Search

Videocystometry, combining x-ray and cystometry, provides unprecedented details on urinary tract function in rodents., Lower urinary tract dysfunction (LUTd) represents a major health care problem with a high, unmet medical need. Design of additional therapies for LUTd requires precise tools to study bladder storage and voiding (dys)function in animal models. We developed videocystometry in mice, combining intravesical pressure measurements with high-speed fluoroscopy of the urinary tract. Videocystometry substantially outperforms current state-of-the-art methods to monitor the urine storage and voiding process, by enabling quantitative analysis of voiding efficiency, urethral flow, vesicoureteral reflux, and the relation between intravesical pressure and flow, in both anesthetized and awake, nonrestrained mice. Using videocystometry, we identified localized bladder wall micromotions correlated with different states of the filling/voiding cycle, revealed an acute effect of TRPV1 channel activation on voiding efficiency, and pinpointed the effects of urethane anesthesia on urine storage and urethral flow. Videocystometry has broad applications, ranging from the elucidation of molecular mechanisms of bladder control to drug development for LUTd.

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. ispartof: EUROPEAN UROLOGY vol:74 issue:3 pages:336-345 ispartof: location:Switzerland status: published

Aims Neurogenic bladder dysfunction is a major issue in Multiple Sclerosis (MS). High intravesical pressure should be treated early. Available therapies are insufficient and there is need for drug development and investigation of pathogenesis. Experimental Autoimmune Encephalomyelitis (EAE) in rodents is a well validated model to study MS. Previous research has shown that these animals develop urinary symptoms. However, from clinical studies, we know that symptoms do not necessarily reflect changes in bladder pressure. This paper aims to provide a complete overview of urodynamic changes in a model for detrusor overactivity in MS. Methods Female C57Bl/6J mice, injected with MOG35–55 and control mice, injected with vehicle (Complete Freund's adjuvant), were monitored daily for neurologic symptoms. Within 1 month after symptom development, mice were used for cystometry or histology of the bladder. Results Increasing disease score correlated with increased micturition frequency, basal pressure, and average pressure, and with a decrease in functional bladder capacity, voiding amplitude, and maximum pressure. Conclusions This paper provides a detailed description of bladder function in C57Bl/6J mice with Myelin Oligodendrocyte Glycoprotein peptide (MOG35–55) induced EAE. This EAE model induces detrusor overactivity in close relationship to neurological impairment. EAE in mice is a suitable model to study detrusor overactivity in MS. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

Affiliations: KU Leuven, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Herestraat 49 box 802, 3000 Leuven KU Leuven, Laboratory of Experimental Urology, Department of Development and Regeneration, Herestraat 49 box 7003 41, 3000 Leuven TRP Research Platform Leuven (TRPLe) Co-first authors Corresponding author: KU Leuven Laboratory of Ion Channel Research Department of Cellular and Molecular Medicine Herestraat 49 bus 802 B-3000 Leuven, Belgium Tel.: +32-16-330217 E-mail: thomas.voets@med.kuleuven.be