Interstitial cystitis (IC) is a disabling disorder characterized by severe urinary frequency, nocturia, and pain which is generally relieved by voiding. Very little is known about the etiology or the functional basis for the bladder abnormalities associated with this disorder. The development of a rational therapy for IC has been hampered by the paucity of knowledge of the mechanisms responsible for the bladder dysfunction and the lack of a good animal model. Our hypothesis is that IC occurs when (a) substances(s) excreted in the urine initiates an antigen-antibody response in the bladder mucosa resulting in an increased permeability of the mucosal surface. The increased permeability results in the penetration of substances within the urine into the underlying tissue, resulting in secondary inflammatory reactions which in turn initiate the urological symptoms. This theory is based on our initial studies using guinea pigs sensitized to ovalbumin. We found that intravesical challenge of sensitized guinea pigs to ovalbumin results in increases in bladder permeability to urea, increases in urinary frequency, and decreases in intravesical pressure and bladder capacity at micturition. Thus, exposure of the bladder mucosa to a normally non-irritative substance induces urological symptoms consistent with those observed with IC. The investigations described in this proposal will use the sensitized guinea pig to test this hypothesis, and will focus on the processes thought to be important in the regulation of bladder function in order to determine which are altered by IC. Such studies should serve to identify (a) logical target(s) for therapeutic intervention. The influence of intravesical heparin and pentosan polysulfate treatment on the functional changes associated with sensitization to ovalbumin will be tested to determine whether protection of the mucosa will prevent the response to challenge with ovalbumin. In addition, the influence of distension and intravesical DMSO, two procedures commonly used to treat IC patients, will be evaluated. IC affects primarily females. Therefore, we will investigate the influence of sex hormones on the functional changes associated with ovalbumin sensitization. Because IC may result from inflammatory processes occurring in the bladder mucosa, and the sensitized guinea pig bladder has been shown to undergo inflammatory changes, the role of inflammatory mediators such as prostaglandins, thromboxanes, and leukotriens on the functional responses of the bladder to ovalbumin challenge will be investigated. In addition, the effects of long-term feeding of fatty acid-free or- enriched diets, which result in changes in prostaglandin and leukotriene synthesis, on functional changes will be evaluated. The release and synthesis of prostaglandins and leukotrienes by bladder from control and sensitized guinea pigs will be measured after challenge with ovalbumin. These studies should improve our knowledge of the mechanisms responsible for the functional changes which occur in IC and may contribute to the development of rational therapeutic approaches for this disorder.
