Human parturition is a tightly controlled process, but for some women, aberrations in this timing give rise to dysfunctional labour, including preterm birth and dystocia; such complications are associated with increased risk of neonatal mortality and morbidity. Current management strategies are limited in their effectiveness, requiring further understanding of the pathways governing uterine activity. The KV7 subfamily of voltage-gated potassium channels, composed of KCNQ- and KCNE-encoded subunits, are key regulators of smooth muscle cell membrane excitability in a range of tissues, but their role in uterine contractions has yet to be fully explored. The working hypothesis was that KV7 channels are expressed and functionally active in myometrial tissue at the end of gestation and during labour (term and preterm), and that KV7 channel activators can inhibit myometrial contractility in vivo sufficiently to delay preterm labour.
Expression of KCNQ1-5 and KCNE1-5 mRNA and protein was analysed in myometrium from pregnant women before and after the onset of labour. The functional contribution of KV7 channels at term was also investigated. A murine model of RU486-induced preterm labour was used to characterise KV7 subunit expression and investigate the in vivo effectiveness of KV7 activators as tocolytics for the treatment of preterm labour.
Protein and mRNA for KCNQ4, KCNE3 were downregulated, while KCNQ3 was increased, after the onset of labour (p<0.05 for all). Application of Kv7 activator and blockers decreased and increased ex vivo myometrial contractility respectively (p<0.05 for all). In preterm murine myometrium, KCNQ4, KCNQ5, KCNE1 and KCNE2 were downregulated during preterm labour (p<0.05 for all). KV7 activators, retigabine and ML213, decreased myometrial activity in vitro and significantly delayed the onset of preterm labour in vivo (p<0.05 for both).
These novel data provide proof of concept that KV7 channels can be targeted for tocolysis. Together with a better understanding of the KV7 channel composition in human myometrium, this study is the first step in translation to the human condition of preterm labour.
|Date of Award
|Paul Taylor (Supervisor) & Rachel Tribe (Supervisor)