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Title: The role of 5-hydroxytryptamine in pre-eclampsia
Author: Kłusek, Aslihan Uğun
ISNI:       0000 0001 3600 8635
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2008
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Pre-eclampsia is a disease specific to human pregnancy. It is characterised by increased blood pressure and proteinuria. The main aim of this work was to investigate comparatively the vasoactive actions of 5-HT on vascular tone in normotensive and preeclamptic placental vessels and also to compare 5-HT2a receptor protein levels in these vessels. Two representative vessels from each placenta were used in these investigations; arteries and veins close to the insertion of the umbilical cord (primary artery/vein) and arteries and veins close to the periphery of the placenta (secondary artery/vein). The main finding of the present study was a reduced contractile response of preeclamptic placental (primary and secondary) veins and (secondary) arteries to 5-HT. This reduction was more pronounced in the secondary vessels. In addition this study revealed that in pre-eclamptic patients maximal contraction of secondary arteries to 5- HT was significantly reduced in comparison to primary arteries; this was not the case for normotensives. This finding demonstrates the importance of studying different branches of the chorionic vessels comparatively and also suggests that chorionic plate vessels may indeed be differently modified in pre-eclamptic conditions. Blood/urine 5-HT and its metabolite 5-HIAA levels (in urine) were also investigated in these patients. Circulating 5-HT levels were generally higher in pre-eclamptic samples. However, there was no significant correlation between a patient's response to 5-HT and blood (or urine) 5-HT levels. Although the maximum difference in the response of normotensive and pre-eclamptic vessels to 5-HT was observed at pM levels, circulating 5-HT levels were found to be around 50 nM in pre-eclamptic patients. However, circulating 5-HT levels could reach pM levels locally due to platelet activation especially in pre-eclamptic patients. Therefore a reduced contractile response to 5-HT may have implications for the maintenance and control of blood flow to the foetus and may also provide a protective mechanism. Western blotting analysis of the 5-HT2a receptor demonstrated similar total receptor levels in primary and secondary vessels and the levels were not affected by preeclampsia. This suggests receptor desensitisation may have a role in the reduced response to 5-HT in pre-eclamptic vessels. Preliminary studies using a cultured placental cell line also indicated no effects of oxidative stress and hypoxia on total 5-HT2a receptor levels. A reduced 5-HT turnover was found in pre-eclamptic samples as determined by a reduced urine 5-HIAA: 5-HT ratio. Since previous studies in our laboratory showed that the catalytic turnover of MAO-A was reduced in pre-eclampsia, km values of MAO-A for its amine substrate was also investigated. Km values were found to be similar in normotensive and pre-eclamptic placental samples suggesting that the affinity of the enzyme for its substrate is not reduced in pre-eclampsia. Possible oxidative/nitrative damage to the enzyme was further investigated using recombinant MAO-A protein. Preliminary studies indicate that MAO-A was highly resistant to short term exposure to hydrogen peroxide and more sensitive to peroxynitrite. In conclusion these findings suggest that 5-HT may have a role in the control of blood flow to the foetus and the reduced responsiveness in pre-eclamptic vessels may be a protective mechanism which prevents excessive vasoconstriction to compensate for the reduced utero-placental blood flow in pre-eclampsia.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available