A positive modulator of K Ca 2 and K Ca 3 channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591), inhibits bladder afferent firing in vitro and bladder overactivity in vivo

Calcium-activated potassium channels are attractive targets for the development of therapeutics for overactive bladder. In the current study, we addressed the role of calcium-activated potassium channels of small (SK; K(Ca)2) and intermediate (IK; K(Ca)3) conductance in bladder function pharmacologically. We identified and characterized a novel positive modulator of SK/IK channels, 4,5-dichloro-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (NS4591). In whole-cell patch-clamp experiments, NS4591 doubled IK-mediated currents at a concentration of 45 +/- 6 nM(n = 16), whereas 530 +/- 100 nM (n = 7) was required for doubling of SK3-mediated currents. In acutely dissociated bladder primary afferent neurons, the presence of SK channels was verified using apamin and 1-ethyl-2-benzimidazolinone. In these neurons, NS4591 (10 microM) inhibited the number of action potentials generated by suprathreshold depolarizing pulses. NS4591 also reduced carbachol-induced twitches in rat bladder detrusor rings in an apamin-sensitive manner. In vivo, NS4591 (30 mg/kg) inhibited bladder overactivity in rats and cats induced by capsaicin and acetic acid, respectively. In conclusion, the present study supports the involvement of calcium-activated potassium channels in bladder function and identifies NS4591 as a potent modulator of IK and SK channels that is effective in animal models of bladder overactivity.