The inwardly rectifying K + channel KIR 7.1 controls uterine excitability throughout pregnancy

Abstract

Abnormal uterine activity in pregnancy causes a range of important clinical disorders, including preterm birth, dysfunctional labour and post‐partum haemorrhage. Uterine contractile patterns are controlled by the generation of complex electrical signals at the myometrial smooth muscle plasma membrane. To identify novel targets to treat conditions associated with uterine dysfunction, we undertook a genome‐wide screen of potassium channels that are enriched in myometrial smooth muscle. Computational modelling identified Kir7.1 as potentially important in regulating uterine excitability during pregnancy. We demonstrate Kir7.1 current hyper‐polarizes uterine myocytes and promotes quiescence during gestation. Labour is associated with a decline, but not loss, of Kir7.1 expression. Knockdown of Kir7.1 by lentiviral expression of mi RNA was sufficient to increase uterine contractile force and duration significantly. Conversely, overexpression of Kir7.1 inhibited uterine contractility. Finally, we demonstrate that the Kir7.1 inhibitor VU 590 as well as novel derivative compounds induces profound, long‐lasting contractions in mouse and human myometrium; the activity of these inhibitors exceeds that of other uterotonic drugs. We conclude Kir7.1 regulates the transition from quiescence to contractions in the pregnant uterus and may be a target for therapies to control uterine contractility. image Only few effective treatments can manipulate uterine contractility for the prevention of dystocia, preterm labor or post‐partum hemorrhage. This study reveals Kir7.1 channel as a potential target for increasing uterine contractions and identifies novel Kir7.1 inhibitors. A genome‐wide scan of all known potassium channels combined with computational modeling identified Kir7.1 as a potentially useful therapeutic target. Kir7.1 expression increases in mid gestation and declines towards the onset of labor in mice and humans. Kir7.1 inhibition in vitro and in vivo increases uterine contractility. Novel inhibitors of Kir7.1 induce contractions of greater magnitude than a commonly used uterine stimulant oxytocin.