Tags

Type your tag names separated by a space and hit enter

Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity.
Eur Urol. 2018 09; 74(3):336-345.EU

Abstract

BACKGROUND

Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling.

OBJECTIVE

To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity.

DESIGN, SETTING, AND PARTICIPANTS

Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate.

RESULTS AND LIMITATIONS

Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4-/-, rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4-/- mice was not apparent in the Trpv4-/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents.

CONCLUSIONS

Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling.

PATIENT SUMMARY

We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder.

Authors+Show Affiliations

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium.Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Translational Cell and Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium.Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium; VIB Center for Brain & Disease Research, Leuven, Belgium.Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; TRP Channel Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium. Electronic address: wouter.everaerts@kuleuven.be.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29875065

Citation

Deruyver, Yves, et al. "Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity." European Urology, vol. 74, no. 3, 2018, pp. 336-345.
Deruyver Y, Weyne E, Dewulf K, et al. Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity. Eur Urol. 2018;74(3):336-345.
Deruyver, Y., Weyne, E., Dewulf, K., Rietjens, R., Pinto, S., Van Ranst, N., Franken, J., Vanneste, M., Albersen, M., Gevaert, T., Vennekens, R., De Ridder, D., Voets, T., & Everaerts, W. (2018). Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity. European Urology, 74(3), 336-345. https://doi.org/10.1016/j.eururo.2018.05.020
Deruyver Y, et al. Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity. Eur Urol. 2018;74(3):336-345. PubMed PMID: 29875065.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intravesical Activation of the Cation Channel TRPV4 Improves Bladder Function in a Rat Model for Detrusor Underactivity. AU - Deruyver,Yves, AU - Weyne,Emmanuel, AU - Dewulf,Karel, AU - Rietjens,Roma, AU - Pinto,Silvia, AU - Van Ranst,Nele, AU - Franken,Jan, AU - Vanneste,Matthias, AU - Albersen,Maarten, AU - Gevaert,Thomas, AU - Vennekens,Rudi, AU - De Ridder,Dirk, AU - Voets,Thomas, AU - Everaerts,Wouter, Y1 - 2018/06/03/ PY - 2017/12/11/received PY - 2018/05/15/accepted PY - 2018/6/8/pubmed PY - 2019/5/21/medline PY - 2018/6/8/entrez KW - Bladder afferent signalling KW - Pelvic nerve injury KW - TRPV4 knockout rats KW - Transgenic rats KW - Transient receptor potential channels KW - Transient receptor potential vanilloid 4 (TRPV4) KW - Underactive bladder KW - Voiding dysfunction SP - 336 EP - 345 JF - European urology JO - Eur Urol VL - 74 IS - 3 N2 - BACKGROUND: Improvement of bladder emptying by modulating afferent nerve activity is an attractive therapeutic strategy for detrusor underactivity. Transient receptor potential vanilloid 4 (TRPV4) is a sensory ion channel in urothelial cells that contribute to the detection of bladder filling. OBJECTIVE: To investigate the potential benefit of intravesical TRPV4 agonists in a pelvic nerve injury rat model for detrusor underactivity. DESIGN, SETTING, AND PARTICIPANTS: Female wild-type and Trpv4 knockout rats underwent sham surgery or bilateral pelvic nerve injury (bPNI). Four weeks later, rats underwent cystometry with infusion of the TRPV4 agonist GSK1016790A. Bladders were harvested for in vitro pharmacological studies, quantitative reverse polymerase chain reaction and immunohistochemistry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data are expressed as median ± interquartile range. Statistical comparisons were made using the Mann-Witney U test and Wilcoxon signed rank test as appropriate. RESULTS AND LIMITATIONS: Rats with bPNI showed a phenotype characteristic of detrusor underactivity with lower-amplitude voiding contractions, decreased voiding frequency, and increased postvoid residual. Intravesical application of GSK1016790A increased voiding frequency and reduced postvoid residual in wild-type, but not Trpv4-/-, rats. In isolated bladder strips, GSK1016790A did not induce relevant contractions, indicating that the observed improvements in bladder function are the result of increased afferent signalling through TRPV4 activation, rather than a local effect on the detrusor. The altered urinary phenotype of Trpv4-/- mice was not apparent in the Trpv4-/- rat model, suggesting species-related functional variations. Our results are limited to the preclinical setting in rodents. CONCLUSIONS: Intravesical activation of TRPV4 improves bladder dysfunction after bPNI by increasing afferent signalling. PATIENT SUMMARY: We demonstrate that the sensory protein transient receptor potential vanilloid 4 (TRPV4) can be targeted to improve bladder function in animals that have iatrogenic injury to the nerves innervating the bladder. Further research is required to determine whether these results can be translated to patients with an underactive bladder. SN - 1873-7560 UR - https://www.unboundmedicine.com/medline/citation/29875065/Intravesical_Activation_of_the_Cation_Channel_TRPV4_Improves_Bladder_Function_in_a_Rat_Model_for_Detrusor_Underactivity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0302-2838(18)30369-5 DB - PRIME DP - Unbound Medicine ER -