No abstract

Novel longer lasting inflammatory bladder animal models are needed to better understand the pathophysiology of chronic cystitis. We previously developed a relatively long‐lasting mouse cystitis model by intravesical injection of hydrogen peroxide (H2O2). To further evaluate its pathophysiology, in this study, we established and analyzed a rat cystitis model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female rats, and kept for 30 min. The H2O2 injection significantly increased the number of micturition events up to day 14 and decreased urine volume per micturition, with the smallest volumes on day 3, compared with the vehicle‐treated group. Cystometric analysis on day 7 revealed that intercontraction intervals were significantly shortened without affecting the baseline, threshold, or maximum pressures. Intravesical resiniferatoxin‐evoked nociceptive behaviors, such as freezing, were significantly enhanced on days 7 and 14. Furthermore, histopathology revealed hemorrhage, edema, infiltration of neutrophils into the lamina propria, and urothelial denudation in the early phase (day 1). These damages were gradually repaired, while hyperplasia of the urothelium, vascularization, increases in fibroblast counts, and infiltration of mast cells and eosinophils were observed through the later phase (days 7 and 14). These results suggest that intravesical H2O2 injection induces relatively long‐lasting cystitis with enhanced bladder activity and pain sensation in rats. This approach thus provides a novel rat long‐lasting cystitis model that allows us to analyze detailed symptoms and pathophysiology of H2O2‐induced cystitis model than the mouse model and may be used to investigate the pathophysiology and treatment of chronic bladder hypersensitive disorders, such as bladder pain syndrome/interstitial cystitis.

We previously established a long-lasting cystitis model by an intravesical injection of hydrogen peroxide (H2O2) into mice. In this study, we assessed the pain-related behaviors in the cystitis model. An intravesical injection of 1.5% H2O2 transiently decreased spontaneous locomotor activity at 3 h after injection, indicative of acute spontaneous pain. In contrast, licking response to a bladder distention was slowly observed as licks to the lower abdomen at 7 and 14 days after injection, which was attenuated by amitriptyline and morphine, but not by oxybutynin. These results suggest that H2O2-induced chronic cystitis model shows delayed and long-lasting painful pathological condition.

The secretion of HCO3(-) in the duodenum is increased by mucosal acidification, and this process is modulated by gas mediators such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon monoxide (CO), in addition to prostaglandins (PGs). The secretion is increased by NOR3 (NO donor), NaHS (H2S donor), and CORM-2 (CO donor). The HCO3(-) responses to NOR3 and CORM-2 are attenuated by indomethacin, while that to NaHS is mitigated by indomethacin and L-NAME as well as sensory deafferentation. NOR3 and CORM-2 increase mucosal PGE2 production, while H2S increases mucosal PGE2 content and luminal NO release. The HCO3(-) response to mucosal acidification is attenuated by indomethacin, propargylglycine, and SnPP, each inhibiting PG, H2S and CO production, respectively. The acid-induced duodenal damage is worsened when either PG, H2S or CO is lacking. These findings suggest that 1) NO, H2S, and CO, generated endogenously or exogenously, stimulate HCO3(-) secretion in the duodenum; 2) the stimulatory action of NO and CO is mediated, at least partly, by endogenous PGs, while that of H2S is mediated by PGs and NO as well as sensory neurons; 3) these gas mediators are involved in the local regulation of acid-induced HCO3(-) secretion, in addition to endogenous PGs; 4) the acid-induced duodenal damage is worsened by agents inhibiting the endogenous production of NO, H2S or CO. It is assumed that these gas mediators play a role in maintaining the integrity of the duodenal mucosa by modulating the secretion of HCO3(-).