Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder

• Published in: Neurourology and urodynamics Vol. 32; no. 8; pp. 1137 - 1143
• Main Authors: Chuang, Shu-Mien, Liu, Keh-Min, Li, Yi-Lun, Jang, Mei-Yu, Lee, Hei-Hwa, Wu, Wen-Jeng, Chang, Wei-Chiao, Levin, Robert M., Juan, Yung-Shun
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.11.2013; Wiley Subscription Services, Inc
• Subjects: Animals; cyclooxygenase-2; Cystitis - chemically induced; Cystitis - enzymology; Cystitis - physiopathology; Ketamine; nitric oxide synthase; Nitric Oxide Synthase - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Sprague-Dawley; ulcerative cystitis; Up-Regulation; Urinary Bladder - enzymology; Urinary Bladder - physiopathology; Urination - physiology; Urodynamics - physiology; nitric oxide synthase; ulcerative cystitis; ketamine; cyclooxygenase-2
• ISSN: 0733-2467; 1520-6777
• DOI: 10.1002/nau.22367

Aims 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. Neurourol. Urodynam. 32:1137–1143, 2013. © 2013 Wiley Periodicals, Inc.