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.
Hougaard
C
C
NeuroSearch A/S, Pederstrupvej 93, DK-2750, Ballerup, Denmark.
Fraser
M O
MO
Chien
C
C
Bookout
A
A
Katofiasc
M
M
Jensen
B S
BS
Rode
F
F
Bitsch-Nørhave
J
J
Teuber
L
L
Thor
K B
KB
Strøbaek
D
D
Burgard
E C
EC
Rønn
L C B
LC
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000344:Afferent Pathways / Q000187:drug effects*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney; D015636:Magnesium Chloride / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation* / Q000502:physiology*; D014554:Urination / Q000187:drug effects / Q000502:physiology
C534785:4,5-dichloro-1,3-diethyl-1,3-dihydrobenzoimidazol-2-one; D001562:Benzimidazoles; D018118:Chloride Channels; D015221:Potassium Channels; D051640:Small-Conductance Calcium-Activated Potassium Channels; D015636:Magnesium Chloride; D002122:Calcium Chloride; D011188:Potassium