THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation
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THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation Helen C Doheny*, Michael J O'Reilly, Donal J Sexton and John J Morrison Address: Department of Obstetrics & Gynaecology, National University of Ireland Galway, Clinical Science Institute, University College Hospital Galway, Newcastle Road, Galway, Ireland Email: Helen C Doheny* - [email protected]; Michael J O'Reilly - [email protected]; Donal J Sexton - [email protected]; John J Morrison - [email protected] * Corresponding author
Published: 16 March 2007 Reproductive Biology and Endocrinology 2007, 5:10
doi:10.1186/1477-7827-5-10
Received: 19 January 2007 Accepted: 16 March 2007
This article is available from: http://www.rbej.com/content/5/1/10 © 2007 Doheny et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: 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. Methods: 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. Results: 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. Conclusion: These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.
Background The mechanisms underlying the onset and maintenance of human parturition are poorly understood [1,2]. During pregnancy and labour the uterus undergoes dramatic changes in its contracti
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