TY - JOUR
T1 - Kv7 positive modulators reduce detrusor over-activity and increase bladder capacity in rats
AU - Svaloe, Julie
AU - Hansen, Henrik H.
AU - Rønn, Lars Christian B.
AU - Sheykhzade, Majid
AU - Munro, Gordon John
AU - Rode, Frederik
PY - 2012/2
Y1 - 2012/2
N2 - The effects of the K v7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of K v7 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 (0.01-1mg/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 (10mg/kg, p.o.) on cystometric parameters was also measured in conscious rats with capsaicin-induced irritated bladders. Localization of K v7 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 K v7 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. K v7.1, K v7.4 and K v7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that K v7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other K v7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of K v7 channels expressed in bladder tissue.
AB - The effects of the K v7 channel modulators retigabine (opener) and XE991 (blocker) on rat bladder function were investigated ex vivo and in vivo to assess the potential of K v7 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 (0.01-1mg/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 (10mg/kg, p.o.) on cystometric parameters was also measured in conscious rats with capsaicin-induced irritated bladders. Localization of K v7 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 K v7 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. K v7.1, K v7.4 and K v7.5 subunit mRNA transcripts were detected in rat bladder. Western blot analysis confirmed that K v7.4 subunit protein was expressed in rat bladder. These results suggest that retigabine and other K v7 channel positive modulators may have beneficial effects on bladder overactivity partly via activation of K v7 channels expressed in bladder tissue.
KW - Det tidligere Farmaceutiske Fakultet
U2 - 10.1111/j.1742-7843.2011.00765.x
DO - 10.1111/j.1742-7843.2011.00765.x
M3 - Tidsskriftartikel
SN - 1742-7835
VL - 110
SP - 145
EP - 153
JO - Basic and Clinical Pharmacology and Toxicology
JF - Basic and Clinical Pharmacology and Toxicology
IS - 2
ER -