Abstract
METHODS: Using isometric DSM tension recordings, Ca imaging, and amphotericin-B perforated patch-clamp electrophysiology, we elucidated the role of ML-213-sensitive KCNQ channels in regulating guinea pig DSM excitability and contractility. RESULTS: ML-213 concentration-dependently (100 nM-30 mM) inhibited spontaneous phasic, pharmacologically-induced, and nerveevoked contractions in DSM isolated strips. ML-213 (10 mM) decreased the global intracellular Ca concentration and inhibited spontaneous Ca transients, effects blocked by the L-type voltage-gated Ca (CaV) channel inhibitor nifedipine (1 mM) and the KCNQ1KCNQ5 channel inhibitor XE991 (10 mM). These data suggests that ML-213 decreases the global intracellular Ca concentration by inhibiting L-type CaV channels through an indirect mechanism downstream from KCNQ channel activation. In addition, ML-213 hyperpolarized the cell membrane potential and inhibited spontaneous action potentials in DSM cells, effects reversible by washout. We next aimed to examine the effects of ML-213 on whole cell KCNQ currents. To isolate KCNQ currents, the bath solution contained the large conductance voltageand Ca-activated K channel inhibitor paxilline (1 mM) and gadolinium chloride (GdCl3, 100 mM), which blocks L-type CaV channels and nonselective cation channels. Under these experimental conditions, ML213 (10 mM) enhanced whole cell KCNQ currents. These findings suggest that the modulation of K transport through ML-213-sensitive KCNQ channels underlies ML-213-induced cell membrane hyperpolarization to decrease the global intracellular Ca concentration and DSM contractility. CONCLUSIONS: These results, using the novel KCNQ channel opener ML-213, suggest that KCNQ2-, KCNQ4-, and KCNQ5-containing channels are essential regulators of the excitability and contractility of DSM, and therefore could represent novel molecular targets for pharmacological or genetic control of overactive bladder.
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