The KV7 channel activator retigabine suppresses mouse urinary bladder afferent nerve activity without affecting detrusor smooth muscle K⁺ channel currents

Key points K V 7 channels are a family of voltage‐dependent K + channels expressed in many cell types, which open in response to membrane depolarization to regulate cell excitability. Drugs that target K V 7 channels are used clinically to treat epilepsy. Interestingly, these drugs also cause urinary retention, but it was unclear how. In this study, we focused on two possible mechanisms by which retigabine could cause urinary retention: by decreasing smooth muscle excitability, or by decreasing sensory nerve outflow. Urinary bladder smooth muscle had no measurable K V 7 channel currents. However, the K V 7 channel agonist retigabine nearly abolished sensory nerve outflow from the urinary bladder during bladder filling. We conclude that K V 7 channel activation likely affects urinary bladder function by blocking afferent nerve outflow to the brain, which is key to sensing bladder fullness. Abstract K V 7 channels are voltage‐dependent K + channels that open in response to membrane depolarization to regulate cell excitability. K V 7 activators, such as retigabine, were used to treat epilepsy but caused urinary retention. Using electrophysiological recordings from freshly isolated mouse urinary bladder smooth muscle (UBSM) cells, isometric contractility of bladder strips, and ex vivo measurements of bladder afferent activity, we explored the role of K V 7 channels as regulators of murine urinary bladder function. The K V 7 activator retigabine (10 μM) had no effect on voltage‐dependent K + currents or resting membrane potential of UBSM cells, suggesting that these cells lacked retigabine‐sensitive K V 7 channels. The K V 7 inhibitor XE‐991 (10 μM) inhibited UBSM K + currents; the properties of these currents, however, were typical of K V 2 channels and not K V 7 channels. Retigabine inhibited voltage‐dependent Ca 2+ channel (VDCC) currents and reduced steady‐state contractions to 60 mM KCl in bladder strips, suggesting that reduction in VDCC current was sufficient to directly affect UBSM function. To determine if retigabine altered ex vivo bladder sensory outflow, we measured afferent activity during simulated transient contractions (TCs) of the bladder wall. Simulated TCs caused bursts of afferent activity that were nearly abolished by retigabine. The effects of retigabine were blocked by co‐incubation with XE‐991, suggesting specific activation of K V 7 channels on afferent nerves. These results indicate that retigabine primarily affects urinary bladder function by inhibiting TC generation and afferent nerve activity, which are key to sensing bladder fullness. Any direct inhibition of UBSM contractility is likely to be from non‐specific effects on VDCCs and K V 2 channels.