Increased Urinary Adenosine Triphosphate in Patients With Bladder Outlet Obstruction Due to Benign Prostate Hyperplasia

Silva-Ramos, Miguel; Silva, Isabel; Oliveira, José Carlos; Correia-de-Sá, Paulo

doi:10.1002/pros.23207

Cited by 20 publications

(13 citation statements)

References 44 publications

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“…To our knowledge, this is the first study in humans to demonstrate the utility of these biomarker concentrations. We hypothesize that OAB is characterized by an increase in urothelial ATP release, as observed by increased urinary [ATP] in OAB (Silva‐Ramos et al., 2013), interstitial cystitis (Sun, Keay, De Deyne, & Chai, 2001) and benign prostatic hypertrophy (Silva‐Ramos, Silva, Oliveira, & Correia‐de‐Sá, 2016), with a small decrease in urothelial NO release. Measurement of a combination of urinary biomarkers provides a more sensitive index of small changes in bladder function attributable to disease onset.…”

Section: Discussionsupporting

confidence: 64%

A pilot study to investigate the associations of urinary concentrations of NO, ATP and derivatives with overactive bladder symptom severity

Firouzmand

Young

2020

Experimental Physiology

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Overactive bladder (OAB) is a highly prevalent symptom complex characterized by symptoms of urinary urgency and increased frequency and waking to void (nocturia), with or without urge incontinence and in the absence of proven infection or other obvious pathology. The underlying pathophysiology of idiopathic OAB is not clearly known, and the existence of several phenotypes has been proposed. Current diagnostic approaches are based on discordant measures, suffer from subjectivity and are incapable of detecting the proposed OAB phenotypes. Nitric oxide, ATP and their metabolites have previously been shown to underlie the perception of bladder fullness, with their release modifying the pathological perception of urgency. Therefore, in this study we assessed the concentrations of NO, ATP and associated metabolites in the urine of 113 consenting participants recruited from the general population. Recruited participants completed a questionnaire to measure the severity of OAB-associated urinary symptoms and provided a mid-stream urine sample. After identification of infection and haematuria using microbiology and microscopy, 95 samples were subjected to assays to measure NO, NO 2 − , NO 3 − , ATP, ADP and creatinine (Cr). There was no correlation between [NO/Cr], [NO 2 − /Cr] or [NO 3 − /Cr] and overall OAB symptom severity. In contrast, [ATP/NO], [ADP/NO] and a combination of these, [ATP/Cr*ADP/Cr]/[NO/Cr], were correlated with OAB symptom severity, and [ATP/Cr*ADP/Cr]/[NO/Cr] was also correlated with the severity of urinary frequency and urgency. This study adds to a growing literature that demonstrates the potential of urinary biomarkers and provides a foundation for a larger, longitudinal study.

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Section: Discussionsupporting

confidence: 64%

A pilot study to investigate the associations of urinary concentrations of NO, ATP and derivatives with overactive bladder symptom severity

Firouzmand

Young

2020

Experimental Physiology

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“…In the pig, partial bladder outlet obstruction resulted in reduced contractions in response to electrical field stimulation as well as to purinergic agonists ( Milicic et al, 2006 ), but in the rat partial outlet obstruction model, contractions to ATP were increased after 2 weeks and 3 months ( Murakami et al, 2008 ). Patients with bladder outflow obstruction release higher amounts of ATP into the urine ( Silva-Ramos et al, 2016 ).…”

Section: Diseases Of the Lower Urinary Tractmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…Participants in our study had, on average, relatively lower OAB symptom score severity (Table 1) compared to previous studies, however, the observation of significant correlations with the total ICIQ‐OAB symptom scores suggests that ATP is elevated even with mild OAB; an observation that adds weight to the argument that it could be a useful diagnostic biomarker. However, studies have shown that ATP is elevated in pyuria 15 ; interstitial cystitis 16 ; and BPH, 17 so a lack of specificity may limit its usefulness. Future studies may want to include additional measures (such as more detailed questionnaires of urinary symptoms) to be certain of excluding these groups when recruiting from the general population.…”

Section: Discussionmentioning

confidence: 99%

Investigating the associations of mucosal P2Y6 receptor expression and urinary ATP and ADP concentrations, with symptoms of overactive bladder

Firouzmand

Ajori

Towse

et al. 2020

Neurourology and Urodynamics

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Aim To characterize purinergic signaling in overactive bladder (OAB). Methods Mucosal biopsies were taken by flexible cystoscopy from patients with storage symptoms referred to Urology Departments of collaborating hospitals. Immunohistochemistry (n = 12) and Western blot analysis (n = 28) were used to establish the qualitative and quantitative expression profile of P2Y6 in human mucosa. Participants from the general population provided a mid‐stream urine sample. Bioluminescent assays were used to quantify adenosine triphosphate (ATP; n = 66) and adenosine diphosphate (ADP; n = 60) concentrations, which were normalized to creatinine (Cr) concentration. All participants completed a questionnaire (International Consultation on Incontinence Questionnaire – Overactive Bladder) to score urinary symptoms of OAB. Results P2Y6 immunoreactivity, more prominent in the urothelium (colocalized with the uroepithelial marker pan‐cytokeratin), was more greatly expressed in OAB compared to age‐ and sex‐matched controls (benign prostatic hyperplasia) without OAB symptoms. Mucosal P2Y6 was positively correlated only with incontinence (P = .009). Both urinary ATP and its hydrolysis product, ADP, an agonist to P2Y6, were positively correlated with total OAB symptom score (P = .010 and P = .042, respectively). Conclusions The positive correlation of P2Y6 only with incontinence may indicate a different phenotype in OAB wet and warrants further investigation. Positive correlations of ATP and ADP with total OAB symptom score demonstrate upregulation in purinergic signaling in OAB; shown previously only in animal models. Further research is required to validate whether purinoceptors are indeed new therapeutic targets for this highly prevalent symptom complex.

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Increased Urinary Adenosine Triphosphate in Patients With Bladder Outlet Obstruction Due to Benign Prostate Hyperplasia

Cited by 20 publications

References 44 publications

A pilot study to investigate the associations of urinary concentrations of NO, ATP and derivatives with overactive bladder symptom severity

A pilot study to investigate the associations of urinary concentrations of NO, ATP and derivatives with overactive bladder symptom severity

Purinergic Signalling: Therapeutic Developments

Investigating the associations of mucosal P2Y6 receptor expression and urinary ATP and ADP concentrations, with symptoms of overactive bladder

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