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 Ca2+ -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.
Written by:
Parajuli SP, Hristov KL, Soder RP, Kellett WF, Petkov GV. Are you the author?
Pharmaceutical & Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, 29208.
Reference: Br J Pharmacol. 2012 Nov 12. Epub ahead of print.
doi: 10.1111/bph.12049
PubMed Abstract
PMID: 23145946
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