title: Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels.
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 Ca(2+)-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 Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, USA.
authors.forename: Kiril L
authors.initials: KL
authors.lastname: Hristov
authors.forename: Shankar P
authors.initials: SP
authors.lastname: Parajuli
authors.forename: Rupal P
authors.initials: RP
authors.lastname: Soder
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Cheng
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rovner
authors.forename: Georgi V
authors.initials: GV
authors.lastname: Petkov
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000502:physiology; D005260:Female; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D001562:Benzimidazoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; C086491:NS 1619; C064719:iberiotoxin; D002118:Calcium