Potential therapeutic targets for the treatment of detrusor overactivity

Chess‐Williams, Russell

doi:10.1517/14728222.8.2.95

Cited by 26 publications

(10 citation statements)

References 78 publications

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“…Muscarinic receptor antagonists that impair UBSM contractility are the main option, but they have limited effectiveness and undesirable side effects (1,23). In recent years, ␤ 3 -adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, and K ϩ channel openers have all been considered to be potential candidates for the treatment of OAB syndrome (10). In this study, urinary pattern analysis using G833C-NCX1.3 tg/tg mice, in which the G883C mutation confers a resistance to KB-R7943-mediated inhibition (22), failed to reproduce the inhibitory effect of KB-R7943 on frequent urination detected in NCX1.3 tg/tg mice.…”

Section: Discussionmentioning

confidence: 99%

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Yamamura

Cole

Kita

et al. 2013

American Journal of Physiology-Cell Physiology

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The Na(+)/Ca(2+) exchanger (NCX) is thought to be a key molecule in the regulation of cytosolic Ca(2+) dynamics. The relative importance of the two Ca(2+) transport modes of NCX activity leading to Ca(2+) efflux (forward) and influx (reverse) in smooth muscle, however, remains unclear. Unexpectedly, spontaneous contractions of urinary bladder smooth muscle (UBSM) were enhanced in transgenic mice overexpressing NCX1.3 (NCX1.3(tg/tg)). The enhanced activity was attenuated by KB-R7943 or SN-6. Whole cell outward NCX current sensitive to KB-R7943 or Ni(2+) was readily detected in UBSM cells from NCX1.3(tg/tg) but not wild-type mice. Spontaneous Ca(2+) transients in myocytes of NCX1.3(tg/tg) were larger and frequently resulted in propagating events and global elevations in cytosolic Ca(2+) concentration. Significantly, NCX1.3(tg/tg) mice exhibited a pattern of more frequent urination of smaller volumes and this phenotype was reversed by oral administration of KB-R7943. On the other hand, KB-R7943 did not improve it in KB-R7943-insensitive (G833C-)NCX1.3(tg/tg) mice. We conclude that NCX1.3 overexpression is associated with abnormal urination owing to enhanced Ca(2+) influx via reverse mode NCX leading to prolonged, propagating spontaneous Ca(2+) release events and a potentiation of spontaneous UBSM contraction. These findings suggest the possibility that NCX is a candidate molecular target for overactive bladder therapy.

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Section: Discussionmentioning

confidence: 99%

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Yamamura

Cole

Kita

et al. 2013

American Journal of Physiology-Cell Physiology

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“…There are data reporting that there are more M 2 receptors in the bladder than M 3 . Despite this, we do not know what physiological role these receptors serve or where they are located [17–22]. Possible mechanisms involving the M 2 ‐dependent regulation of detrusor contraction have been suggested.…”

Section: Discussionmentioning

confidence: 99%

Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M₃‐ and M₂‐dependent components of a motor/sensory system

2007

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OBJECTIVES To analyse pressure changes induced by muscarinic agonists on the isolated bladder in order to examine whether there are different responses representing different components of a motor/sensory system within the bladder wall. MATERIALS AND METHODS Whole isolated bladders from 19 female guinea‐pigs (280–400 g) were used. A cannula was inserted into the urethra to monitor intravesical pressure and the bladder was suspended in a heated chamber containing carboxygenated physiological solution at 33–36 °C. Initially, the responses to the cholinergic agonists, arecaidine but‐2‐ynyl ester tosylate and carbachol were assessed. Then, in an attempt to identify the muscarinic receptor subtypes involved, the effects of selective muscarinic antagonists on the arecaidine‐induced bladder responses were assessed. The antagonists used were the relatively M3‐selective 4‐diphenylacetoxy‐N‐methylpiperidine methobromide (4‐DAMP) and darifenicin, and relatively M2‐selective AFDX‐116. All drugs were added to the solution bathing the ablumenal surface of the bladder. RESULTS The whole bladders exposed to cholinergic agonists respond with complex changes in intravesical pressure. Immediately after application of the agonist there was a burst of high frequency transient contractions. During continued application of agonist the frequency of the transients decreased and their amplitude increased. Thus, there appear to be two components to the response: an initial fast phase and a later slow component. The maximum frequency of the initial burst increased with increasing concentrations of agonist. By contrast, the frequency of the transients in the steady state showed little dependence on agonist concentration. There were quantitative differences between the responses to arecaidine and carbachol. Arecaidine was less effective in generating the initial burst of high‐frequency activity and the transients were significantly larger. At low dose, arecaidine was more effective in producing the large transients in the steady state. Pre‐exposure of the bladder to 4‐DAMP (0.1–10 nm) or darifenicin (0.1–10 nm) significantly reduced the frequency of the initial burst of activity; 0.3 nm 4‐DAMP reduced the frequency by half. In this concentration range, 4‐DAMP reduced the amplitude of the initial transients but did not affect the frequency of the transients in the steady state. There were similar results with darifenicin. However, darifenicin was less effective in reducing the amplitude of the initial transients. By contrast, ADFX‐116 had little effect on the frequency of the initial transients but did reduce amplitude; 300 nm AFDX‐116 was needed to reduce the frequency of the initial burst by half. CONCLUSIONS This analysis suggests that there are different but interrelated mechanisms in the isolated bladder contributing to complex contractile activity. Three components can be identified: a mechanism operating during voiding to produce a global contraction of the whole bladder and two mechanisms, pacemaker and conductive, involved in generati...

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“…Release of chemical mediators (NO, ATP, acetylcholine, substance P, PGs) (10,11,19,26,28,33) from urothelial cells suggests that these cells exhibit specialized sensory and signaling properties that could allow reciprocal communication with neighboring urothelial cells as well as nerves or other cells (i.e., immune, myofibroblasts, inflammatory) in the bladder wall. Recent studies have shown that both afferent as well as autonomic axons are located in close proximity to the urothelium (8,12).…”

Section: "Transducer" Function Of the Urothelium And Cell-cell Signalingmentioning

confidence: 99%

More than just a barrier: urothelium as a drug target for urinary bladder pain

Birder

2005

American Journal of Physiology-Renal Physiology

162

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Although the urinary bladder urothelium has classically been thought of as a passive barrier to ions/solutes, a number of novel properties have been recently attributed to these cells. Studies have revealed that the urothelium is involved in sensory mechanisms (i.e., ability to express a number of sensor molecules or respond to thermal, mechanical, and chemical stimuli) and can release chemical mediators. Localization of afferent nerves next to the urothelium suggests these cells may be targets for transmitters released from bladder nerves or that chemicals released by urothelial cells may alter afferent excitability. Taken together, these and other findings highlighted in this review suggest a sensory function for the urothelium. Elucidation of mechanisms impacting on urothelial function may provide insights into the pathology of bladder dysfunction.

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Potential therapeutic targets for the treatment of detrusor overactivity

Cited by 26 publications

References 78 publications

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M₃‐ and M₂‐dependent components of a motor/sensory system

More than just a barrier: urothelium as a drug target for urinary bladder pain

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Potential therapeutic targets for the treatment of detrusor overactivity

Cited by 26 publications

References 78 publications

Overactive bladder mediated by accelerated Ca2+ influx mode of Na+/Ca2+ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca2+ influx mode of Na+/Ca2+ exchanger in smooth muscle

Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M3‐ and M2‐dependent components of a motor/sensory system

More than just a barrier: urothelium as a drug target for urinary bladder pain

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Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Overactive bladder mediated by accelerated Ca²⁺ influx mode of Na⁺/Ca²⁺ exchanger in smooth muscle

Cholinergic activation of phasic activity in the isolated bladder: possible evidence for M₃‐ and M₂‐dependent components of a motor/sensory system