Bladder overactivity due to global impairment of ecto-NTPDases in humans with lower urinary tract disorders exhibiting unbalanced ATP/adenosine formation

Silva, I.; Correia, Joana; Ferreirinha, Fátima; Magalhães-Cardoso, M.T.; Silva‐Ramos, Miguel; Sévigny,; Correia‐de‐Sá, P.

doi:10.1016/j.autneu.2011.05.038

Cited by 3 publications

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“…Decreased ATP metabolism could also explain high levels of ATP in the urine of OAB patients as compared to controls. Reports from our and others groups, have shown that ATP catabolism is hindered in the bladder of patients with outlet obstruction and detrusor overactivity [27], [37], [38], which could also be the case of women with OAB. Thus, our findings are consistent with urinary ATP being a putative dynamic biomarker of detrusor overactivity in women with OAB.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it is known that parasympathetic nerves from overactive or obstructed human bladder strips release more ATP than controls [15], [26], [27]. Enhanced urinary ATP content may also result from impairment of ecto-NTPDase activity observed in cells from OAB patients, as this finding may determine slower nucleotide inactivation kinetics in the bladder wall and its urinary accumulation [37], [38].…”

Section: Discussionmentioning

confidence: 99%

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Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

et al. 2013

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BackgroundNowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic-noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls.MethodsPatients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze-preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA.ResultsThe urinary content of ATP, but not of NGF, normalized to patients’ urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary.ConclusionA high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62–0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

et al. 2013

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“…Bladder overactivity may be partly reversed through the hydrolysis of ATP into ADP by E‐NTPDases. Previous reports from our group demonstrated that ADP acts through inhibitory P2Y 1 receptors to decrease nerve‐evoked ACh release in the human bladder (Silva et al ., ). Here, we showed that VAChT‐positive cholinergic nerve efferents to the detrusor, but not NF160‐labelled sub‐urothelial sensory nerves, exhibit immunoreactive P2Y 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Besides the relevance of sub-urothelial P2X3 receptors to initiate the micturition reflex, blockade of P2Y1 receptors may remove an accommodatory, inhibitory drive to the detrusor muscle in urethane-anaesthetized female rats (King et al, 2004). In the human urinary bladder, ATP stimulation of bladder activity may be partly reversed by its catabolism by E-NTPDases to ADP, leading to the activation of inhibitory P2Y1 receptors on cholinergic nerve endings (Silva et al, 2011). In this context, we investigated the contribution of P2X3 and P2Y1 receptors to bladder hyperactivity caused by UDP (100 μM).…”

Section: Participation Of Excitatory P2x3 and Inhibitory P2y 1 Receptmentioning

confidence: 99%

“…Thus, intravesical ATP decreases bladder capacity and micturition volume in a concentration‐dependent manner, with limited effects on detrusor tension (Pandita and Andersson, ). ATP stimulation of micturition may be partly counteracted by its catabolism, by ecto‐nucleoside triphosphate diphosphohydrolases (E‐NTPDases) of the urinary bladder, into ADP, which could then act through inhibitory P2Y 1 receptors on cholinergic nerve endings in the human bladder (Silva et al ., ; nomenclature see Alexander et al ., ). Recently, evidence has emerged supporting a role for sub‐urothelial myofibroblasts in detrusor contraction, which also express P2X and P2Y purinoceptors (Fry and Rossen, ; Fry et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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Activation of P2Y₆ receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium

Carneiro

Timóteo

Silva

et al. 2014

British J Pharmacology

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Background and purpose Despite the abundant expression of the UDP‐sensitive P2Y6 receptor in urothelial cells and sub‐urothelial myofibroblasts its role in the control of bladder function is not well understood. Experimental approach We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [3H]‐ACh overflow experiments. Key results Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP‐induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [3H]‐ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid. Conclusions and Implications Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub‐urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E‐NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors.

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ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors

Timóteo

Carneiro

Silva

et al. 2014

Biochemical Pharmacology

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Bladder overactivity due to global impairment of ecto-NTPDases in humans with lower urinary tract disorders exhibiting unbalanced ATP/adenosine formation

Cited by 3 publications

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Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

Activation of P2Y₆ receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium

ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors

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Bladder overactivity due to global impairment of ecto-NTPDases in humans with lower urinary tract disorders exhibiting unbalanced ATP/adenosine formation

Cited by 3 publications

References 0 publications

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

Urinary ATP May Be a Dynamic Biomarker of Detrusor Overactivity in Women with Overactive Bladder Syndrome

Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium

ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors

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Activation of P2Y₆ receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium