Impact of Kv7 voltage-gated potassium channel modulators on contractile activity of myometrium from pregnant women at term.

Background: Voltage gated potassium (Kv) channels play an important role in regulating resting membrane potential, and in smooth muscle are key determinants of contractile frequency. KCNQ-encoded Kv7 channels have been extensively studied in the cardiac and nervous systems due to their importance in normal physiological function. There is now an established role for these channels in smooth muscle and we have recently identified mRNA for these channels (Kv7.1-7.5), and their modulatory subunits (KCNE1-5), in pregnant human myometrium1. The aim of this study was to characterise the functional effects of a range of Kv7 activators and blockers on the contractility of myometrium from pregnant women at term ex vivo. Methods: Myometrial tissue was obtained, with informed written consent, from pregnant women undergoing elective lower segment Caesarean section at term (> 37 weeks', not in labour) (Ethics approval number EC00/137). Spontaneous contractile activity (mean integral tension, MIT and contraction frequency) was measured in isolated myometrial strips and the effect of Kv7 inhibitors (XE991, 20 µM; Chromanol 293B, 20 µM) and activators (retigabine, 20 µM; maxipost, 20 µM; acrylamide S-1, 20 =µM) determined and compared to vehicle controls (DMSO). The effect of the ERG inhibitor (dofetilide, 10 µM) was also assessed. Results: Retigabine significantly decreased %MIT (35.98% ± 11.28 versus control 83.43% ± 5.4; n=5, p<0.05) and acrylamide S-1 appeared to have a more potent relaxant effect than retigabine. The pan Kv7 blocker (7.2-7.5) XE991 increased %MIT and contractile frequency (n=10) whereas the Kv7.1-specific blocker chromanol 293B (n=10) had no significant effect on MIT. Administration of maxipost had no demonstrable effect on MIT. Conclusions: These data suggest that Kv7.2-7.5, but not Kv7.1, and ERG channels contribute significantly to the regulation of spontaneous myometrial contractions in tissues from pregnant women at term. The relaxation induced by Kv7 activators highlights a potential use of these agents for the treatment of spontaneous preterm birth. [ABSTRACT FROM AUTHOR]