The contribution of Kv7 channels to pregnant mouse and human myometrial contractility.
Premature birth accounts for approximately 75% of neonatal mortality and morbidity in the developed world. Despite this, methods for identifying and treating women at risk of preterm labour are limited and many women still present in preterm labour requiring tocolytic therapy to suppress uterine contractility. The aim of this study was to assess the utility of Kv7 channel activators as potential uterine smooth muscle (myometrium) relaxants in tissues from pregnant mice and women. Myometrium was obtained from early and late pregnant mice and from lipopolysaccharide (LPS)-injected mice (day 15 of gestation; model of infection in pregnancy). Human myometrium was obtained at the time of Caesarean section from women at term (38-41 weeks). RT-PCR/qRT-PCR detected KCNQ and KCNE expression in mouse and human myometrium. In mice, there was a global suppression of all KCNQ isoforms, except KCNQ3, in early pregnancy (n= 6, P < 0.001 versus late pregnant); expression subsequently increased in late pregnancy (n= 6). KCNE isoforms were also gestationally regulated (P < 0.05). KCNQ and KCNE isoform expression was slightly down-regulated in myometrium from LPS-treated-mice versus controls (P < 0.05, n= 3-4). XE991 (10 μM, Kv7 inhibitor) significantly increased spontaneous myometrial contractions in vitro in both human and mouse myometrial tissues (P < 0.05) and retigabine/flupirtine (20 μM, Kv7 channel activators) caused profound myometrial relaxation (P < 0.05). In summary, Kv7 activators suppressed myometrial contraction and KCNQ gene expression was sustained throughout gestation, particularly at term. Consequently, activation of the encoded channels represents a novel mechanism for treatment of preterm labour.
Maternal and Fetal Research Unit, Division of Reproduction and Endocrinology, King's College London, St Thomas' Hospital Campus, London, UK.
Laura A
LA
McCallum
Stephanie L
SL
Pierce
Sarah K
SK
England
Iain A
IA
Greenwood
Rachel M
RM
Tribe
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D006801:Humans; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D011247:Pregnancy; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014590:Uterine Contraction / Q000187:drug effects / Q000235:genetics* / Q000502:physiology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000631:Aminopyridines; D000873:Anthracenes; D000927:Anticonvulsants; D002219:Carbamates; D051656:KCNQ Potassium Channels; C092068:Kcne1 protein, mouse; D008070:Lipopolysaccharides; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; C101866:ezogabine; C034161:flupirtine