Strong labour contractions require calcium influx through voltage-gated calcium channels. Thus, myometrial smooth muscle membrane potential is critical for good labour progress. Dysfunctional labour (DL) is a significant problem in the labour ward, and is the most common indication for caesarean delivery. We recently discovered a marked excessive negative membrane potential in myometrium of both lean and obese DL women. We hypothesized that this negative membrane potential is caused by excessive activity and/or levels of K+ channels, the resulting negativity suppressed opening of calcium channels resulting in weak contraction and DL.
Electrophysiology was used to record membrane potential and K+ channel activity in term not-in-labour (NIL) and in labour (IL) myometrium. K+ channel protein levels were determined using western blotting.
Myometrial strips from women progressing well IL had spontaneous contractions (n=7). DL strips did not contract spontaneously (n=9), although contraction could be achieved using experimental depolarizations. Resting membrane potential in myometrium from normally progressing women NIL was -58±1mV (n=17) and IL was -58±1mV (n=7). DL myometrium was significantly more negative IL (-73±2mV, n=9). Blockade of KV7 channels, using XE-991, returned resting potential to normal levels (-61±2mV) in high negative DL myometrium. Levels of KV7.1 protein did not change in myometrium from normally progressing women before versus in labour, but was significantly increased in DL (21.2±2.4, n=5) versus normal progress IL (11.9±1.6, n=5, p=0.02). Levels of KV7.4 protein were also significantly increased in myometrium from DL IL women (1.18±0.14, n=5) versus normally progressing labour (0.26±0.04, n=5, p=0.0008). In acutely isolated myometrial cells the KV7 current (at 20mV) was enhanced in IL DL (6.1±1.1pA/pF) versus normal progress (2.5±0.5pA/pF, p=0.02). In DL myometrium, depolarization evoked by oxytocin (10nM) was 8±2mV, insufficient to overcome the negativity and so did not cause contraction. Dysfunction of KV7 channels is a major contributor to DL in women.