Interstitial cystitis (IC) is one of the most commonly seen chronic inflammatory diseases of the urinary bladderand is characterized by a wide range of symptoms, including pelvic or lower abdominal pain and irritative voiding symptoms such as urinary frequency, urgency, and nocturia [1-3]. Overlapping patterns of lower urinary tract symptoms and pelvic pain are common in patients with IC [4], and these overlapping patterns create challenges for clinical research and practice and warrant further investigation of their causes, diagnosis, and effective treatments.

The conditions of IC and overactive bladder (OAB) share irritative voiding symptoms [1,4]. Theoretically, then, anticholinergic drugs could be considered to provide an alternate mechanism of action, which could decrease these embarrassing symptoms. In practice, however, many studies have shown that most IC patients do not respond appropriately to treatment with anticholinergic medications, whereas OAB patients with benign prostatic hyperplasiarespond well [5,6]. Thus, we need to clarify the urodynamic findings and mechanismsin these two experimental conditions in animal models.

The OAB syndrome is defined as urinary urgency, with or without urge incontinence, that is usually accompanied by urinary frequency and nocturia [7]. In other words, this urgency is regarded as a core symptom in diagnosis, which may correspond to detrusor overactivity (DO) during the filling phase in human urodynamic study [7,8]. Assuming that nonvoiding contractions (NVCs) interpreted on the basis of simultaneous changes in intraabdominal pressure (IAP) in an animal model can be used as a substitute parameter for DO in humans, the rat model of chemical cystitis and bladder outlet obstruction (BOO) may allow us to study the pathophysiology of different responsesto anticholinergic drugs.

In this study, we investigated bladder function, with a special focus on the NVCs, in awake rats with chemical cystitis and BOO by use of simultaneous registrations of intravesical and intraabdominal pressures. In addition, we tested the effects of tolterodine on the NVCs in these models.

Our study showed that tolterodine had no significant effect on urodynamic parameters, including pressure/volume and DO-related variables, except MP in a chronic IC model. Only MP showed a decrease with treatment without changes in DO frequency or pressure. This suggests that toleterodine may have an unfavorable effect on voiding without any effect on DO during the filling phase. In the BOO model, however, the drug resulted in adecrease inboth frequency and pressure of DO and some changes in pressure/volume parameters. The anticholinergic drug showed some effects on both the filling and voiding phases. IC is a chronic inflammatory disease of the bladder [1], but its etiology and pathogenesis remain obscure. It is characterized by irritative voiding symptoms and vague pain related to the bladder and shareswith OAB syndromeurinary urgency as a key symptom in diagnosis [1,4]. The urgency symptom is known to be correlated with the DO, which is defined as a urodynamic observation of involuntary detrusor contractions during the bladder-filling phase [7,8]. About 15% of patients with IC have been reported to have spontaneous DO as measured by urodynamic testing [11]. The treatment of this DO has incorporated the application of anticholinergic drugs, but many clinical reports have shownthat these drugs are ineffective in many patients with IC [5,6]. There havebeen few reports directly showing the effects of anticholinergic drugs on urodynamic results, including objective report of DO in an awake animal IC model. According to our results, DO was not affected by the anticholinergic drug in the IC model, unlike in the BOO model. Such study to find the cause of the ineffectiveness in an animal model is important to improve our understanding of these drugs and to find possible alternative treatments.

The uncertainty over the benefit of anticholinergic drugs in IC appears to stem from two separate factors of unclear diagnostic criteria and etiology or pathophysiology. In the diagnosis of IC, after ruling out other obvious pathology and overlapping syndromes through an extensive and specific series of tests [12], the exclusion of other often confused diseases is still encouraged, because there are no definitive diagnostic tests. Since the National Institute for Diabetes and Diseases of the Kidney (NIDDK) reported the diagnostic criteria for IC in 1990 [13], the definitions and terminology have undergone some changes. Different organizations have proposed different terms, such as painful bladder syndrome or bladder pain syndrome [14,15]. Enigmatic pain related to the bladder was emphasized more than the other symptoms in these reports [3,14]. However, because these small changes in diagnostic criteria can result in noticeably different patient groups being studied, we need to unify the terms or definitions and focus on how to delineate the patients accurately by use of accurate diagnostic criteria internationally. The heterogeneous characteristics of IC subgroups could be the starting obstacle in finding a solution to the ineffectiveness of anticholinergic drugs. It will be important to find a subgroup of IC patients who respond well to this drug or to determine how to use this drug as a palliative agent.

Second, several decades of research on IC has revealed that inflammation, as determined by the presence of cytokines, chemokines and mast cells, may have vital role in the pathogenesis of this disease [16,17]. Although it is suggested that increased permeability of or neuropathic pain in the bladder mucosa results in OAB through the activation of afferent reflex circuitry [18-20], our limited understanding of the fundamental mechanisms causing OAB in IC has continued to frustrate efforts aimed at its treatment. The detailed mechanism needs further elucidation.

Our proposed model of chronic chemical cystitis showed the characteristics of OAB in view of DO-related parameters. Our modelshowed DO in 50% of the rats, even with no increased BP, TP, or MP and no decreased BC, MV, RV, or MI compared with the control rats. These animals at 4 weeks did not show differences compared with animals at 2 weeks in our previous study [21]. Our model of BOO also showed characteristics similar to the results of previous studies with BOO. The BOO rats showed an increased ratio of bladder to body weight, increased BP, and increased TP, but no increases in BC, MI, or RV. After theadministration of tolterodine, the BOO model showed a decrease inTP, MP, and DO pressure/frequency and an increase in RV, corresponding to the original effects of that drug.

In the obstructed bladder, supersensitivity of the detrusor muscle secondary to denervation was found to play a predominant pathophysiologic role in OAB [22,23]. This has been suggested to be caused by bladder overdistention resulting from BOO [24]. Clinically, DO in men with OAB responds well to antimuscarinics, which is similar the results of our study [25]. An anticholinergic agent is a substance that blocks the acetylcholine of a neurotransmitter by competitive inhibition in neurons of the central and peripheral nervous system. This is known to reduce the effects mediated by acetylcholine on muscarinic receptors in those neurons [26]. We suspect that the different response between BOO and IC is caused by the basic difference in the pathophysiologic characteristics of the bladder in these two conditions, which needs to be elucidated further in future studies. Clinically, we also need further study to improve the treatment effect of anticholinergic drugs inIC patients with OAB.