Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels

Kiril L. Hristov, Shankar P. Parajuli, Rupal P. Soder, Qiuping Cheng, Eric S. Rovner, Georgi Petkov

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Overactive bladder syndrome is frequently associated with increased detrusor smooth muscle (DSM) contractility. We tested the hypothesis that pharmacological activation of the large-conductance voltage- and Ca2+-activated K+ (BK) channel with NS-1619, a selective BK channel opener, reduces the excitability and contractility of human DSM. We used the amphotericin-perforated whole cell patch-clamp technique on freshly isolated human DSM cells, live-cell Ca2+ imaging, and isometric DSM tension recordings of human DSM strips obtained from open bladder surgeries. NS-1619 (30 μM) significantly increased the amplitude of the voltage step-induced whole cell BK currents, and this effect was abolished by pretreatment with 200 nM iberiotoxin (IBTX), a selective BK channel inhibitor. In current-clamp mode, NS-1619 (30 μM) significantly hyperpolarized the resting membrane potential, and the hyperpolarization was reversed by IBTX (200 nM). NS-1619 (30 μM) significantly decreased the intracellular Ca2+ level in isolated human DSM cells. BK channel activation with NS-1619 (30 μM) significantly inhibited the amplitude, muscle force, frequency, duration, and tone of the spontaneous phasic and pharmacologically induced DSM contractions from human DSM isolated strips. IBTX (200 nM) suppressed the inhibitory effects of NS-1619 on spontaneous contractions. The amplitude of electrical field stimulation (0.5-50 Hz)-induced contractions was significantly reduced by NS-1619 (30 μM). Our data suggest that pharmacological activation of BK channels could represent a novel treatment option to control bladder dysfunction in humans.

Original languageEnglish (US)
Pages (from-to)1632-1641
Number of pages10
JournalAmerican Journal of Physiology - Cell Physiology
Volume302
Issue number11
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

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Calcium-Activated Potassium Channels
Large-Conductance Calcium-Activated Potassium Channels
Smooth Muscle
Pharmacology
Smooth Muscle Myocytes
Urinary Bladder
Overactive Urinary Bladder
Muscle Tonus
Amphotericin B
Patch-Clamp Techniques
Muscle Contraction
NS 1619
Membrane Potentials
Electric Stimulation
Muscles

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Physiology

Cite this

Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels. / Hristov, Kiril L.; Parajuli, Shankar P.; Soder, Rupal P.; Cheng, Qiuping; Rovner, Eric S.; Petkov, Georgi.

In: American Journal of Physiology - Cell Physiology, Vol. 302, No. 11, 01.06.2012, p. 1632-1641.

Research output: Contribution to journalArticle

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