TY - JOUR

T1 - Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder

AU - Rode, Frederik

AU - Svalø, Julie

AU - Sheykhzade, Majid

AU - Rønn, Lars Christian B

N1 - Copyright © 2010 Elsevier B.V. All rights reserved. Paper id:: 20385123

PY - 2010

Y1 - 2010

N2 - The anticonvulsant retigabine has previously been reported to inhibit bladder overactivity in rats in vivo but the mechanism and site of action are not known. In the present study we investigated the effect of retigabine in isolated rat bladder tissue. Bladders from Sprague-Dawley rats were cut transversally into rings and mounted on an isometric myograph. The average tension, the amplitude and frequency of bladder muscle twitches were measured. The bladder tissue was stimulated with carbachol, KCl (5, 10 and 60mM), and by electric field stimulation. Dose-response curves were obtained with increasing concentrations of the KCNQ((2-5)) selective positive modulator, retigabine or with the KCNQ((1-5)) negative modulator XE991. Retigabine experiments were repeated in the presence of 10microM XE991. Retigabine reduced both the contractility and the overall tonus of bladder tissue independent of the mode of stimulation with EC(50) values ranging from 3.3microM (20mM KCl) to 8.3microM (0.2microM carbachol). In support of a KCNQ-specific effect, retigabine had only weak effects after 60mM KCl pre treatment and all retigabine effects could be reversed by XE991. XE991 increased both the amplitude and mean tension of the bladder but was more potent at increasing the number rather than the size of the stimulated twitches. In conclusion, this study demonstrates an efficacious KCNQ dependent effect of retigabine and XE991 on rat bladder contractility.

AB - The anticonvulsant retigabine has previously been reported to inhibit bladder overactivity in rats in vivo but the mechanism and site of action are not known. In the present study we investigated the effect of retigabine in isolated rat bladder tissue. Bladders from Sprague-Dawley rats were cut transversally into rings and mounted on an isometric myograph. The average tension, the amplitude and frequency of bladder muscle twitches were measured. The bladder tissue was stimulated with carbachol, KCl (5, 10 and 60mM), and by electric field stimulation. Dose-response curves were obtained with increasing concentrations of the KCNQ((2-5)) selective positive modulator, retigabine or with the KCNQ((1-5)) negative modulator XE991. Retigabine experiments were repeated in the presence of 10microM XE991. Retigabine reduced both the contractility and the overall tonus of bladder tissue independent of the mode of stimulation with EC(50) values ranging from 3.3microM (20mM KCl) to 8.3microM (0.2microM carbachol). In support of a KCNQ-specific effect, retigabine had only weak effects after 60mM KCl pre treatment and all retigabine effects could be reversed by XE991. XE991 increased both the amplitude and mean tension of the bladder but was more potent at increasing the number rather than the size of the stimulated twitches. In conclusion, this study demonstrates an efficacious KCNQ dependent effect of retigabine and XE991 on rat bladder contractility.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.ejphar.2010.03.050

DO - 10.1016/j.ejphar.2010.03.050

M3 - Journal article

C2 - 20385123

VL - 638

SP - 121

EP - 127

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

IS - 1-3

ER -