Reactive oxygen species mediate detrusor overactivity via sensitization of afferent pathway in the bladder of anaesthetized rats

Abstract

Objectives: To investigate the effects of reactive oxygen species (ROS) on the micturition reflex in vivo, especially in bladder afferent signalling in rats, as several pathophysiological conditions in the urinary bladder (e.g. ischaemia/reperfusion and inflammation) are characterized by the formation of ROS.

Materials and methods: Adult female Sprague-Dawley rats under urethane anaesthesia (normal or pretreated with 125 mg/kg capsaicin, subcutaneously, 4 days before) were assessed by continuous cystometrography (CMG) with or without the intravesical administration of H(2)O(2) (0.003-3%) to stimulate ROS damage. To investigate the mechanism of H(2)O(2), catalase (a H(2)O(2) scavenger) was applied intravesically (2000 IU/mL), or rats were given intravenous injections with superoxide dismutase (SOD, 20,000 IU/kg, a superoxide anion scavenger), dimethylthiourea (DMTU, 100 mg/kg, a hydroxyl radical scavenger), deferoxamine (20 mg/kg, an iron-chelator that prevents the formation of hydroxyl radical), indomethacin (3 mg/kg, a cyclooxygenase inhibitor) or ketoprofen (1 mg/kg, a cyclooxygenase inhibitor) just before or during the intravesical administration of H(2)O(2). Prostaglandin (PG) levels (PGE(2) and 6-keto-PGF(1 alpha)) were measured in the bladder of rats treated with intravesical 0.3% H(2)O(2) for 30 min with or without indomethacin.

Results: Intravesical administration of H(2)O(2) induced detrusor overactivity, as shown by a reduction in the mean (sem) intercontraction interval (ICI), in a dose-dependent manner in normal rats (0.3% H(2)O(2,) P < 0.01, 36.2 (4.7)% of the control ICI). H(2)O(2)-induced detrusor overactivity was almost abolished by catalase and significantly suppressed by DMTU, deferoxamine, capsaicin pretreatment, indomethacin or ketoprofen but not by SOD. The level of PGs was significantly increased by H(2)O(2) instillation, and indomethacin significantly inhibited the increase in PGs.

Conclusion: These results indicate that oxidative stress induced by H(2)O(2) activates capsaicin-sensitive C-fibre afferent pathways, at least in part, mediated via stimulation of the cyclooxygenase pathway, thereby inducing detrusor overactivity. Thus, rats treated with intravesical H(2)O(2) appear to be a suitable model for the study of detrusor overactivity.