Doheny Helen C, O'Reilly Michael J, Sexton Donal J, Morrison John J
Department of Obstetrics & Gynaecology, National University of Ireland Galway, Clinical Science Institute, University College Hospital Galway, Newcastle Road, Galway, Ireland.
Reprod Biol Endocrinol. 2007 Mar 16;5:10. doi: 10.1186/1477-7827-5-10.
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. 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.
Single 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.
Single 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.
These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.
前列腺素F2α（PGF2α）对子宫肌层具有显著的收缩作用，是人类分娩的关键因素。THG113.31是一种特异性非竞争性PGF2α受体（FP）拮抗剂，对子宫肌层收缩力具有抑制作用。大电导钙激活钾通道（BKCa通道）在人类子宫组织中普遍存在，在调节子宫肌层细胞膜电位和兴奋性方面发挥重要作用。本研究的目的是探讨BKCa通道在人类子宫肌层对THG113.31反应中的潜在作用。
在有无THG113.31的情况下，对新鲜分离的肌细胞进行单通道和全细胞BKCa通道电生理记录。功能研究在有无BKCa通道阻滞剂iberiotoxin的情况下，研究THG113.31对离体子宫肌层自发收缩的影响。
单通道记录确定BKCa通道是THG113.31的作用靶点。THG113.31显著增加了这些通道的开放概率[对照组0.023±0.006；10μM THG113.31 0.087±0.012（P = 0.009）；50μM THG113.31 0.1356±0.018（P = 0.001）]。此外，THG113.31在一系列膜电位范围内增加了全细胞BKCa电流，这种作用被100 nM IbTX逆转。等长张力研究表明，THG113.31对人类子宫肌层组织具有显著的浓度依赖性舒张作用，用IbTX预孵育条带可消除其对自发收缩的这种作用。
这些数据表明，BKCa通道的激活可能至少部分地促成了THG113.31的子宫舒张作用。
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