title: Bladder contractility is modulated by Kv7 channels in pig detrusor.
abstract: Kv7 channels are involved in smooth muscle relaxation, and accordingly we believe that they constitute potential targets for the treatment of overactive bladder syndrome. We have therefore used myography to examine the function of Kv7 channels in detrusor, i.e. pig bladder, with a view to determining the effects of the following potassium channel activators: ML213 (Kv7.2/Kv7.4 channels) and retigabine (Kv7.2-7.5 channels). Retigabine produced a concentration-dependent relaxation of carbachol- and electric field-induced contractions. The potency was similar in magnitude to that of ML213-induced relaxation, suggesting that Kv7.2 and/or Kv7.4 channels constitute the subtypes that are relevant to bladder contractility. The effects of retigabine and ML213 were attenuated by pre-incubation with 10µM XE991 (Kv7.1-7.5 channel blocker) (P<0.05), which in turn confirmed Kv7 channel selectivity. Subtype-selective effects were further investigated by incubating the detrusor with 10µM chromanol 293B (Kv7.1 channel blocker). Regardless of the experimental protocol, this did not cause a further increase in the evoked contraction. In contrast, the addition of XE991 potentiated the KCl-induced contractions, but not those induced by carbachol or electric field, indicating the presence of a phosphatidyl-inositol-4,5-biphosphate-dependent mechanism amongst the Kv7 channels in detrusor. qRT-PCR studies of the mRNA transcript level of Kv7.3-7.5 channels displayed a higher level of Kv7.4 transcript in detrusor compared to that present in brain cortex and heart tissues. Thus, we have shown that Kv7.4 channels are expressed and functionally active in pig detrusor, and that the use of selective Kv7.4 channel modulators in the treatment of detrusor overactivity seems promising.
authors.affiliation: Smooth Muscle Research Center, Department of Clinical Biochemistry, Copenhagen University Hospital at Koege, Denmark. juliesvaloe@hotmail.com
authors.forename: Julie
authors.initials: J
authors.lastname: Svalø
authors.forename: Michala
authors.initials: M
authors.lastname: Bille
authors.forename: Neeraja
authors.initials: N
authors.lastname: Parameswaran Theepakaran
authors.forename: Majid
authors.initials: M
authors.lastname: Sheykhzade
authors.forename: Jørgen
authors.initials: J
authors.lastname: Nordling
authors.forename: Pierre
authors.initials: P
authors.lastname: Bouchelouche
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D009213:Myography; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects*
chemical_list: D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D011189:Potassium Chloride; D002217:Carbachol
keywords: Detrusor; K(v)7 channels; KCNQ channels; Lower urinary tract symptoms; ML213; Overactive bladder syndrome; Retigabine