Activation of the calcineurin pathway is associated with detrusor decompensation: a potential therapeutic target.
OBJECTIVE
We hypothesized that the calcineurin pathway mediated some of the complex remodeling process that allows a bladder subjected to partial outlet obstruction to adapt to its new workload. Atrial natriuretic factor mRNA expression served as a marker of calcineurin activation.


METHODS
A total of 16 New Zealand White rabbits underwent surgical creation of partial outlet obstruction, followed by randomization to receive cyclosporin A (20 mg/kg intramuscularly twice daily) or no additional treatment for 14 days. Three animals underwent 2 weeks of partial bladder outlet obstruction followed by bladder biopsy and the reversal of obstruction.


RESULTS
Atrial natriuretic factor expression was seen only in bladders with severe hypertrophy and it disappeared with the reversal of outlet obstruction. Cyclosporin A treatment resulted in a decrease in atrial natriuretic factor mRNA expression (p <0.05) and a marked shift in myosin heavy chain A-to-B ratios toward normal (p <0.01) and an increase in smooth muscle cross sectional area (p <0.05). Bladder mass decreased 40% but did not attain statistical significance (p = 0.08).


CONCLUSIONS
The calcineurin pathway has a significant role in bladder wall hypertrophy following partial outlet obstruction. Bladder hypertrophy could not be fully prevented by cyclosporin A, suggesting that multiple signaling pathways are involved in this pathophysiology. The expression of myosin heavy chain AB isoforms is regulated in part by the calcineurin pathway.
Clement
Michele R
MR
Division of Urology, Children's Hospital of Philadelphia, 34th and Civic Center Boulevards, Philadelphia, PA 19104, USA.
Delaney
Daniel P
DP
Austin
J Christopher
JC
Sliwoski
Joanna
J
Hii
George C
GC
Canning
Douglas A
DA
DiSanto
Michael E
ME
Chacko
Samuel K
SK
Zderic
Stephen A
SA
D000818:Animals; D019703:Calcineurin / Q000502:physiology*; D016572:Cyclosporine / Q000627:therapeutic use; D008297:Male; D011817:Rabbits; D015398:Signal Transduction; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy / Q000503:physiopathology*
D016572:Cyclosporine; D019703:Calcineurin