Effects of potassium channel modulators on human detrusor smooth muscle myogenic phasic contractile activity: Potential therapeutic targets for overactive bladder

ObjectivesIncreased urinary bladder detrusor smooth muscle phasic contractility has been suggested to be associated with idiopathic bladder overactivity (OAB). We examined the role of voltage-dependent l-type calcium channels, adenosine triphosphate-sensitive potassium (KATP) channels, and calcium-activated potassium (BKCa and SKCa) channels in the regulation of human detrusor phasic contractile activity.MethodsIsolated human bladder strip phasic contractions were measured and quantified as the mean area under the force-time curve, amplitude, and frequency of phasic contractions in 22 bladder samples.ResultsHuman detrusor strips displayed myogenic phasic contractions in the presence of atropine (10−6 M), phentolamine (10−6 M), propranolol (10−6 M), suramin (10−5 M), and tetrodotoxin (10−6 M). The l-type calcium channel inhibitor nifedipine (300 nM) abolished the contractile activity. Blockade of KATP channels by glibenclamide (1 and 10 μM) did not alter myogenic contractions. In contrast, the KATP channel opener pinacidil (10 μM) markedly inhibited phasic contractility. Iberiotoxin (100 nM) and apamin (100 nM), potent and selective inhibitors of BKCa and SKCa channels, respectively, significantly increased the area under the force-time curve and the amplitude of contractions.ConclusionsPhasic contractions of human detrusor are dependent on calcium entry through l-type calcium channels. BKCa and SKCa channels play a key role in the modulation of human detrusor smooth muscle phasic contractility. Furthermore, these observations support the concept that increasing conductance through KATP, BKCa, and SKCa channels may represent attractive pharmacologic targets for decreasing phasic contractions of detrusor smooth muscle in OAB.