Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Rajandram, Retnagowri; Ong, Teng Aik; Razack, Azad Hassan Abdul; MacIver, Bryce; Zeidel, Mark L.; Yu, Weiqun

doi:10.1152/ajprenal.00483.2015

Cited by 41 publications

(45 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Spontaneous VSA. VSAs were performed as described previously (58)(59)(60). Individual mice were gently placed in a standard polycarbonate mouse cage with Blicks Cosmos Blotting Paper (catalog 10422-1005) placed in the bottom, for 4 hours.…”

Section: Myography Bladders From Male Wild-type P2y 12 -/-mentioning

confidence: 99%

See 1 more Smart Citation

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

Hao¹,

Wang²,

Chen³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Myography Bladders From Male Wild-type P2y 12 -/-mentioning

confidence: 99%

“…A volume/area standard curve on this paper determined that 1 mm 2 is equal to 0.283 μL urine. Voiding spots that have an area ≥80 mm 2 are considered to be PVSs (59,60).…”

Section: Myography Bladders From Male Wild-type P2y 12 -/-mentioning

confidence: 99%

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

Hao¹,

Wang²,

Chen³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…As opposed to these findings, Rajandram et al found an intact mucosal surface, no detached urothelium and normal umbrella cells with appropriately expressed tight junctions and no significant changes in the permeability of the urothelium in both controls and mice with KC 51 . Nevertheless, these data might merely indicate an earlier urothelial injury phase, which could have been repaired.…”

Section: Evidencementioning

confidence: 78%

“…All patients with late‐phase KIU (severe bladder fibrosis and upper tract involvement) failed first, and second‐line therapies in all series and their symptoms and quality of life improved only after surgery 3,51,67,75,77,82‐85 . Surgery is characterized by two steps: partial cystectomy and reconstruction.…”

Section: Evidencementioning

confidence: 99%

What urologists need to know about ketamine‐induced uropathy: A systematic review

Castellani

Pirola

Gubbiotti

et al. 2020

Neurourology and Urodynamics

View full text Add to dashboard Cite

Aims: Ketamine is a general anesthetic. Dissociative effects and low cost led ketamine becoming an illegal recreational drug in young adults. Ketamineinduced uropathy (KIU) is one of the complications observed in abusers. This study aimed to provide a systematic literature review on KIU clinical presentation, pathophysiology, and treatments. Methods: We performed the literature search in PubMed, Web of Science, Scopus, and Embase using the terms ketamine and bladder. English papers on human and animal studies were accepted. Results: A total of 75 papers were selected. Regular ketamine users complain about severe storage symptoms and pelvic pain. Hydronephrosis may develop in long-term abusers and is correlated to the contracted bladder, ureteral stenosis, or vesicoureteral reflux due to ureteral involvement and/or bladder fibrosis. Cystoscopy shows ulcerative cystitis. Ketamine in urine might exert direct toxicity to the urothelium, disrupting its barrier function and enhancing cell apoptosis. The presence of ketamine/ions in the bladder wall result in neurogenic/IgE-mediated inflammation, stimulation of the inducible nitric oxide synthase-cytokines-cyclooxygenase pathway with persistent inflammation and fibrosis. Abstinence is the first therapeutic step. Anti-inflammatory drugs, analgesics and anticholinergics, intravesical instillation of hyaluronic acid, hydrodistension and intravesical injection of botulin toxin-A were helpful in patients with early-stage KIU. In patients with end-stage disease, the control of intractable symptoms and the increase of bladder capacity were the main recommendations to perform augmentation enterocystoplasty.Conclusions: KIU is becoming a worldwide health concern, which should be taken into account in the differential diagnosis of ulcerative cystitis. K E Y W O R D S cystitis, inflammation, ketamine, lower urinary tract symptoms, substance-related disorders, urinary tract 1050 | CASTELLANI ET AL.

show abstract

“…Ketamine is accumulated in urine, and urothelial ulceration is commonly observed in severe ketamine cystitis patients, which might be the major reason for the hypothesis that ketamine disrupts urothelial barrier function and causes ketamine cystitis. Several recent articles also indicate a detrimental effect of ketamine on urothelial cells (1).…”

mentioning

confidence: 99%

Reply to “Letter to the editor: ‘Urothelial barrier dysfunction: cause or outcome of ketamine-induced voiding dysfunction’”

2016

American Journal of Physiology-Renal Physiology

Self Cite

View full text Add to dashboard Cite

REPLY: We would like to thank Wang et al. (3) for their interest in and comment on our article. Since the first report of ketamine cystitis by Shahani et al. (2) 10 years ago, the mechanism of this new urinary dysfunction is still a mystery. Ketamine is accumulated in urine, and urothelial ulceration is commonly observed in severe ketamine cystitis patients, which might be the major reason for the hypothesis that ketamine disrupts urothelial barrier function and causes ketamine cystitis. Several recent articles also indicate a detrimental effect of ketamine on urothelial cells (1).Urothelial cells form the tightest barrier in our body, which allows the bladder to temporarily store urine toxins. Recent research also indicates that the superficial cells of the urothelium are mechanosensory and undergo dramatic membrane trafficking in response to urine filling and emptying. Our key finding is that we observed voiding dysfunction by voiding spot assay and cystometrogram, but the barrier function is intact. We used a ketamine dosage that was sufficient to induce voiding dysfunction, but no urothelial abnormality could be detected, which indicates that ketamine-induced voiding dysfunction precedes the emergence of barrier dysfunction. We do agree with the comment that the urothelial barrier likely plays some role in the pathogenesis of ketamine cystitis, allowing urine to leak into the bladder interstitial spaces and aggravate the cystitis and voiding dysfunction. We tend to believe that this disrupted barrier is not due to direct toxicity, but is more likely a secondary effect of ketamine, affecting perhaps mechanosensory function and membrane trafficking. We also should bear in mind that there are extensive pathological changes in the other bladder tissues of ketamine cystitis patients, including neuronal and myogenic. It is also worth noting that not all patients have disrupted barrier function. We therefore strongly believe that ketamine might disrupt some yet unknown cellular pathways which causes extensive pathological changes in the bladder and also other organs. Understanding these ketamineaffected signal pathways will be critical for the treatment of ketamine cystitis.

show abstract

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction

Cited by 41 publications

References 31 publications

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

What urologists need to know about ketamine‐induced uropathy: A systematic review

Reply to “Letter to the editor: ‘Urothelial barrier dysfunction: cause or outcome of ketamine-induced voiding dysfunction’”

Contact Info

Product

Resources

About