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Br J Pharmacol. 2014 Jul;171(14):3394-403. doi: 10.1111/bph.12682.

Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations.

Author information

1
Department of Biochemistry and Physiology, FHMS, University of Surrey, Guildford, UK.

Abstract

BACKGROUND AND PURPOSE:

The aim of this study was to quantify and characterize the mechanism of non-neuronal ACh release from bladder urothelial cells and to determine if urothelial cells could be a site of action of anti-muscarinic drugs.

EXPERIMENTAL APPROACH:

A novel technique was developed whereby ACh could be measured from freshly isolated guinea pig urothelial cells in suspension following mechanical stimulation. Various agents were used to manipulate possible ACh release pathways in turn and to study the effects of muscarinic receptor activation and inhibition on urothelial ATP release.

KEY RESULTS:

Minimal mechanical stimulus achieved full ACh release, indicating a small dynamic range and possible all-or-none signal. ACh release involved a mechanism dependent on the anion channel CFTR and intracellular calcium concentration, but was independent of extracellular calcium, vesicular trafficking, connexins or pannexins, organic cation transporters and was not affected by botulinum-A toxin. Stimulating ACh receptors increased ATP production and antagonizing them reduced ATP release, suggesting a link between ACh and ATP release.

CONCLUSIONS AND IMPLICATIONS:

These results suggest that release of non-neuronal ACh from the urothelium is large enough and well located to act as a modulator of ATP release. It is hypothesized that this pathway may contribute to the actions of anti-muscarinic drugs in reducing the symptoms of lower urinary tract syndromes. Additionally the involvement of CFTR in ACh release suggests an exciting new direction for the treatment of these conditions.

KEYWORDS:

ATP; CFTR; anti-muscarinic agents; non-neuronal ACh; urinary bladder; urothelial cells

PMID:
24628015
PMCID:
PMC4105928
DOI:
10.1111/bph.12682
[Indexed for MEDLINE]
Free PMC Article

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