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.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Hougaard, C; Fraser, MO; Chien, C; Bookout, A; Katofiasc, M; Jensen, BS; Rode, F; Bitsch-Nørhave, J; Teuber, L; Thor, KB; Strøbaek, D; Burgard, EC; Rønn, LCB

Published Date

  • January 2009

Published In

Volume / Issue

  • 328 / 1

Start / End Page

  • 28 - 39

PubMed ID

  • 18820135

Pubmed Central ID

  • 18820135

Electronic International Standard Serial Number (EISSN)

  • 1521-0103

Digital Object Identifier (DOI)

  • 10.1124/jpet.108.143123

Language

  • eng

Conference Location

  • United States