BK channel activation by NS11021 decreases excitability and contractility of urinary bladder smooth muscle

Abstract

Large-conductance Ca(2+)-activated potassium (BK) channels play an important role in regulating the function and activity of urinary bladder smooth muscle (UBSM), and the loss of BK channel function has been shown to increase UBSM excitability and contractility. However, it is not known whether activation of BK channels has the converse effect of reducing UBSM excitability and contractility. Here, we have sought to investigate this possibility by using the novel BK channel opener NS11021. NS11021 (3 microM) caused an approximately threefold increase in both single BK channel open probability (P(o)) and whole cell BK channel currents. The frequency of spontaneous action potentials in UBSM strips was reduced by NS11021 from a control value of 20.9 + or - 5.9 to 10.9 + or - 3.7 per minute. NS11021 also reduced the force of UBSM spontaneous phasic contractions by approximately 50%, and this force reduction was blocked by pretreatment with the BK channel blocker iberiotoxin. NS11021 (3 microM) had no effect on contractions evoked by nerve stimulation. These findings indicate that activating BK channels reduces the force of UBSM spontaneous phasic contractions, principally through decreasing the frequency of spontaneous action potentials.

Ethanol-mediated relaxation of guinea pig urinary bladder smooth muscle: involvement of BK and L-type Ca2+ channels

“…Supporting data, provided for DSM studies using rat, guinea pig, mouse, and importantly human tissues and cells (5,17,18,22,24,25,46), demonstrate the role of BK channels in the regulation of the resting membrane potential, modulation of the repolarization phase of DSM action potentials, and generation of spontaneous transient BK currents (TBKCs), also known as spontaneous transient outward currents. For example, the BK channel blockade with either iberiotoxin or charybdotoxin prolonged the action potentials correlating with enhanced contractility (16,18), whereas the BK channel opener NS11021 reduced action potential generation and DSM contractility in guinea pigs (29). In human DSM, the selective BK channel inhibitor iberiotoxin and activator NS1619 increased and decreased, respectively, the contractility of tissue strips and excitability of freshly isolated DSM cells confirming the important regulatory role of this K ϩ channel subtype (22,25).…”

“…Isolated DSM cells were allowed to adhere to a glass-plated chamber for at least 30 min and then rinsed with the 140 mM K ϩ solution containing free Ca 2ϩ concentration of ϳ300 nM (WEBMAXC Standard: http://www.stanford.edu/ϳcpatton/ webmaxcS.htm; Chris Patton; see Solutions and compounds). Single BK channel recordings were done on excised inside-out or outside-out patches using symmetrical 140 mM KCl solution for both the bath and pipette compartments based on previous reports (29,34,45) with ϳ300 nM, ϳ2 M, or 10 M free [Ca 2ϩ ], as indicated. In all excised patch single-channel recordings, the pipette solution contained ϳ300 nM free [Ca 2ϩ ].…”

Unique properties of muscularis mucosae smooth muscle in guinea pig urinary bladder

“…Because BK and SK channels play such a central role in mediating action potential repolarization, blocking them with toxins such as iberiotoxin (IbTX) or apamin, respectively, potentiates the detrusor smooth muscle action potential and greatly increases the force of the resulting contractions (32,44,69). Activating BK channels with novel compounds such as NS11021 (43) or SK channels with NS309 decreases contraction force (unpublished observations).…”

“…Nerve-evoked contractions of the detrusor are caused by release of ATP and acetylcholine (ACh) from parasympathetic nerve varicosities onto detrusor myocytes. ATP and ACh bind to purinergic and muscarinic receptors, respectively, triggering action potentials that increase intracellular Ca 2ϩ and initiate contraction (31,43,53). In contrast, SPCs are induced by spontaneous action potentials in detrusor myocytes.…”

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

“…Antimuscarinic drugs, which are currently the primary pharmacologic therapy for OAB, have adverse side effects and limited effectiveness (1). Since BK channels have been identified to play a prominent role in the regulation of DSM excitability and contractility, they may be a valid pharmacological target for the treatment of bladder disorders such as OAB (5,15,20,23,31,34,35,38). Development of drugs that can enhance BK channel activity have been proposed and investigated particularly as a treatment option for urinary bladder dysfunction (3,4,17,37).…”