The role of histamine in modulating urothelial contractile activity

Introduction: Although selective antimuscarinics are the first-line pharmacotherapy for overactive bladder, a large proportion of patients discontinue this treatment regimen, due to side-effects and lower than expected treatment benefits. As such, the use of combination therapies has been of interest, and there is benefit to identifying alternative therapeutic targets that can modulate or inhibit the spontaneous contractile activity. Mast cells infiltrate the urothelium and lamina propria, and release inflammatory mediators such as histamine and prostaglandin, which can potentially upset the normal contractile responses and provide an underlying mechanism which stimulates spontaneous contractions. The aim of this study was to investigate the urothelium and lamina propria (U&LP) contractile response to the inflammatory mediator histamine and identify the receptor subtype mediating the effects. Materials & methods: Isolated strips of porcine U&LP (2cm long) were suspended in a 10ml organ bath containing Krebs-bicarbonate solution at 37°C. Histamine was added to each tissue in the presence and absence of the histamine antagonists pyrilamine, cimetidine and thioperamide. A paired student's t-test was used in data analysis with p<0.05 being considered significant. Results: The U&LP responded to the presence of histamine with maximal contractions of 1.14±0.3g (100µM, n=26). Pyrilamine (H1 antagonist) 30 nM inhibited the peak contractile response (p<0.01, n=8) and decreased resting tension for up to 6 minutes after contraction (p<0.01, n=8). In the presence of 1µM cimetidine (H2 antagonist) maximal contraction to histamine were enhanced (100µM, p=0.05, n=10). In the presence of 1µM thioperamide (H3 and H4 antagonist), contractions were also increased (p=0.03, n=6) in the U+LP and remained elevated 6 minutes after contraction (p=0.01, n=6). Conclusions: Histamine produces both a contractile and relaxation response in the U&LP. The contraction appears mediated by the H1 receptor, while relaxation is mediated by the H2 receptor. The research is ongoing, but this preliminary data presents these receptors as potential targets in future therapeutic treatments for overactive bladder or other bladder contractile diseases.