ESPU Congress 2017 - Abstract book

CONGRESS OF THE ESPU

16:17–16:20

S2-8 (PP)

IMPROVED BLADDER DYSFUNCTION FOLLOWING

PARTIAL BLADDER OUTLET OBSTRUCTION: IN VITRO

AND IN VIVO EFFECTS OF A HIF INHIBITOR

Nao IGUCHI

, Irfan DÖNMEZ

, Anna MALYKHINA

and Duncan WILCOX

1) University of Colorado Denver, Surgery, Aurora, USA - 2) Children’s Hospital Colorado, Urology, Aurora, USA

PURPOSE

Posterior urethral valves are the most common cause of partial bladder outlet obstruction (PBOO) in

pediatric population. Pathological changes in the bladder developed during PBOO are responsible

for long-lasting bladder dysfunction in this population despite early surgical interventions. We previ-

ously showed that Hypoxia-inducible factors (HIFs) play roles in PBOO-induced bladder pathology,

and a HIF inhibitor, 17-DMAG abated pathological changes. This study aimed to examine our

hypothesis that blocking HIFs would improve bladder function following 2 weeks of PBOO.

MATERIAL AND METHODS

PBOO was surgically created by ligation of the bladder neck in young male mice. Sham operated

animals served as controls. PBOO mice received intraperitoneal injection of saline (placebo) or

17-DMAG, every other day from day 1 post-surgery. Bladder function was examined in vitro by

physiological tests, and in vivo by void spot assays that evaluates micturition patterns as well as

urodynamic tests in freely moving mice.

RESULTS

PBOO caused significant decreases in detrusor contractility in response to electric field stimula-

tion, carbachol, and KCl, which was partially restored by 17-DMAG treatment (60 percent in

PBOO+P vs. 80 percent in PBOO+T, controls as 100 percent). Spontaneous detrusor contractions

were significantly increased by PBOO, suggesting detrusor overactivity; while the level of increase

was smaller in PBOO+T mice (mean frequency in Hz; 3.1 in PBOO+P, 1.7 in PBOO+T, vs 1.0 in

controls). PBOO mice tended to void small volume compared to controls, while the change was

less prominent in PBOO+T group. PBOO+P mice showed marked increases in bladder pressure

by 2-fold, residual urine by 8%, and non-void contractions. 17-DMAG treatment improved these

urodynamic parameters, suggesting that 17-DMAG had preventative effects on overall bladder

function following PBOO.

CONCLUSIONS

This study provided the direct evidences that 17-DMAG significantly alleviated PBOO-induced

bladder dysfunction. Blocking HIF pathways can be a potential target for novel pharmacological

therapies to treat PBOO-associated bladder dysfunction.