Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA310

Poster Communications

Repeated intravesical gemcitabine increases voiding frequency, compliance and urothelial release of ATP and PGE2 in the murine bladder

C. McDermott1, S. Farr1, R. Chess-Williams1

1. Centre for Urology Research, Bond University, Robina, Queensland, Australia.

  • Figure 1: Total number of voiding events, number of small voids and total voided area were measured pre- and post- repeat intravesical gemcitabine or isotonic saline instillation. Data represents mean

Intravesical chemotherapy for bladder cancer limits systemic absorption but significant local urological side effects including dysuria and urgency of urination still occur. A newer agent, gemcitabine, has a favourable efficacy and toxicity profile in patients compared to other commonly used chemotherapies (Addeo et al, 2010). Here we investigate the effects of repeated intravesical gemcitabine instillations on bladder function. Female C57BL/6JArc mice (age 32 weeks, n=6 per group), received two intravesical instillations of 0.9% saline (control) or 40mg/mL gemcitabine, 1 week apart under anaesthesia (1-3% isoflurance gas). Micturition was induced 1-hour post-intravesical instillation to expel drug/saline. Voiding pattern analysis (VPA) was conducted (Sugino et al, 2008) prior to both first intravesical instillation and euthanasia by cervical dislocation, 24 h after second instillation. A modified isolated whole bladder preparation (Tanaka et al, 2011) was used to assess bladder compliance and contractile responses. Luminal contents were also collected following distension for analysis of urothelial mediator release. ATP, Ach and PGE2 levels were quantified using commercially available kits. Data was analysed using one- or two-way ANOVA with Bonferroni post-hoc test. Repeated intravesical gemcitabine instillations significantly increased the number of voiding events (1.9 fold; p<0.05) with a corresponding increase in the number of small voids (2.4 fold; p<0.05) (Figure 1). Release of ATP and PGE2 into the lumen of the bladder was increased significantly by 2.8 (p<0.001) and 3.2 (p<0.05) fold respectively, while acetylcholine release was unchanged following gemcitabine treatment. Surprisingly, repeat intravesical gemcitabine significantly increased compliance in murine bladders, resulting in enhanced filling volume. Contractile response to carbachol, KCl and αβ-mATP was unchanged following gemcitabine treatment, unlike response to electric field stimulation which was significantly depressed at 20Hz (p<0.05). All parameters were unchanged in saline instilled mice. These results indicate that intravesical gemcitabine causes an overactive bladder phenotype, potentially mediated by enhanced urothelial ATP and PGE2 acting on C-afferent fibres, and depressed efferent nerve mediated contractions.

Where applicable, experiments conform with Society ethical requirements