title: Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction.
abstract: Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachuesetts; Department of Surgery, Faculty of Medicine, Kuala Lumpur, Malaysia; and.
authors.forename: Retnagowri
authors.initials: R
authors.lastname: Rajandram
authors.affiliation: Department of Surgery, Faculty of Medicine, Kuala Lumpur, Malaysia; and University Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Teng Aik
authors.initials: TA
authors.lastname: Ong
authors.affiliation: Department of Surgery, Faculty of Medicine, Kuala Lumpur, Malaysia; and University Malaya Medical Centre, Kuala Lumpur, Malaysia.
authors.forename: Azad H A
authors.initials: AH
authors.lastname: Razack
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachuesetts;
authors.forename: Bryce
authors.initials: B
authors.lastname: MacIver
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachuesetts;
authors.forename: Mark
authors.initials: M
authors.lastname: Zeidel
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachuesetts; wyu2@bidmc.harvard.edu.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Yu
mesh_terms: D000778:Anesthetics, Dissociative; D000818:Animals; D003556:Cystitis / Q000139:chemically induced* / Q000473:pathology*; D005260:Female; D007649:Ketamine; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D062725:Tight Junction Proteins / Q000378:metabolism; D001743:Urinary Bladder / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000139:chemically induced / Q000503:physiopathology; D019459:Urothelium / Q000473:pathology* / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D000778:Anesthetics, Dissociative; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein; D007649:Ketamine
keywords: ketamine cystitis; permeability; umbrella cell; urinary bladder; voiding spot assay