Aims: To characterize the detrusor muscle of the mouse urinary bladder in order to understand more precisely spontaneous contractile behavior of this organ. This study examined the spontaneous electrical activity and Ca 2þ dynamics of the detrusor smooth muscle and investigated the role of the urothelium. Materials and Methods: Detrusor smooth muscle strips were isolated from mouse bladders. The urothelium was either kept intact or removed. Changes in membrane potential were recorded using sharp electrode intracellular recording. To image Ca 2þ dynamics, tissue strips were exposed to 10 mM Oregon Green 488 BAPTA-1 AM for 70 min, and then image series were acquired with a laser-scanning confocal microscope. Results: (1) Mouse detrusor smooth muscle cells (SMCs) generate nifedipine-sensitive spontaneous action potentials (sAPs) at a low frequency (1.3 AE 0.9 min À1 , n ¼ 11) in preparations with intact urothelium. This frequency increased when the urothelium was removed (7 AE 8.3 min À1 , n ¼ 17) (P < 0.05, Student's t test). (2) Frequent ATP-mediated spontaneous depolarizations were recorded in all cells. (3) The frequency of whole cell Ca 2þ flashes of detrusor smooth muscle cells was higher in preparations with the urothelium removed (median 1.2 min À1 , n ¼ 7) than in urothelium denuded preparations (median 0.6 min À1 , n ¼ 7) (P < 0.01, Mann-Whitney U-test). Conclusions: Spontaneous activity of the mouse detrusor smooth muscles was characterized enabling future comparative work on gene knock-out strains. Evidence suggesting release of an inhibitory factor by the urothelium was apparent.

Spontaneous purinergic neurotransmission was characterized in the mouse urinary bladder, a model for the pathological or ageing human bladder. Intracellular electrophysiological recording from smooth muscle cells of the detrusor muscle revealed spontaneous depolarizations, distinguishable from spontaneous action potentials (sAPs) by their amplitude (< 40 mV) and insensitivity to the L-type Ca 2+ channel blocker nifedipine (1 μm) (100 ± 29%). Spontaneous depolarizations were abolished by the P2X 1 receptor antagonist NF449 (10 μm) (frequency 8.5 ± 8.5% of controls), insensitive to the muscarinic acetylcholine receptor antagonist atropine (1 μm) (103.4 ± 3.0%), and became more frequent in latrotoxin (LTX; 1 nm) (438 ± 95%), suggesting that they are spontaneous excitatory junction potentials (sEJPs). Such sEJPs were correlated, in amplitude and timing, with focal Ca 2+ transients in smooth muscle cells (measured using confocal microscopy), suggesting a common origin: ATP binding to P2X 1 receptors. sAPs were abolished by NF449, insensitive to atropine (126 ± 39%) and increased in frequency by LTX (930 ± 450%) suggesting a neurogenic, purinergic origin, in common with sEJPs. By comparing the kinetics of sAPs and sEJPs, we demonstrated that sAPs occur when sufficient cation influx through P2X 1 receptors triggers L-type Ca 2+ channels; the first peak of the differentiated rising phase of depolarizations -attributed to the influx of cations through the P2X 1 receptor -is of larger amplitude for sAPs (2248 mV s −1 ) than sEJPs (439 mV s −1 ). Surprisingly, sAPs in the mouse urinary bladder, unlike those from other species, are triggered by stochastic ATP release from parasympathetic nerve terminals rather than being myogenic.

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At 8 weeks mice treated with ketamine showed increased voiding frequency and decreased bladder capacity, the same symptoms that develop in human ketamine abusers. Enhanced noncholinergic contractions and P2X1 receptor expression in the ketamine bladder indicate that dysregulation of purinergic neurotransmission may underlie detrusor overactivity in cases of ketamine induced bladder dysfunction.

Overactive bladder syndrome (OAB), characterized by urinary frequency, nocturia and urgency with or without incontinence, is a widespread medical condition with significant impact on quality of life. Three main factors have been proposed regarding the cause of OAB: myogenic, neurogenic and urotheliogenic. Disturbance of any of the three factors or a combination of these factors can attribute to OAB. Metabolic derangement, bladder outlet obstruction and inflammation can increase the excitability of nerve, detrusor muscle and alter the sensory and barrier functions of the urothelium. The detection of proteins in the urine such as NGF, PGE2, and proinflammatory chemokines may advance our understanding of the pathophysiology of OAB and offer novel diagnostic biomarkers of OAB.

The aim of the current study was to evaluate the histopathological features of inflammation and the expression levels of inflammatory markers in tissue samples from patients with ketamine-induced cystitis. Bladder biopsy samples for histological analysis were obtained from 23 patients (18 men and 5 women) with a self-reported history of ketamine use and who were treated for cystitis at the Tri-Service General Hospital of Taipei, Taiwan. Immunohistochemical staining for cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metallopeptidase-9 (MMP-9), mammalian target of rapamycin (mTOR), and phosphorylated 40S ribosomal protein S6 (Phos-S6) was performed. The results revealed urothelial atypia in all patients, and intravascular eosinophil accumulation in 22 patients. Histopathological features included denuded urothelial mucosa, ulceration, collagen deposition, smooth muscle degeneration and vessel proliferation. Tissue samples were immunopositive for all of the inflammation markers, including the urothelium, vessel walls, and smooth muscle. COX-2 staining revealed a significant difference between the inflammatory levels in the urothelium and smooth muscle, and iNOS staining differed significantly between inflammatory levels in smooth muscle (p=0.029). A positive correlation was observed between the percentage of Phos-S6-positive cells and the levels of inflammation in the urothelium. These results add to the descriptive literature on the histopathological aspects of ketamine-induced cystitis, emphasizing the inflammatory nature and a possible role for proteins such as COX-2, iNOS and Phos-S6 in the degree of inflammation.

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We aimed to explore the correlation between ketamine abuse and lower urinary tract symptoms (LUTS) and epidemiology of ketamine cystitis. Questionnaire records of ketamine abusers, such as sex, age, and details of using ketamine, including consumption method, amount, duration of ketamine use, and LUTS, were obtained from two private rehabilitation centers. We analyzed these factors and established a severity forecasting module. One hundred and six ketamine abusers completed the questionnaires. LUTS showed an onset time of 24.67 ± 26.36 months among ketamine abusers. Overactive bladder symptom score, international prostate symptom score-storage, interstitial cystitis symptom index, interstitial cystitis problem index, and visual analogue scale score were 5.25 ± 4.43, 5.95 ± 5.72, 10.96 ± 6.66, 9.73 ± 5.82, and 2.55 ± 3.18, respectively. All symptom scores were positively correlated with the duration of ketamine abuse. Ketamine snorting was significantly correlated with all symptom scores compared to smoking. Hydrodistention, intravesical hyaluronic acid instillation, intravesical injection with botulinum toxin, and hyperbaric-oxygen therapy showed better effect than oral treatment. Ketamine can induce severe storage symptoms, such as frequency or nocturia depending on the duration of abuse. Ketamine snorting may cause worse LUTS than smoking. Combining ketamine and other substances may exacerbate LUTS. Intravesical therapy may lead to better outcomes than oral treatment.