Bonferroni’s post-hoc test.

Spontaneous myometrial contractions were attenuated with advancing labour (P<0.001). Before labour-onset, PGE2 and AGN201734 induced a biphasic response, initially suppressing contractions compared to vehicle controls (P<0.05–P<0.01) with some excitation at 10−5M. As labour progressed, PGE2 fully inhibited myogenic activity. In all donor tissues, EP2 agonists reduced contractions in a monophasic concentration-dependent manner (P<0.05–P<0.001), whilst the other EP4 mimetics and ONO-D1-004 produced no response. Sulprostone evoked moderate stimulation even during late labour (P<0.01).

These results suggest that predominant utero-relaxant EP2 transcripts facilitate passage of the foetus during the parturition process whilst EP1/3 receptors regulate muscle tonus. Targeting these receptors may help to improve tocolytic therapies for labour-associated disorders.

Durn, JH et al. Society for Reproduction and Fertility Online 2008 P87.

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