Specific PGF(2alpha) receptor (FP) antagonism and human uterine contractility in vitro.
OBJECTIVE: PGF(2alpha) acts through its receptor, FP, as an important smooth muscle contractile agent. The aim of this study was to investigate the effects of specific FP antagonism, using the novel-specific FP non-competitive antagonist THG113.31, on spontaneous and agonist-elicited contractions in pregnant and non-pregnant human myometrium in vitro. DESIGN: Scientific study. SETTING: University hospital and laboratories. Population Women undergoing caesarean section or hysterectomy. METHODS: Biopsies of human myometrium were obtained at elective caesarean section (n= 22) and from hysterectomy specimens from premenopausal women (n= 8). Dissected strips were mounted in tissue baths under physiological conditions. The effects of THG113.31 on spontaneous and oxytocin-induced contractions, in pregnant myometrium, and on phenylephrine-induced contractions, in non-pregnant myometrium, were measured. The effects of PGF(2alpha) on spontaneous contractions, in pregnant tissue, in the presence and absence of THG113.31, were investigated. The integrals of contractile activity measured were compared with those from simultaneously run control experiments. The pD(2) and mean maximal effect observed for THG113.31, and for PGF(2alpha) in the presence and absence of THG113.31, were calculated. MAIN OUTCOME MEASURES: Changes in contractility. RESULTS: THG113.31 exerted a potent relaxant effect in both spontaneous and oxytocin-induced contractility in pregnant tissue (P < 0.001), and phenylephrine-induced contractility in non-pregnant tissue (P < 0.001), compared with control experiments. PGF(2alpha) exerted a significant contractile effect on spontaneous contractions in pregnant tissue and this effect was not significantly attenuated by THG113.31 (P > 0.05). CONCLUSION: THG113.31 exerted a significant relaxant effect on human spontaneous and oxytocin-induced contractility but did not alter PGF(2alpha)-elicited contractility. These data raise questions about the exact mechanism of effect of THG113.31 and its interaction with FP. The uterorelaxant potency of THG113.31 in human myometrium in vitro indicates that it may be of limited use as a tocolytic compound.
Friel, AM; O'Reilly, MW; Sexton, DJ; Morrison, JJ
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