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NEUROPHARMACOLOGY

A Positive Modulator of K_Ca2 and K_Ca3 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

NeuroSearch A/S, Pederstrupvej, Ballerup, Denmark (C.H., B.S.J., F.R., J.B.-N., L.T., D.S., L.C.B.R.); and Dynogen Pharmaceuticals Inc., Durham, North Carolina (M.O.F., C.C., A.B., M.K., K.B.T., E.C.B.)

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_Ca2) and intermediate (IK; K_Ca3) 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 µM) 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.

Address correspondence to: Dr. Lars Christian B. Rønn, NeuroSearch A/S, Pederstrupvej 93, DK-2750, Ballerup, Denmark. E-mail: lcr{at}neurosearch.dk