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Title: The roles of prostanoid EP receptors in the control of contractions of human myometrium
Author: Arulkumaran, Shankari
ISNI:       0000 0004 2715 0252
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The primary function of the uterus during pregnancy is to harbour the growing fetus in a quiescent environment. Upon maturation of the fetus, the uterus generates forceful contractions during labour. Prostaglandins are central in the parturition process. PGE2 in particular, is produced in large quantities by fetal membranes and possible roles include cervical ripening and the stimulation of uterine contractions. PGE2 exhibits a wide spectrum of physiological actions depending on the distribution and subtypes of EP receptors. EP1 and EP3 mediate contractions, but there is no consensus about their relative importance. Preliminary experiments were undertaken to examine the possible expression patterns of EP1 and EP3. The expression data showed there to be no significant changes between the localisation in upper or lower segment biopsies using both RNA and protein samples. However, there was a labour associated change seen in EP3 isoform expression at mRNA level together with changes in the protein expression of EP3 in the lower segment using immunofluorescence. Given that the expression studies suggest that it is the EP3 receptor, and not the EP1 receptor, that is most important in myometrial contractility, I established an in vitro tissue bath to conduct functional studies examining contractility in upper and lower segment myometrial biopsies. My data demonstrated that stretch of term human myometrium results in spontaneous contractions. There was no difference between upper and lower segment myometrium, so subsequent experiments were conducted on lower segment biopsies. The addition of acetyl salicylic acid (a non-selective COX inhibitor) did not completely stop spontaneous contractility but reduced the total work done significantly. This could be reversed by add back of PGE2. Prostaglandins are therefore significant but not crucial for spontaneous contractility. Both PGE2 and PGF2α increased the total work done significantly compared to spontaneous contractions; E2 more so than F2α. The PGF2α antagonist did not inhibit spontaneous contractions, but did inhibit PGF2α induced contractions. The EP1 antagonist did not inhibit spontaneous contractions but EP3 antagonist did. These results suggest that an EP3 antagonist is a better candidate as a new tocolytic compound compared to FP or EP1 antagonist.
Supervisor: Bennett, Phillip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral