Small (SK) and intermediate (IK) conductance Ca2+-activated K+ channels have been suggested to be involved in determining the excitability and contractility of detrusor smooth muscle (DSM). We used SKA-31, a novel SK/IK channel activator to probe the therapeutic potential of SK/IK channel activation to control bladder function. Isometric tension recordings of isolated Guinea pig DSM strips indicated that SKA-31 (100 nM-10 μM) significantly inhibited the spontaneous contraction amplitude, muscle force, frequency, and duration. This inhibitory effect was blocked by apamin (1 μM), a selective SK channel inhibitor. SK channel activation with SKA-31 (3 μM) also reduced the contractions evoked by electrical field stimulation. TRAM-34 (30 μM), an IK channel selective inhibitor, did not suppress the inhibitory effect of SKA-31, indicating a role only for the SK channel in detrusor contractility. Using the perforated patch-clamp technique, we observed that SKA-31 (10 μM) increased the voltage-step induced SK currents in freshly isolated DSM cells. In current clamp mode, SKA-31 (10 μM) hyperpolarized the resting membrane potential by ~3 mV. These effects were blocked by apamin (1 μM). Collectively, our data indicate that activation of SK channels may provide a novel therapeutic approach to control bladder function. Supported by NIH DK084284 & DK083687 to GVP. SKA-31 is a gift from Dr. Heike Wulff.