TY - JOUR
T1 - Kv 7 Positive Modulators Reduce Detrusor Overactivity and Increase Bladder Capacity in Rats
AU - Svalø, Julie
AU - Hansen, Henrik H
AU - Rønn, Lars Christian B
AU - Sheykhzade, Majid
AU - Munro, Gordon
AU - Rode, Frederik
AU - Jakobsen, Julie Svalø
N1 - © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.
PY - 2012/2
Y1 - 2012/2
N2 - The effects of the Kv 7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of Kv 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 Kv 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 Kv 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. Kv 7.1, Kv 7.4 and Kv 7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that Kv 7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other Kv 7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of Kv 7 channels expressed in bladder tissue.
AB - The effects of the Kv 7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of Kv 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 Kv 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 Kv 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. Kv 7.1, Kv 7.4 and Kv 7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that Kv 7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other Kv 7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of Kv 7 channels expressed in bladder tissue.
U2 - 10.1111/j.1742-7843.2011.00765.x
DO - 10.1111/j.1742-7843.2011.00765.x
M3 - Journal article
C2 - 21895977
SN - 1742-7843
VL - 110
SP - 145
EP - 153
JO - Basic & Clinical Pharmacology & Toxicology Online
JF - Basic & Clinical Pharmacology & Toxicology Online
IS - 2
ER -