Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder.
OBJECTIVE
The aims of the present study were to investigate voiding patterns, tissue constituents and the expressions of cyclooxygenase-2 (COX-2) and nitric oxide synthase (NOS) involved in ketamine-induced ulcerative cystitis in rat urinary bladder.


METHODS
Thirty Sprague-Dawley rats were distributed into three groups which received saline or ketamine (25 mg/kg/day) for a period of 14 and 28 days. In each group, cystometry was performed weekly and the concentration of ketamine and its metabolites (norketamine) was assayed. Paraffin-embedded sections were stained with Masson's trichrome stain, and ketamine-induced morphological changes were examined. Western blot analyses were carried out to examine the expressions of COX-2 and different NOS isoforms in bladder tissues. Immunofluorescence study was done to evaluate the expressions of COX-2 and macrophage infiltration (stained with ED-1 macrophage cell surface antigen) within the bladder.


RESULTS
Ketamine treatment resulted in bladder hyperactivity and the non-voiding contractions were significantly increased. The urine concentrations of ketamine and norketamine were much higher in ketamine-treated group. Moreover, ulcerated urothelium and mononuclear cell infiltration were noted in ketamine-treated group. These alterations in urodynamic functions and tissue constituents were accompanied by increases in the expression of COX-2. Two NOS isoforms (iNOS and eNOS) were also overexpressed, but no significant change was observed for nNOS. COX-2 positive stained cells were significantly increased. Meanwhile, increased amounts of ED-1 positive stained macrophages were present and most of COX-2 expressed cells were co-stained with ED-1 in the early stage of ketamine treatment.


CONCLUSIONS
Ketamine treatment affected bladder tissues by enhancing interstitial fibrosis and accelerating macrophages infiltration. Ketamine also initiated the up-regulations of COX-2 and iNOS and eNOS expressions. These up-regulated enzymes might play an important role in contributing to ketamine-induced alterations in micturition patterns and ulcerative cystitis.
Yuh-Ing Junior College of Health Care and Management, Kaohsiung, Taiwan.
Shu-Mien
SM
Chuang
Keh-Min
KM
Liu
Yi-Lun
YL
Li
Mei-Yu
MY
Jang
Hei-Hwa
HH
Lee
Wen-Jeng
WJ
Wu
Wei-Chiao
WC
Chang
Robert M
RM
Levin
Yung-Shun
YS
Juan
D000818:Animals; D003556:Cystitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007649:Ketamine; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D001743:Urinary Bladder / Q000201:enzymology* / Q000503:physiopathology; D014554:Urination / Q000502:physiology; D014563:Urodynamics / Q000502:physiology
D007649:Ketamine; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases
cyclooxygenase-2; ketamine; nitric oxide synthase; ulcerative cystitis