Kv7 Positive Modulators Reduce Detrusor Overactivity and Increase Bladder Capacity in Rats

The effects of the K(v)7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of K(v)7 openers for the treatment of overactive bladder. In organ bath studies, capsaicin-stimulated rat urinary bladder rings were exposed to retigabine and XE991 and the effect on tension and amplitude was evaluated. In anaesthetized rats, retigabine (0.01-1 mg /kg, i.v.) effects on bladder function, in which overactivity was induced by continuous infusion of 0.5% acetic acid, were assessed. The effect of retigabine (10 mg/kg, p.o.) on cystometric parameters was also measured in conscious rats with capsaicin-induced irritated bladders. Localization of K(v)7 subunits within bladder tissue was analysed by RT-qPCR and western blotting. In organ bath studies, retigabine robustly reduced capsaicin-induced contractility of bladder rings and this effect was blocked by XE991 confirming the specificity of action via K(v)7 channels. In anaesthetized rats with acetic acid-irritated bladders, retigabine markedly increased bladder capacity with no concomitant reduction in blood pressure. Retigabine also reduced bladder pressure and delayed voiding in conscious rats with capsaicin-irritated bladders. K(v)7.1, K(v)7.4 and K(v)7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that K(v)7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other K(v)7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of K(v)7 channels expressed in bladder tissue.