title: A rat long-lasting cystitis model induced by intravesical injection of hydrogen peroxide.
abstract: Novel longer lasting inflammatory bladder animal models are needed to better understand the pathophysiology of chronic cystitis. We previously developed a relatively long-lasting mouse cystitis model by intravesical injection of hydrogen peroxide (H2O2). To further evaluate its pathophysiology, in this study, we established and analyzed a rat cystitis model. Under anesthesia, 1.5% H2O2solution was introduced transurethrally into the bladder of female rats, and kept for 30 min. The H2O2injection significantly increased the number of micturition events up to day 14 and decreased urine volume per micturition, with the smallest volumes on day 3, compared with the vehicle-treated group. Cystometric analysis on day 7 revealed that intercontraction intervals were significantly shortened without affecting the baseline, threshold, or maximum pressures. Intravesical resiniferatoxin-evoked nociceptive behaviors, such as freezing, were significantly enhanced on days 7 and 14. Furthermore, histopathology revealed hemorrhage, edema, infiltration of neutrophils into the lamina propria, and urothelial denudation in the early phase (day 1). These damages were gradually repaired, while hyperplasia of the urothelium, vascularization, increases in fibroblast counts, and infiltration of mast cells and eosinophils were observed through the later phase (days 7 and 14). These results suggest that intravesical H2O2injection induces relatively long-lasting cystitis with enhanced bladder activity and pain sensation in rats. This approach thus provides a novel rat long-lasting cystitis model that allows us to analyze detailed symptoms and pathophysiology of H2O2-induced cystitis model than the mouse model and may be used to investigate the pathophysiology and treatment of chronic bladder hypersensitive disorders, such as bladder pain syndrome/interstitial cystitis.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Dogishi
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Minami-ku, Kyoto, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Majima
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Minami-ku, Kyoto, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Konishi-Shiotsu
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Minami-ku, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Homan
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Kodera
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Oyama
authors.affiliation: Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Minami-ku, Kyoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan tknakaga@kuhp.kyoto-u.ac.jp.
authors.forename: Takayuki
authors.identifier: http://orcid.org/0000-0003-1890-0843
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003556:Cystitis / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006861:Hydrogen Peroxide; D059225:Nociception / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014554:Urination / Q000502:physiology*
chemical_list: D006861:Hydrogen Peroxide
keywords: Chronic cystitis; hydrogen peroxide; hypersensitivity of bladder nerve; remodeling