In Mice, KCNQ Channel Modulators Affect Afferent Nerve Activity and not Urinary Bladder Smooth Muscle Contractility Directly

Abstract

KCNQ channels are a family of voltage‐dependent K+ channels, which open in response to membrane depolarization to regulate cell excitability. KCNQ activators, such as retigabine, have been used successfully to treat epilepsy; interestingly, these drugs also caused urinary retention. Using ex vivo measurements of bladder pressure and afferent nerve activity, isometric contractility of bladder strips, and electrophysiological recordings from freshly isolated urinary bladder smooth muscle (UBSM) cells, we explored the role of KCNQ channels as regulators of murine urinary bladder function. In the ex vivo bladder, both the KCNQ activator retigabine and the voltage‐gated Ca2+ channel inhibitor diltiazem blocked transient contractions (TCs) and associated bursts of afferent nerve activity. In addition, retigabine reduced baseline afferent nerve activity in the absence of TCs. Simulating TCs by mechanical deformation of the bladder wall also caused bursts of afferent activity; retigabine, but not diltiazem, inhibited these afferent bursts as well. This suggests that the effects of retigabine were not limited to detrusor muscle, and also included inhibition of afferent nerve activity. In bladder strips, neither retigabine (10 μM) nor the KCNQ antagonist XE‐991 (10 μM) altered contractions in response to electrical field stimulation (0.5 – 50 Hz). Retigabine did, however, significantly reduce 60 mM KCl‐induced contractions, possibly indicative of voltage‐dependent Ca2+ channel inhibition and not KCNQ activation. Consistent with contractility data, retigabine inhibited currents through voltage‐dependent Ca2+ channels and had no effect on K+ currents, as measured in UBSM cells using the patch‐clamp technique. Lastly, retigabine had no effect on resting membrane potential in UBSM cells, using the current‐clamp configuration of the patch clamp technique. Taken together, these data indicate that UBSM cells lack functional KCNQ channels, and the effects of retigabine on detrusor contractility may be due instead to non‐specific inhibition of voltage‐gated Ca2+ channels. Alternatively, urinary retention caused by retigabine may be related to inhibition of afferent nerve activity and not diminished detrusor contractility.Support or Funding InformationSupported by NIH K01DK103840 to NRT and NIH R37DK053832 to MTN.