Although prostaglandins (PG) and oxytocin are crucial mediators of uterine
contractility, their receptor-mediated effects during the menstrual cycle, pregnancy
and labour are not fully understood. The aim of this thesis was to elucidate the
functional expression of EP, FP, TP and oxytocin receptors in isolated human
myometrium relative to myocyte mRNA and signal transduction pathways.
Myometrial samples were obtained from consenting non-pregnant and pregnant
donors. Functional techniques were used to determine isometric muscle contractions.
Primary uterine myocytes and fibroblasts were cultured at term to identify stimulated
changes in calcium (Ca2+), cyclic adenosine monophosphate (cAMP) and mRNA.
Myometrial strips exhibited spontaneous contractions, which were most active midcycle
under oestrogenic conditions. At this time intrinsic contractility and
responsiveness to uterotonins decreased towards the fundus. PGE2 produced bellshaped
responses with predominant utero-relaxant effects mediated via the EP2
subtype. Although activity was partially restored by PGE2 through EP3/1 receptors,
tissue excitation was more pronounced at FP, TP and oxytocin receptors. Despite high
FP mRNA expression, the lower segment uterus was particularly responsive to
U46619 and oxytocin at term pregnancy. Even so, Ca2+ mobilisation by oxytocin was
greater via principal release from intracellular stores. Incubations with atosiban,
progesterone and a rho-kinase inhibitor reduced oxytocin-stimulated Ca2+ transients.
EP2 also attenuated oxytocic effects but this appeared to be mediated through cAMP
rather than Ca2+ signalling pathways. With advancing labour, intrinsic myogenic
activity declined in parallel with oxytocin desensitisation. However, TP-induced
contractions were continued in the lower parturient uterus.
These findings demonstrate that PG and oxytocin receptor expression are regulated in
a hormone-dependent temporal and spatial manner. EP2-mediated cAMP formation
appears to promote uterine quiescence, whilst TP receptors may control muscle tonus
during parturition. These receptors and their messenger systems represent effective
tocolytic targets for uterine hypercontractile disorders, such as dysmenorrhoea and
preterm labour. / Allergan Inc.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/4470 |
| Date | January 2010 |
| Creators | Fischer, Deborah P. |
| Contributors | Marshall, Kay M. |
| Publisher | University of Bradford, Pharmacy Innovation Research Group, Bradford School of Pharmacy. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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