Effect of doxazosin on stretch-activated adenosine triphosphate release in bladder urothelial cells from patients with benign prostatic hyperplasia

Abstract

Objectives. Recent data suggest that the bladder urothelium may have a sensory function by way of release of adenosine triphosphate (ATP) during stretch, which then acts as a sensory neurotransmitter. Because benign prostatic hyperplasia (BPH) can give rise to irritative (hypersensory) voiding patterns, we questioned whether the bladder urothelium from patients with BPH released more ATP during in vitro stretch and whether doxazosin, an alpha 1-adrenoceptor blocker, affects this purinergic mechanism. Methods. Bladder urothelial biopsies from patients with BPH (n = 4) and controls (n = 4) were cultured using established techniques. In vitro stretch was performed with a Flexcell 2000 device that uses vacuum to deform the cell growth surface to impart a stretch force. Doxazosin (5 μM and 20 μM) was added to cells, and supernatants were collected at various points for ATP assay. ATP was assayed using the luciferin-luciferase reaction. ATP data were normalized to the time 0 value and expressed as a percentage of the baseline value. Results. After 96 hours of stretch, the BPH urothelial cells released significantly more ATP than did the control urothelial cells (62.6% ± 11.2% versus 24.2% ± 5.4%, P = 0.005) and nonstretched BPH urothelial cells (62.6% ± 11.2% versus 15.1% ± 5.1%, P = 0.004). The augmented release of ATP by stretched BPH bladder urothelial cells was completely blocked by treatment with 20 μM doxazosin. Conclusions. Irritative voiding secondary to BPH may arise from increased ATP release by bladder urothelium during stretch. Doxazosin inhibits ATP release by way of an unknown mechanism that may or may not involve the alpha 1-adrenoreceptor. Treatment for hypersensory voiding symptoms secondary to BPH might also target the urothelial purinergic pathway.