Involvement of mitochondrial pathway of apoptosis in urothelium in ketamine-associated urinary dysfunction.
BACKGROUND
Long-term use of ketamine results in ketamine-associated urinary dysfunction (KAUD), which is characterized by frequent micturition, urgent urination, urine pain, hematuria, dysuria and urge incontinence. This study aims to examine the effect of ketamine on the urothelium and investigate the underlying mechanisms responsible for KAUD.


METHODS
A rat model of KAUD by ketamine injection was developed. Histological changes in bladder tissues were measured by hematoxylin and eosin staining, and apoptosis by the TUNEL assay. Primary bladder epithelial cells were treated with ketamine, and cell proliferation measured by a CellTiter 96 AQ cell proliferation assay, apoptosis assessed by TUNEL assay and levels of apoptosis-related proteins determined by Western blotting.


RESULTS
Animals injected with ketamine displayed a decrease in body weight, behavioral signs of addiction, urinary dysfunction and damage to the epithelial layer of the bladder, particularly in the group receiving high-dose ketamine for 3 months. Ketamine increased apoptosis both in bladder tissues and bladder epithelial cells. In addition, ketamine induced the expression of Bax, cytochrome c and capase-3, but inhibited the expression of NF-κB and bcl-2.


CONCLUSIONS
These results suggest that the mitochondrial pathway of apoptosis in bladder epithelium may contribute to KAUD.
Department of Urology (PW, ZS, QW, JH, SZ), Nanfang Hospital, Southern Medical University, Guangzhou, China; and Department of Urology (ZS), Yuhuangding Hospital, Yantai, China.
Peng
P
Wu
Zhengfei
Z
Shan
Qiang
Q
Wang
Jun
J
Huang
Shaobin
S
Zheng
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D020287:In Situ Nick-End Labeling; D007649:Ketamine / Q000009:adverse effects*; D008928:Mitochondria / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D001743:Urinary Bladder / Q000187:drug effects; D014555:Urination Disorders / Q000139:chemically induced*; D019459:Urothelium / Q000187:drug effects
D007649:Ketamine