P.023| Volume 163, ISSUE 1-2, P49-50, September 01, 2011

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

      Inflammation and mechanical perturbations (e.g. shear stress, stretching) stimulate ATP release from urinary bladder cells. Urodynamic and in vitro studies demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladders (OAB) exhibit a 3-fold increase in ATP release. Clinical studies led us to propose that urinary ATP may be a non-invasive biological marker of overactive bladder syndromes, exhibiting higher sensitivity and specificity (AUC: 83.2%, CI 95%: 69.7–96.7) than other experimental markers (e.g. NGF); urinary ATP shows no correlation with voided urine volume, urinary creatinine and urinary lactate dehydrogenase (LDH) activity. Increased ATP bioavailability explains hyperactivity of bladder nerves (via P2X3 receptors) and detrusor contractions (via P2X1). The role of ATP may, however, be complicated by compartmentalization of purinoceptors together with ecto-NTPDases at cell surface microdomains. Previously, our group demonstrated that the detrusor from patients with benign prostatic obstruction (BPH) exhibits slow inactivation kinetic of ATP into biologically-active derivatives as compared to cadaveric controls. Implications of these findings on the activity of co-localized inhibitory metabotropic P2Y and P1 receptors by ATP hydrolyzing products ADP and adenosine were investigated. Data obtained using selective receptor agonists and enzymatic inhibitors suggest that adenosine A1 receptors negatively modulating cholinergic nerve activity are up-regulated in obstructed bladders. Immunolocalization studies showed that human urothelial cells are highly enriched in ecto-NTPDase3 enzyme, whereas the detrusor smooth muscle layer exhibits predominantly the ecto-NTPDase1/CD39 marker; these findings were confirmed by HPLC kinetic experiments. Thus, the global impairment of ecto-NTPDase activity in OAB samples leading to enhanced bioavailability of ATP and decreased formation of inhibitory adenosine may contribute to detrusor overactivity. In this context, we hypothesized that blockade of adenosine inactivation pathways, both uptake and extracellular deamination, could be therapeutically useful to control bladder overactivity regarding up-regulation of A1 receptors.
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