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Title: An investigation into the combination of nifedipine with potassium channel openers as potential tocolytic therapy for preterm labour, and a novel potassium channel blocker as potential therapy for post-partum haemorrhage
Author: Bailey, Elizabeth Helen
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Background Preterm labour and post-partum haemorrhage are leading causes of pregnancy morbidity and mortality. Previous work identified potassium channels expressed in myometrium and hypothesized modulation of channels with greater expression in MSMC than VSMC will influence contractility and avoid cardiovascular effects. By combining calcium channel blockers with potassium channel openers an enhanced tocolytic effect is anticipated. VU590 inhibits Kir 7.1 and it was hypothesised would elicit a contractile effect with therapeutic potential for post-partum haemorrhage. Aim To determine the effect of select potassium channel openers and a specific potassium channel blocker in myometrial contractility. Methods Human and murine myometrial strips were used in contractility organ bath experiments. Select combined doses were tested in myometrial small arteries using wire myography. Western blotting was carried out to determine the gestational and labour-state expression of potassium channels in human myometrium and myometrial small arteries. Results Pinacidil demonstrated a relaxatory effect on both myometrial and vascular smooth muscle. Riluzole reduced contractility alone and greater inhibition in combination with nifedipine than nifedipine alone. Riluzole appeared to have a mild effect on myometrial arteries. Kir 7.1 showed a trend of diminished expression by gestation and was downregulated in term and preterm labour states. VU590 elicited a significant increase contractility characterised by a prolonged contraction phase of up to 6.7±1.9 hrs (VU590 10 µM). A gestational-dependent effect was seen on murine myometrium. Conclusion The combination of nifedipine with potassium channel openers has a more potent effect on reducing contractility than either compound alone. Riluzole combined with nifedipine warrants further investigation for potential tocolytic therapy. VU590 augments spontaneous contractions profoundly in human myometrium in vitro and could have potential therapeutic benefits in the treatment of postpartum haemorrhage.
Supervisor: Not available Sponsor: University Hospitals Coventry and Warwickshire NHS Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RG Gynecology and obstetrics