Kv7 channels in the human urinary bladder

Physiology 2014 (London, UK) (2014) Proc Physiol Soc 31, PCA198

Poster Communications: Kv7 channels in the human urinary bladder

J. Svalø1,2, M. Sheykhzade1, J. Nordling3, C. Matras4, P. Bouchelouche2

1. Dept. of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. 2. Smooth Muscle Research Center, K°ge Hospital, K°ge, Denmark. 3. Dept. of Urology, Herlev Hospital, Herlev, Denmark. 4. Dept. of Urology, Nµstved Hospital, Nµstved, Denmark.

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Up to 17% of the adult population suffers from overactive bladder, a disease that is related to urine storage and is often due to increased reflex activity of the bladder wall. Patients with overactive bladder suffer from a high frequency of voiding both at day and at night, in combination with an increased urge to void. Importantly, most of the patients have an impaired quality-of-life due to incontinence. In the present study we aim at elucidating novel treatment targets for overactive bladder, more specifically Kv7 potassium channels. This is done by functional studies and expression analysis using myography and qRT-PCR, respectively, as previously described by Svalø et al (2013). The studies are performed on human bladder specimens from patients with normal bladder function (n=13) and from patients with bladder outlet obstruction (n=3). Biopsies are obtained at cystoscopy or cystectomy after informed written consent. Values are presented as mean values ± S.E.M. and statistical significance is evaluated by Mann Whitney t-test or by two-way ANOVA followed by Bonferroni post test for qRT-PCR and myograph data, respectively.We have shown that in the urinary bladder of humans, mRNA transcript of KCNQ4 and KCNQ5 was abundantly expressed in both patient groups compared to heart tissue. To be precise, KCNQ4 and KCNQ5 mRNA was 4.1- and 56-fold higher in normal bladder tissue (n=7) compared to heart tissue (P<0.05). These findings were supported by organ bath studies using bladder biopsies; the positive modulator retigabine (ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate, Kv7.2 – 7.5, 0.01 – 30µM) induced a concentration-dependent reduction in mean tension on 1µM carbachol-precontracted bladder strips. This effect was equal in magnitude to that of the more selective positive modulator ML213 (N-mesitylbicyclo[2.2.1]heptane-2-carboxamide, Kv7.2 and Kv7.4, 0.01 – 30µM) (P=0.20). The potency of retigabine (n=6) and ML213 (n=6) was 2.08 µM (1.26 – 2.91µM) and 1.01µM (0.69 – 1.33µM) whereas the maximum efficacy was 48.01 ± 3.70% and 42.51 ±2.60%, respectively.The expression profile and the potency of Kv7 channel modulators indicate that the use of selective Kv7.4 or Kv7.5 channel modulators could prove useful for the treatment of overactive bladder.



Where applicable, experiments conform with Society ethical requirements.

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