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

Abstract

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.

Urinary ATP Levels Are Controlled by Nucleotidases Released from the Urothelium in a Regulated Manner

“…Previous studies have suggested that ATP might be degraded at the luminal surface of the bladder mucosa. Thus, bladder umbrella cells appear to express ATP-metabolizing enzymes [ 66 , 67 ] and ATP metabolites have been found in the lumen of mouse and monkey bladders [ 3 , 4 ] and in human urine samples [ 23 , 68 ]. In contrast, studies in rabbit mucosa sheets mounted in Ussing chambers failed to detect hydrolysis of exogenous ATP added to the mucosal chamber [ 8 , 69 ].…”

“…Conversely, decreased intravesical ATP has been found in patients with refractory detrusor overactivity and bacteriuria [ 19 ] and in patients with underactive bladder syndrome [ 20 ]. Such observations have increasingly suggested ATP as a relevant biomarker of bladder dysfunctions [ 11 , 12 , 21 , 22 , 23 , 24 ]. It was recently alluded that ATP might be a better urinary marker than acetylcholine and prostaglandin E2, as the majority of ATP in urine is thought to originate in the lower urinary tract (LUT), whereas the other two substances may also arise from extraction from the plasma into the urine in the kidneys [ 25 ].…”

The profile of urinary biomarkers in overactive bladder

“…4,5 Previous studies demonstrated that the levels of different proteins and /or metabolites are increased in patients with OAB as compared to controls and they may also correlate with the severity of OAB symptoms. 6,7 To date, evidence has shown that urinary proteins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are increased in patients with OAB, but also in a number of conditions including bladder outlet obstruction (BOO) and interstitial cystitis. [8][9][10][11][12] However, knowledge gaps regarding the causality persist and the clinical utility of these observations is not yet quantified.…”