Sensory and motor roles of tachykinins, vanilloids and acid in the urinary bladder mucosa

The bladder mucosa plays an essential role in bladder function. Several receptors are expressed on mucosal cells and the mucosal release of mediators is considered to contribute to bladder afferent signalling. However, mucosal motor activity has not been previously examined. The aim of this thesis was to examine the role of vanilloid TRPV1 and tachykinin NK2 receptors in the bladder mucosa. In addition, the expression and function of novel acid sensing ion channels (ASICs) was explored.Pig and rat models were employed to examine potential species specific differences. In organ bath experiments, the tachykinin, neurokinin A (NKA), was demonstrated to be a potent contractile agent of the pig mucosa. Mucosal responses to NKA were higher than those in intact strips and were mediated by the NK2 receptor, as evidenced by antagonist studies. Immunostaining revealed smooth muscle actin expression on suburothelial myofibroblasts, suggesting their potential role in mucosal contractile activity.To examine the endogenous sources of NKA, contraction and ATP release in response to TRPV1 agonists. capsaicin and acid, were assessed in pig and rat mucosa. In pig mucosal strips, capsaicin did not evoke contraction or ATP release. However, acid (in the physiological range of normal urine) resulted in contraction and a 25-fold increase in ATP release compared with basal. In contrast, in rat mucosal strips, both capsaicin and acid were potent stimuli for ATP release. Acid-evoked ATP release was shown to be mediated via both the TRPV1 and ASIC receptors. ASIC receptor mRNA expression was demonstrated in the rat bladder mucosa and detrusor.Results from this thesis demonstrate novel characteristics of the bladder mucosa: its ability to contract, distinct from the detrusor muscle. The contraction of the mucosa via NK2 receptors has provided a new (so far, overlooked) target for drugs in the treatment of bladder diseases. In addition, acid has been shown to be an important stimulus in modulating bladder function. With the focus of current bladder research shifting towards the sensory pathways, acid may represent an important endogenous initiator of bladder sensation