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

Hristov KL, Parajuli SP, Soder RP, Cheng Q, Rovner ES, Petkov GV. Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels. Am J Physiol Cell Physiol 302: C1632-C1641, 2012. First published March 14, 2012; doi:10.1152/ajpcell.00417.2011.-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 amphotericinperforated 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 mu M) 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 mu M) significantly hyperpolarized the resting membrane potential, and the hyperpolarization was reversed by IBTX (200 nM). NS-1619 (30 mu M) significantly decreased the intracellular Ca2+ level in isolated human DSM cells. BK channel activation with NS-1619 (30 mu M) 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 mu M). Our data suggest that pharmacological activation of BK channels could represent a novel treatment option to control bladder dysfunction in humans.