SK and IK Ca2+‐activated K+ channels as novel pharmacological targets to control urinary bladder smooth muscle excitability and contractility

Abstract

The role of small conductance Ca2+‐activated K+ (SK) and intermediate conductance Ca2+‐activated K+ (IK) channels in the rat urinary bladder smooth muscle (UBSM) excitability and contractility was studied using the novel SK/IK channel opener – NS309 and the SK and IK channels specific inhibitors, apamin and TRAM‐34, respectively. To identify SK/IK channels in rat UBSM, we employed studies on UBSM contractility and the perforated patch‐clamp technique. NS309 inhibits spontaneous contraction amplitude, frequency, force, and muscle tone of isolated UBSM strips. In current‐clamp mode, NS309 caused ∼2 mV membrane potential hyperpolarization in single UBSM cells. Apamin increased UBSM spontaneous contraction amplitude and frequency, whereas TRAM‐34 had no effect on spontaneous contractility. Pretreatment with NS309 followed by a washout of the drug led to an increase in UBSM contractility indicating for a functional role of the IK channel in this tissue. Both apamin and TRAM‐34 shifted the NS309 concentration‐response curves for spontaneous contractility to the right. Apamin and TRAM‐34 had no significant effect on the resting membrane potential but blocked NS309‐induced hyperpolarization. Collectively, our data reveal a functional role of the IK channel in rat UBSM and suggest that both SK/IK channels are potential therapeutic targets to control overactive urinary bladder. Supported by DK070909 to G.V.P.