title: Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder.
abstract: 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 10 microM 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 3.3 microM (20mM KCl) to 8.3 microM (0.2 microM 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.
authors.affiliation: Neurosearch A/S, Ballerup, Denmark. Fro@neurosearch.com
authors.forename: Frederik
authors.initials: F
authors.lastname: Rode
authors.forename: Julie
authors.initials: J
authors.lastname: Svalø
authors.forename: Majid
authors.initials: M
authors.lastname: Sheykhzade
authors.forename: Lars Christian B
authors.initials: LC
authors.lastname: Rønn
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000927:Anticonvulsants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002219:Carbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D010655:Phenylenediamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011189:Potassium Chloride / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D000927:Anticonvulsants; D002219:Carbamates; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; C101866:ezogabine; D011189:Potassium Chloride; D002217:Carbachol