Abstract
BackgroundPGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31.MethodsSingle and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin.ResultsSingle channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions.ConclusionThese data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.
Highlights
PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour
These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31
Subsequent addition of IbTX (100 nM), a specific extracellular BKCa channel blocker, reversed NS1619-stimulated channel activity. These properties, the conductance value, NS1619- and IbTX- sensitivity are in accordance with the characteristics of the BKCa channels in smooth muscle myocytes described in literature [26,27]
Summary
PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. PGF2α plays a pivotal role in parturition [7,8,9] It is the most effective smooth muscle contractile prostaglandin [7], which exerts a significant stimulatory effect on the myometrium [10], and is a potent compound for inducing labour [8]. From our laboratory, support this tocolytic effect by demonstrating that THG113.31 exerted a potent concentration dependent relaxant effect on both spontaneous and oxytocin induced contractions, in human myometrial tissue [15,16]
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