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16:02 - 16:05
S2-10
(PP)
ESTABLISHING A NEW MODEL FOR EVALUATION OF DRUG TREATMENT IN THE
CLINICALLY RELEVANT PHASE OF BLADDER DE-OBSTRUCTION: GENE
EXPRESSION AND FUNCTIONAL ANALYSES
Darius BAGLI
1
, Jia-Xin JIANG
2
, Annette SCHROEDER
1
, Martin SIDLER
2
, Alaleh SAMIEI
2
, Tyler KIRWAN
2
and Karen
AITKEN
2
1) Sickkids Hospital, Division of Urology, Department of Surgery, Toronto, CANADA - 2) Research Institute, Sickkids
Hospital, Developmental and Stem Cell Biology, Toronto, CANADA
PURPOSE
The mTOR-inhibitor rapamycin attenuates bladder smooth muscle hypertrophy during developing in vivo partial bladder
outlet obstruction (PBO). Clinically, however, treatment begins after release of established obstruction. PURPOSE: Our
objectives were to establish a model to evaluate pharmacotherapy following release of PBO (REL). We hypothesise that
the release (REL) phase has associated persistent functional and specific gene expression changes that can be targeted
with novel treatments.
MATERIAL AND METHODS
78 Sprague-Dawley female rats received a moderate PBO or sham for 6 weeks. A PBO alone control was sacrificed at 6
weeks. Prior to PBOR, by removal of the obstructing suture, voiding was recorded in metabolic cages and residual urine
was measured. After PBOR, daily s.c. rapamycin/vehicle treatment began. Six weeks later voiding was recorded.
Residual volumes, bladders and body weights, and muscle bundle size (by histology) were measured. Gene expression
was examined by HT-QPCR on 62 genes curated from PBO literature.
RESULTS
Bladder/body weight ratios with PBO were 5.8 fold those of sham operated groups and remained high in REL. Residual
urine, micturition fractions and voiding frequencies were significantly improved toward sham levels in rapamycin- vs.
vehicle-treated rats. KCNB2, was significantly dysregulated in both PBO and REL compared to shams. Rapamycin
treatment significantly altered expression of several genes during REL that pertained to ECM, growth, SMC phenotype,
and free radicals (p<0.05).
CONCLUSIONS
New treatments during the recovery phase after release of obstruction can be proposed through analysis of function,
histology and gene expression patterns associated with recovery, as with rapamycin-induced recovery.