Water avoidance stress induces frequency through cyclooxygenase-2 expression: A bladder rat model

Keisuke Yamamoto, Tetsuya Takao, Jiro Nakayama, Hiroshi Kiuchi, Hidenobu Okuda, Shinichiro Fukuhara, Iwao Yoshioka, Yasuhiro Matsuoka, Yasushi Miyagawa, Akira Tsujimura, Norio Nonomura

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Objectives: Water avoidance stress is a potent psychological stressor and it is associated with visceral hyperalgesia, which shows degeneration of the urothelial layer mimicking interstitial cystitis. Cyclooxygenase-2 inhibitors have been recognized to ameliorate frequency both in clinical and experimental settings. We investigated the voiding pattern and cyclooxygenase-2 expression in a rat bladder model of water avoidance stress. Methods: After being subjected to water avoidance stress or a sham procedure, rats underwent metabolic cage analysis and cystometrography. Real time reverse transcription polymerase chain reaction was carried out to examine cyclooxygenase-2 messenger ribonucleic acid in bladders of rats. Protein expression of cyclooxygenase-2 was analyzed with immunohistochemistry and western blotting. Furthermore, the effects of the cyclooxygenase-2 inhibitor, etodolac, were investigated by carrying out cystometrography, immunohistochemistry and western blotting. Results: Metabolic cage analysis and cystometrography showed significantly shorter intervals and less volume of voiding in water avoidance stress rats. Significantly higher expression of cyclooxygenase-2 messenger ribonucleic acid was verified by reverse transcription polymerase chain reaction. Immunohistochemistry and western blotting showed significantly higher cyclooxygenase-2 protein levels in water avoidance stress bladders. Furthermore, immunohistochemistry showed high cyclooxygenase-2 expression exclusively in smooth muscle cells. All water avoidance stress-induced changes were reduced by cyclooxygenase-2 inhibitor pretreatment. Conclusions: Chronic stress might cause frequency through cyclooxygenase-2 gene upregulation in bladder smooth muscle cells. Further study of cyclooxygenase-2 in the water avoidance stress bladder might provide novel therapeutic modalities for interstitial cystitis.

Original languageEnglish
Pages (from-to)155-162
Number of pages8
JournalInternational Journal of Urology
Issue number2
Publication statusPublished - Feb 2012
Externally publishedYes


  • Cyclooxygenase-2
  • Interstitial cystitis
  • Voiding frequency
  • Water avoidance stress

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