Abstract
The pathogenesis of ketamine-induced cystitis (KC) remains unclear. In this study, bladder microvascular injury was investigated as a possible contributing mechanism. A total of 36 KC patients with exposure to ketamine for more than 6 months, and 9 control subjects, were prospectively recruited. All participants completed questionnaires, including the O’Leary–Sant interstitial cystitis symptom index (ICSI) and the interstitial cystitis problem index (ICPI). All KC patients received a urodynamic study and radiological exams. Bladder tissues were obtained from cystoscopic biopsies in the control group and after hydrodistention in the KC group. Double-immunofluorescence staining of N-methyl-d-aspartate receptor subunit 1 (NMDAR1) and the endothelial marker, cluster of differentiation 31 (CD31), was performed to reveal the existence of NMDAR1 on the endothelium. Electron microscopy (EM) was applied to assess the microvascular change in the urinary bladder and to measure the thickening of the basement membrane (BM). A proximity ligation assay (PLA) was used to quantify the co-localization of the endothelial CD31 receptor and the mesenchymal marker [fibroblast-specific protein 1 (FSP-1)]. The Mann–Whitney U test and Spearman’s correlation coefficient were used for statistical analysis. The mean ICSI [14.38 (± 4.16)] and ICPI [12.67 (± 3.54)] scores of the KC group were significantly higher than those (0 and 0, respectively) of the control group (both p < 0.001). The KC patients had decreasing cystometric bladder capacity (CBC) with a mean volume of 65.38 (± 48.67) mL. NMDAR1 was expressed on endothelial cells in both groups under immunofluorescence staining. Moreover, KC patients had significant BM duplication of microvessels in the mucosa of the urinary bladder under EM. The co-expression of the endothelial marker CD31 and mesenchymal marker FSP1 was significantly stained and calculated under PLA. In conclusion, microvascular injury and mesenchymal phenotypic alteration of endothelial cells can potentially contribute to KC-induced bladder dysfunction.
Highlights
Ketamine, considered pharmacologically as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been used clinically since 1970 in dissociative anesthesia for elective surgeries of infants and children [1,2]
All ketamine-induced cystitis (KC) patients were investigated with questionnaires, including the O’Leary–Sant interstitial cystitis symptom index (ICSI) and the interstitial cystitis problem index (ICPI) [14]
Li et al demonstrated that intraperitoneal injection of a low dosage of ketamine into rats rapidly activated the mammalian target of the rapamycin pathway, thereby increasing the number of synaptic signaling proteins and increasing the number and function of new spine synapses in the prefrontal cortex [21,22]
Summary
Ketamine, considered pharmacologically as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been used clinically since 1970 in dissociative anesthesia for elective surgeries of infants and children [1,2]. Since Shahani et al first reported that patients with ketamine-induced cystitis (KC) can display severe dysuria, hematuria, and urinary frequency, many researchers have proposed possible pathogenic mechanisms for these signs and symptoms [4,5,6,7,8,9]. Fibrotic change of the urinary bladder after chronic inflammation may be a cause of diminished bladder capacity, leading to severe urinary frequency with extremely short intervals [10]. Chu et al proposed that ketamine might induce microvascular changes in the bladder, causing endothelial cell injury of microvessels and subsequent compromised intrinsic microcirculation [5]. Similar to brain and other organ systems, endothelial cells of the urinary bladder might be possible targets of microvascular injury (MVI) and result in fibrosis during ketamine abuse [11,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
