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F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis

BACKGROUND AND PURPOSE: The aims of the present study were to characterize the role of PAR1 in rat bladder under inflammatory conditions and determine whether a selective PAR1 antagonist, F16357, can prevent the pathophysiological symptoms of cyclophosphamide‐induced interstitial cystitis (IC). EXPE...

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Autores principales: Monjotin, N, Gillespie, J, Farrié, M, Le Grand, B, Junquero, D, Vergnolle, N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919585/
https://www.ncbi.nlm.nih.gov/pubmed/27111354
http://dx.doi.org/10.1111/bph.13501
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author Monjotin, N
Gillespie, J
Farrié, M
Le Grand, B
Junquero, D
Vergnolle, N
author_facet Monjotin, N
Gillespie, J
Farrié, M
Le Grand, B
Junquero, D
Vergnolle, N
author_sort Monjotin, N
collection PubMed
description BACKGROUND AND PURPOSE: The aims of the present study were to characterize the role of PAR1 in rat bladder under inflammatory conditions and determine whether a selective PAR1 antagonist, F16357, can prevent the pathophysiological symptoms of cyclophosphamide‐induced interstitial cystitis (IC). EXPERIMENTAL APPROACH: Immunohistochemistry, contractile activity in isolated bladder and urodynamics were determined before and after cyclophosphamide treatment. F16357 was administered intravesically during the acute phase of inflammation, and effects on PAR1 and PAR1‐related bladder contraction evaluated 24 h after cyclophosphamide injection. Urodynamics and associated voided volumes were recorded 7 and 24 h after cyclophosphamide. KEY RESULTS: In control conditions, PAR1 was present only in some umbrella cells. Cyclophosphamide disrupted the urothelium and expression of PAR1 by all remaining urothelial cells. After F16357 treatment, urothelial damage was absent and PAR1 immunoreactivity similar to control tissues. Thrombin and TFLLR‐NH(2) induced bladder contractions. These were increased in inflammatory conditions and antagonized by F16357 in a concentration‐dependent manner. In telemetric experiments, furosemide increased urine production and voiding frequency for 60 min, 7 h after cyclophosphamide injection. Intravesical administration of F16357 blocked these changes with a return to a physiological profile; 24 h after cyclophosphamide, the volume of micturition was still lower with no increase in number of micturitions. F16357 30 μM reduced the number of micturitions and improved bladder capacity, but did not affect diuresis. Under similar experimental conditions, lidocaine 2% induced comparable effects. CONCLUSIONS AND IMPLICATIONS: PAR1 is expressed in rat bladder, overactivated in inflammatory conditions and involved in bladder function and sensation. F16357 could represent an interesting candidate for IC treatment.
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spelling pubmed-49195852016-11-18 F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis Monjotin, N Gillespie, J Farrié, M Le Grand, B Junquero, D Vergnolle, N Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The aims of the present study were to characterize the role of PAR1 in rat bladder under inflammatory conditions and determine whether a selective PAR1 antagonist, F16357, can prevent the pathophysiological symptoms of cyclophosphamide‐induced interstitial cystitis (IC). EXPERIMENTAL APPROACH: Immunohistochemistry, contractile activity in isolated bladder and urodynamics were determined before and after cyclophosphamide treatment. F16357 was administered intravesically during the acute phase of inflammation, and effects on PAR1 and PAR1‐related bladder contraction evaluated 24 h after cyclophosphamide injection. Urodynamics and associated voided volumes were recorded 7 and 24 h after cyclophosphamide. KEY RESULTS: In control conditions, PAR1 was present only in some umbrella cells. Cyclophosphamide disrupted the urothelium and expression of PAR1 by all remaining urothelial cells. After F16357 treatment, urothelial damage was absent and PAR1 immunoreactivity similar to control tissues. Thrombin and TFLLR‐NH(2) induced bladder contractions. These were increased in inflammatory conditions and antagonized by F16357 in a concentration‐dependent manner. In telemetric experiments, furosemide increased urine production and voiding frequency for 60 min, 7 h after cyclophosphamide injection. Intravesical administration of F16357 blocked these changes with a return to a physiological profile; 24 h after cyclophosphamide, the volume of micturition was still lower with no increase in number of micturitions. F16357 30 μM reduced the number of micturitions and improved bladder capacity, but did not affect diuresis. Under similar experimental conditions, lidocaine 2% induced comparable effects. CONCLUSIONS AND IMPLICATIONS: PAR1 is expressed in rat bladder, overactivated in inflammatory conditions and involved in bladder function and sensation. F16357 could represent an interesting candidate for IC treatment. John Wiley and Sons Inc. 2016-06-03 2016-07 /pmc/articles/PMC4919585/ /pubmed/27111354 http://dx.doi.org/10.1111/bph.13501 Text en © 2016 Laboratories Pierre Febre. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Papers
Monjotin, N
Gillespie, J
Farrié, M
Le Grand, B
Junquero, D
Vergnolle, N
F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title_full F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title_fullStr F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title_full_unstemmed F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title_short F16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
title_sort f16357, a novel protease‐activated receptor 1 antagonist, improves urodynamic parameters in a rat model of interstitial cystitis
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919585/
https://www.ncbi.nlm.nih.gov/pubmed/27111354
http://dx.doi.org/10.1111/bph.13501
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