Bladder contractility is modulated by Kv7 channels in pig detrusor

Julie Svalø; Michala Bille; Neeraja Parameswaran Theepakaran; Majid Sheykhzade; Jørgen Nordling; Pierre Bouchelouche

doi:10.1016/j.ejphar.2013.05.005

Bladder contractility is modulated by Kv7 channels in pig detrusor

Julie Svalø, Michala Bille, Neeraja Parameswaran Theepakaran, Majid Sheykhzade, Jørgen Nordling, Pierre Bouchelouche

20 Citations (Scopus)

Abstract

K_v7 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 K_v7 channels in detrusor, i.e. pig bladder, with a view to determining the effects of the following potassium channel activators: ML213 (K_v7.2/K_v7.4 channels) and retigabine (K_v7. 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 K_v7.2 and/or K_v7.4 channels constitute the subtypes that are relevant to bladder contractility. The effects of retigabine and ML213 were attenuated by pre-incubation with 10 μM XE991 (K_v7.1-7.5 channel blocker) (P<0.05), which in turn confirmed K_v7 channel selectivity. Subtype-selective effects were further investigated by incubating the detrusor with 10 μM chromanol 293B (K_v7.1 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 K_v7 channels in detrusor. qRT-PCR studies of the mRNA transcript level of K_v7.3-7.5 channels displayed a higher level of K_v7.4 transcript in detrusor compared to that present in brain cortex and heart tissues. Thus, we have shown that K_v7.4 channels are expressed and functionally active in pig detrusor, and that the use of selective K_v7.4 channel modulators in the treatment of detrusor overactivity seems promising.

Original language	English
Journal	European Journal of Pharmacology
Volume	715
Issue number	1-3
Pages (from-to)	312-320
Number of pages	9
ISSN	0014-2999
DOIs	https://doi.org/10.1016/j.ejphar.2013.05.005
Publication status	Published - 21 May 2013

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@article{1092944bb38b44df9445c78233531277,

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 10 μM 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 10 μM 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.",

author = "Julie Sval{\o} and Michala Bille and {Parameswaran Theepakaran}, Neeraja and Majid Sheykhzade and J{\o}rgen Nordling and Pierre Bouchelouche",

note = "Copyright {\textcopyright} 2013. Published by Elsevier B.V.",

year = "2013",

month = may,

day = "21",

doi = "10.1016/j.ejphar.2013.05.005",

language = "English",

volume = "715",

pages = "312--320",

journal = "European Journal of Pharmacology",

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TY - JOUR

T1 - Bladder contractility is modulated by Kv7 channels in pig detrusor

AU - Svalø, Julie

AU - Bille, Michala

AU - Parameswaran Theepakaran, Neeraja

AU - Sheykhzade, Majid

AU - Nordling, Jørgen

AU - Bouchelouche, Pierre

PY - 2013/5/21

Y1 - 2013/5/21

N2 - 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 10 μM 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 10 μM 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.

AB - 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 10 μM 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 10 μM 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.

U2 - 10.1016/j.ejphar.2013.05.005

DO - 10.1016/j.ejphar.2013.05.005

M3 - Journal article

C2 - 23707187

SN - 0014-2999

VL - 715

SP - 312

EP - 320

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1-3

ER -

Bladder contractility is modulated by Kv7 channels in pig detrusor

Abstract

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