Document Detail


NS309 decreases rat detrusor smooth muscle membrane potential and phasic contractions by activating SK3 channels.
MedLine Citation:
PMID:  23145946     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Overactive bladder (OAB) is often associated with abnormally increased detrusor smooth muscle (DSM) contractions. We used NS309, a selective and potent opener of the small or intermediate conductance Ca(2+) -activated K(+) (SK or IK, respectively) channels, to evaluate how SK/IK channel activation modulates DSM function.
EXPERIMENTAL APPROACH: We employed single-cell RT-PCR, immunocytochemistry, whole cell patch-clamp in freshly isolated rat DSM cells and isometric tension recordings of isolated DSM strips to explore how the pharmacological activation of SK/IK channels with NS309 modulates DSM function.
KEY RESULTS: We detected SK3 but not SK1, SK2 or IK channels expression at both mRNA and protein levels by RT-PCR and immunocytochemistry in DSM single cells. NS309 (10 μM) significantly increased the whole cell SK currents and hyperpolarized DSM cell resting membrane potential. The NS309 hyperpolarizing effect was blocked by apamin, a selective SK channel inhibitor. NS309 inhibited the spontaneous phasic contraction amplitude, force, frequency, duration and tone of isolated DSM strips in a concentration-dependent manner. The inhibitory effect of NS309 on spontaneous phasic contractions was blocked by apamin but not by TRAM-34, indicating no functional role of the IK channels in rat DSM. NS309 also significantly inhibited the pharmacologically and electrical field stimulation-induced DSM contractions.
CONCLUSIONS AND IMPLICATIONS: Our data reveal that SK3 channel is the main SK/IK subtype in rat DSM. Pharmacological activation of SK3 channels with NS309 decreases rat DSM cell excitability and contractility, suggesting that SK3 channels might be potential therapeutic targets to control OAB associated with detrusor overactivity.
Authors:
Shankar P Parajuli; Kiril L Hristov; Rupal P Soder; Whitney F Kellett; Georgi V Petkov
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1611-25     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apamin / pharmacology
Cell Size / drug effects
Electric Stimulation
Female
Indoles / pharmacology*
Intermediate-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors,  metabolism*
Ion Channel Gating
Male
Membrane Potentials / drug effects
Muscle Contraction / drug effects
Muscle, Smooth / drug effects*,  physiology
Myocytes, Smooth Muscle / cytology,  drug effects,  physiology
Oximes / pharmacology*
Pyrazoles / pharmacology
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors,  genetics,  metabolism*
Urinary Bladder / drug effects*,  physiology
Grant Support
ID/Acronym/Agency:
DK083687/DK/NIDDK NIH HHS; DK084284/DK/NIDDK NIH HHS; R01 DK084284/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/6,7-dichloro-1H-indole-2,3-dione 3-oxime; 0/Indoles; 0/Intermediate-Conductance Calcium-Activated Potassium Channels; 0/Oximes; 0/Pyrazoles; 0/RNA, Messenger; 0/SK3 protein, rat; 0/Small-Conductance Calcium-Activated Potassium Channels; 0/TRAM 34; 24345-16-2/Apamin
Comments/Corrections

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