Baker, Simon C., Shabir, Saqib, Georgopoulos, Nikolaos T. and Southgate, Jennifer (2016) Ketamine-Induced Apoptosis in Normal Human Urothelial Cells. The American Journal of Pathology. ISSN 0002-9440 (In Press)
- Accepted Version
Restricted to Repository staff only until 18 March 2017.
Recreational abuse of ketamine has been associated with the emergence of a new bladder pain syndrome, ketamine‐induced cystitis, characterised by chronic inflammation and urothelial ulceration. This study investigated the direct effects of ketamine on normal human urothelium maintained in organ culture or as finite cell lines in vitro.
Exposure of urothelium to ketamine resulted in apoptosis, with cytochrome c release from mitochondria and significant subsequent caspase 9 and 3/7 activation. The anaesthetic mode‐of‐action for ketamine is mediated primarily through N‐methyl Daspartate receptor (NMDAR) antagonism; however, NHU cells were unresponsive to NMDAR agonists or antagonists and no expression of NMDAR transcript was detected. Exposure to non‐cytotoxic concentrations of ketamine (≤1 mM) induced rapid release of ATP, which activated purinergic P2Y receptors and stimulated the inositol trisphosphate receptor to provoke transient release of calcium from the endoplasmic reticulum into the cytosol. Ketamine concentrations >1 mM were cytotoxic and provoked a largeramplitude increase in cytosolic [Ca2+] that was unresolved. The sustained elevation in cytosolic [Ca2+] was associated with pathological mitochondrial oxygen consumption and ATP deficiency.
Damage to the urinary barrier initiates bladder pain and in ketamine‐induced cystitis, loss of urothelium from large areas of the bladder wall is a reported feature. This study offers first evidence for a mechanism of direct toxicity of ketamine to urothelial cells by activating the intrinsic apoptotic pathway.
|Subjects:||Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
|Schools:||School of Applied Sciences|
|Depositing User:||Elizabeth Boulton|
|Date Deposited:||29 Mar 2016 09:44|
|Last Modified:||29 Mar 2016 09:53|
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