NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation

Luke Grundy, Russ Chess-Williams, Stuart M. Brierley, Kylie Mills, Kate Hilda Moore, Kylie Mansfield, Roselyn Rose’Meyer, Donna J Sellers, David Grundy

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Tachykinins are expressed within bladder innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium, or sensory afferents directly. Here we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signalling from the bladder during distension, urothelial transmitter release ex-vivo, and direct responses to NKA on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100nM). Intravesical NKA significantly decreased bladder compliance, but had no direct effect on mechanosensitivity to bladder distension (30µl/min). GR159897 alone enhanced bladder compliance, but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells, but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, while acetylcholine levels were reduced. NKA mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.
Original languageEnglish
Pages (from-to)F1174-F1185
JournalAmerican Journal of Physiology - Renal Physiology
Volume315
Issue number4
Early online date13 Jun 2018
DOIs
Publication statusPublished - 5 Oct 2018

Fingerprint

Urinary Bladder
Tachykinins
Diagnosis-Related Groups
Compliance
Tachykinin Receptors
Neurons
Urothelium
Urination
Nifedipine
Baths
Acetylcholine
Adenosine Triphosphate
Calcium
Pressure

Cite this

Grundy, Luke ; Chess-Williams, Russ ; Brierley, Stuart M. ; Mills, Kylie ; Moore, Kate Hilda ; Mansfield, Kylie ; Rose’Meyer, Roselyn ; Sellers, Donna J ; Grundy, David. / NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 315, No. 4. pp. F1174-F1185.
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abstract = "Tachykinins are expressed within bladder innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium, or sensory afferents directly. Here we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signalling from the bladder during distension, urothelial transmitter release ex-vivo, and direct responses to NKA on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100nM). Intravesical NKA significantly decreased bladder compliance, but had no direct effect on mechanosensitivity to bladder distension (30µl/min). GR159897 alone enhanced bladder compliance, but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells, but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, while acetylcholine levels were reduced. NKA mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.",
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NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation. / Grundy, Luke; Chess-Williams, Russ; Brierley, Stuart M.; Mills, Kylie; Moore, Kate Hilda; Mansfield, Kylie; Rose’Meyer, Roselyn; Sellers, Donna J; Grundy, David.

In: American Journal of Physiology - Renal Physiology, Vol. 315, No. 4, 05.10.2018, p. F1174-F1185.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Grundy, Luke

AU - Chess-Williams, Russ

AU - Brierley, Stuart M.

AU - Mills, Kylie

AU - Moore, Kate Hilda

AU - Mansfield, Kylie

AU - Rose’Meyer, Roselyn

AU - Sellers, Donna J

AU - Grundy, David

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AB - Tachykinins are expressed within bladder innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium, or sensory afferents directly. Here we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signalling from the bladder during distension, urothelial transmitter release ex-vivo, and direct responses to NKA on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100nM). Intravesical NKA significantly decreased bladder compliance, but had no direct effect on mechanosensitivity to bladder distension (30µl/min). GR159897 alone enhanced bladder compliance, but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells, but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, while acetylcholine levels were reduced. NKA mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.

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M3 - Article

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