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Protein kinase C contributes to abnormal capsaicin responses in DRG neurons from cats with feline interstitial cystitis.

Interstitial cystitis (IC) is a painful disorder which affects urinary bladder function in cats and humans. We have used patch clamp techniques to examine the possibility that the properties of primary afferent neurons are changed in feline interstitial cystitis (FIC). We measured transient receptor potential vanilloid receptor 1 (TRPV1) responses to capsaicin (CAPS) in dorsal root ganglion (DRG) neurons (L4-S3) from normal cats and cats with FIC. We show that FIC neurons are increased in size and exhibit CAPS responses which are increased in amplitude and desensitize slowly. CAPS responses desensitized seven times slower in FIC neurons. Phorbol 12,13-dibutyrate (PDBu), an activator of PKC, slowed the desensitization of CAPS responses in normal cat bladder and non-bladder neurons, but had no effect in FIC neurons. Bisindolylmaleimide, an inhibitor of PKC, reversed the PDBu effects in normal cat neurons and normalized the desensitization of CAPS responses in FIC neurons. Our data suggest that FIC afferent neurons exhibit abnormal CAPS responses. The latter may be due to enhanced endogenous activities of PKC.

Animals↗

Abnormal excitability in capsaicin-responsive DRG neurons from cats with feline interstitial cystitis.

Interstitial cystitis (IC) is a painful disorder which affects urinary bladder function in cats and humans. We used patch clamp techniques to measure firing properties and K+ currents of dorsal root ganglion (DRG) neurons (L4-S3) from normal cats and cats with feline interstitial cystitis (FIC) to examine the possibility that the properties of primary afferent neurons are changed in cats with FIC. We found that capsaicin (CAPS)-responsive neurons from FIC cats were increased in size, had increased firing in response to depolarizing current pulses and expressed more rapidly inactivating K+ currents. CAPS-sensitive neurons from FIC cats were 28% larger than those from normal cats but were otherwise similar with respect to membrane potential and action potential (AP) threshold. CAPS-responsive neurons from normal cats fired 1.5 APs in response to a 600 ms depolarizing current pulse, 60-200 pA in intensity. The number of APs was increased 4.5 fold in FIC neurons. Neurons from FIC cats also exhibited after hyperpolarization potentials which were on the average 2x slower than those in normal cat neurons. In addition, there was a lack of K+ currents in the critical voltage range of action potential generation (between -50 to -30 mV). These changes were not detected in CAPS-unresponsive neurons from normal and FIC cats. Our data suggest that FIC afferent neurons exhibit abnormal firing which may be due to changes in the behavior of K+ currents and show that these changes are restricted to a subpopulation of CAPS-responsive neurons.

Animals↗

Complete transurethral resection of ulcers in classic interstitial cystitis.

Interstitial cystitis (IC) is a chronic disease of obscure etiology. It commonly affects females, who present with symptoms of pain on bladder filling and urinary frequency. There are two types of IC: classic and non-ulcer disease, which differ in many respects, including response to different therapies. In this retrospective study we evaluated the hitherto largest series of patients with classic IC treated by transurethral resection (TUR) of visible ulcers. Altogether 259 TURs of Hunner ulcers were performed on 103 patients: 92 experienced amelioration, and in 40% symptom relief lasted more than 3 years. In the remaining patients, although symptom recurrence was common, the majority responded well to subsequent TUR. In conclusion, TUR has a good outcome in patients with classic interstitial cystitis, and we suggest it as first-line treatment in this patient group.

Aged↗

Treatment of refractory interstitial cystitis.

Interstitial cystitis is the most therapeutically frustrating condition of the urinary tract. The vast array of treatments available clearly indicates that none is particularly effective. As the majority of patients fail to experience a significant and prolonged response to standard treatments, new options are frequently being developed. These include the oral administration of cimetidine, the intravesical use of hyaluronic acid and BCG, and total cystectomy with the formation of a continent urinary diversion. Unfortunately, the acceptance of many new treatments is based on incomplete evaluation, and this has resulted in a confusing array of disparate alternatives. Effective and durable treatment will not be available until the nature of the disease is better understood and the mechanisms of action of current therapies are elucidated.

Adjuvants, Immunologic↗

Interstitial cystitis.

Interstitial cystitis (IC) is a multifactorial syndrome with symptoms of pelvic or perineal pain, urinary frequency and urgency. The etiologies are unknown, but several theories have been proposed. Diagnosis is often delayed because most of the conventional evaluation is normal. Pelvic examination is normal except for bladder tenderness. Urodynamics are normal except for increased bladder sensitivity and low capacity. Urinalysis, urine culture and office cystoscopy are also normal. The diagnostic test is cystoscopy under anesthesia with bladder distension. Small submucosal hemorrhages (glomerulations) or ulcers appear after distension. Many empiric treatments have been proposed for IC. None is universally effective, and so treatments are tried sequentially until good symptom relief is achieved. Bladder distension gives excellent (but transient) relief in some patients, especially those with severe bladder inflammation (who also tend to be older). A variety of oral, intravesical and adjunctive treatments are also described.

Cystitis, Interstitial↗

Pentosanpolysulphate for interstitial cystitis.

Interstitial Cystitis (IC) is a chronic disease of unknown etiology which primarily affects women aged 40-60 years. Many plausible theories for the development of IC have been postulated, and one current theory is that these patients have a quantitative and qualitative defect in the glycosaminoglycan (GAG) layer of the urothelium. Such a defect may allow toxic substances in the urine to gain access to the lamina propria and initiate a chronic inflammatory process. Pentosanpolysulphate (PPS) is a sulphated proteoglycan similar in structure to heparin sulphate, which is quantitatively the major GAG on cell surfaces. Exogenously administered PPS has been shown in several studies to decrease bladder pain and urinary frequency and to increase the voided volume. Further studies are required to evaluate the role of PPS in the management of IC patients, with particular emphasis on dosage, route of administration and combination with other compounds.

Anti-Inflammatory Agents, Non-Steroidal↗

[Diagnosis of interstitial cystitis].

Interstitial cystitis (IC) represents a rare and complex inflammatory bladder condition in which diagnostics can be challenging. Strict NIH criteria for its diagnosis were designed for research purposes. Their routine application would miss large proportions of IC patients. When IC is suspected, history and physical exam are followed by an evaluation of long-term voiding diaries. Large voided volumes (functional capacity > 250 cc) or longer micturition intervals (> 2 h.), absence of nocturia or symptom-free periods reduce the likelihood of IC. Further exclusion diagnostics include urine tests (infection), cytology (in-situ carcinoma), ultrasound (calculi, bulks, anomalies) and urodynamics in selected cases. Bladder capacity measurements under sedoanalgesia are of limited value, since functional low-volume bladders can be mechanically extendable. Cystoscopy under general anesthesia represents the diagnostic standard procedure for IC during which 90% of IC-patients present with characteristic mucosal glomerulations after bladder distension. Biopsies are recommended for exclusion of malignancy. Potassium-leak testing plays no relevant role in routine diagnostics due to its poor sensitivity. Similarly, complex determinations of novel IC markers (histamine, tryptase, cytokines, growth factors, substance P, nitric oxide) are of no relevance in clinical settings and should be restricted to research projects.

Biopsy↗

Treatment guidelines for classic and non-ulcer interstitial cystitis.

Interstitial cystitis (IC) is a chronic disease of as yet unknown etiology. It commonly affects females, presenting with symptoms of pain on bladder filling, and urinary frequency. Accumulated evidence indicates that IC is a heterogeneous syndrome. Compared to classic IC, the non-ulcer type appears different concerning symptomatic, endoscopic and histological findings, as well as the response to various forms of treatment. This review gives an introduction to the syndrome of IC, concerning epidemiology, clinical characteristics, diagnostic criteria and etiological considerations. A variety of treatment modalities have been suggested and are assessed and reviewed, such as hydrodistension of the bladder, intravesical instillation therapy, oral medication, transcutaneous electrical nerve stimulation, transurethral resection of diseased bladder tissue, and supratrigonal cystectomy followed by enterocystoplasty and urinary diversion. Our algorithm on non-surgical and surgical treatment for classic and non-ulcer IC is presented.

Anti-Inflammatory Agents↗

Interstitial cystitis.

Interstitial cystitis is an enigmatic and frustrating condition to manage as a physician and to cope with as a patient. Traditionally, it has been defined as a chronic sterile inflammatory disease of the bladder of unknown aetiology. However, the International Continence Society prefers the term painful bladder syndrome and it has been decided to follow this terminology and refer to the disease as painful bladder syndrome/interstitial cystitis (PBS/IC). The condition is characterized by bladder pain, urinary frequency, urgency and nocturia. The quality of life of patients with PBS/IC is significantly degraded. Its aetiology is unknown, but might involve microbiologic, immunologic, mucosal, neurogenic and other yet unidentified agents. History, physical examination, urine analysis and culture as well as cystoscopy and hydrodistension are useful diagnostic tools but the final diagnosis tends to be a diagnosis of exclusion. This article will review the major theories of aetiology for PBS/IC and discuss diagnosis as well as the current treatment options with relevance to the proposed aetiologies.

Amitriptyline↗

Diagnosis, treatment, and lifestyle changes of interstitial cystitis.

Interstitial cystitis (IC) is a chronic inflammation of all the layers of the bladder wall. As it is difficult to diagnose and it affects mostly women, many physicians misdiagnose it as a psychological problem. Almost half a million individuals in the United States suffer from this cureless disorder. This article will review the anatomy, physiology, etiology, diagnosis, treatments, and current research foci of IC, along with the effects of the disease on lifestyle and personal issues from the patient's perspective.

Adult↗

The relationship between fibromyalgia and interstitial cystitis.

Interstitial cystitis (IC) is a relatively uncommon and enigmatic disorder characterized by pain in the bladder and pelvic region, typically accompanied by urinary urgency and frequency. Fibromyalgia is a more common disorder, with the prominent symptoms being diffuse musculoskeletal pain and fatigue, and it has been well established that there is substantial clinical overlap between fibromyalgia and chronic fatigue syndrome (CFS). Although genitourinary and musculoskeletal symptoms predominate in IC and fibromyalgia respectively, both disorders share a number of features, including similar demographics, "allied conditions" (e.g. irritable bowel syndrome, headaches, etc.), natural history, aggravating factors, and efficacious therapy. We hypothesized that there was substantial clinical overlap between fibromyalgia and IC, and examined cohorts of individuals with these two disorders in parallel, to compare the spectrum of symptomatology. Sixty fibromyalgia patients, 30 IC patients, and 30 age-matched healthy controls were questioned regarding current symptomatology. A dolorimeter examination was also performed in the three groups to assess peripheral nociception. We found that the frequency of current symptoms was very similar for the fibromyalgia and IC groups. Both the fibromyalgia and IC patients displayed increased pain sensitivity when compared to healthy individuals, at both tender and control points. These data suggest that IC and fibromyalgia have significant overlap in symptomatology, and that IC patients display diffusely increased peripheral nociception, as is seen in fibromyalgia. Although central mechanisms have been suspected to contribute to the pathogenesis of fibromyalgia for some time, we speculate that these same types of mechanisms may be operative in IC, which has traditionally been felt to be a bladder disorder.

Adult↗

New theories in interstitial cystitis.

Interstitial cystitis (IC) is a chronic symptom-complex characterized by pathological sensation of the bladder (i.e. bladder pain in addition to augmented sensory signals such as urinary frequency and urgency) without evidence of bacterial cystitis or other identifiable lower urinary tract disease. Patients with IC typically describe feeling the urge to void frequently, as well as pain in the bladder and/or urethra. The painful sensation may be described as burning, pressure, sharp, or aching, and is often difficult for the patient to localize precisely. Multiple theories as to the cause of IC have been proposed with varying degrees of evidence. The current body of literature supports the idea that IC is associated with an intrinsic pathology of the bladder urothelial cells. The identification and complete characterization of antiproliferative factor (APF), which is uniquely expressed by urothelial cells in bladders affected by IC, are major advances in the understanding of IC. Additionally, urothelial cells have been likened to neurons because of their ability to express neuronal receptors and release neurotransmitters. The purinergic pathway has been shown to be upregulated in urothelial cells in bladders affected by IC. These new findings should help to direct the development of newer clinical treatments for IC. A complete understanding of IC will only be possible with parallel advances in both basic and clinical sciences.

Cystitis, Interstitial↗

Current and future directions in diagnostic markers in interstitial cystitis.

Interstitial cystitis (IC) is a chronic bladder disorder of unknown etiology that is often diagnosed by symptom criteria with or without cystoscopic findings. Several potential diagnostic markers have recently been described that may facilitate diagnosis of this disorder. A summary of the literature and a discussion regarding these biomarkers is provided, along with a brief discussion of new biomarkers presented at the meeting.

Biomarkers↗

Decreased levels of S-100 protein in non-ulcer interstitial cystitis.

Interstitial cystitis (IC) is a chronic debilitating condition which mainly affects women. Accumulated evidence indicates that IC is a heterogeneous syndrome. As compared to classic IC, the non-ulcer type of IC appears to be different concerning symptomatic, endoscopical and histological findings, as well as in response to various forms of treatment. S-100 is a neural protein considered to be located primarily in the axons. To explore further the neurogenic nature of the disease, we compared bladder wall S-100 content in controls and in patients with classic and non-ulcer IC. We noticed a decrease in S-100 content in non-ulcer IC as compared to controls. This may be an expression of altered peripheral innervation in non-ulcer IC, which, in turn, may be an indication of primary neurogenic etiology. The difference in S-100 content between classic and non-ulcer IC supports the hypothesis that they represent separate entities, which may explain differences in response to various treatments.

Adult↗

Interstitial cystitis.

Interstitial cystitis (IC) is a debilitating chronic inflammatory disorder of the bladder. It affects predominantly middle-aged Caucasian women. The diagnosis, made from the combination of symptoms, cystoscopic findings and bladder biopsies, is often delayed in the gynaecology setting because of a low index of suspicion. The pathophysiology is incompletely understood, although mast cell activation, altered bladder epithelial permeability and sensory afferent nerve up-regulation are thought to play key roles. Recent theories include the role of an antiproliferative factor. A wide assortment of therapies is available and many more are under trial. Until the causes and pathogenesis of IC are unraveled, mainstream medical treatment will remain palliative and cystectomy with urinary diversion, the only potential cure. In addition to our long experience on managing this disorder, we present a comprehensive review of the current thoughts on the aetiology and management of IC.

Cystitis, Interstitial↗

Recontextualizing sexuality in chronic illness: women and interstitial cystitis.

Interstitial cystitis (IC) is a chronic bladder condition that affects ten times more women than men. The major symptoms of IC include urinary frequency, urgency, and suprapubic pain. Dyspareunia is another common complaint. The construct of sexuality can best be understood in context, from the perspective of the study participants. To better understand the changes in sexuality experienced by women with IC, the findings from a survey of 138 women with IC are compared with responses from an earlier pilot interview with ten women with IC. Managing any chronic illness requires changes in many aspects of one's life, including activities, self-perceptions, relationships, and roles. Women with IC described what was important to them "as women" in the context of their current primary life values of health, love, and family. Changes in the sexual relationship were described in the context of the effects of having IC and the centrality of maintaining relationships. The healing potential of participation in support groups is discussed in relation to the women's desire to maintain independence and to help others with the disease.

Adaptation, Psychological↗

Augmented extracellular ATP signaling in bladder urothelial cells from patients with interstitial cystitis.

Interstitial cystitis (IC) is an idiopathic hypersensory condition of the bladder associated with increased urinary ATP and increased stretch-activated ATP release by bladder urothelial cells (BUCs), suggesting augmented purinergic signaling in the bladder. To test this theory further, monolayers of cultured BUCs derived from bladder biopsies obtained from patients with IC and control patients were stimulated with 10-30 microM ATP with subsequent measurement of extracellular ATP levels using the luciferin-luciferase assay. Stimulation with 30 microM ATP resulted in IC supernatant containing several-fold more ATP than control BUCs initially, followed by a slower decrease in ATP levels. This difference in ATP levels was not completely due to activity of cellular ecto-ATPase, because blockade with ARL67156 did not normalize the difference. Exposure to hypotonic solutions resulted in similar extracellular ATP concentrations in IC and control BUCs, but there was a slower decrease in ATP levels in IC supernatants. Treatment of IC BUCs with 10-40 microM suramin, a nonspecific P2 receptor antagonist, significantly attenuated the IC BUC response to extracellular ATP, restoring IC BUCs to a control phenotype. Pretreatment of IC BUCs with 20 ng/ml of heparin-binding EGF-like growth factor (HB-EGF), which previously has been shown to be decreased in IC urine specimens, also restored IC BUCs to a control phenotype with respect to response to ATP stimulation. In conclusion, IC BUCs have augmented extracellular ATP signaling that could be blocked by suramin and HB-EGF. These findings suggest the possible development of future novel therapeutic techniques.

Adenosine Triphosphatases↗

A pilot open label study of Cystoprotek in interstitial cystitis.

Interstitial cystitis (IC) is a disorder of the urinary bladder characterized by urgency, frequency, nocturia and suprapubic pain. IC occurs primarily in women and symptoms are exacerbated by stress, ovulatory hormones and certain foods. IC pathogenesis is unknown, but the most consistent findings involve some dysfunction of the bladder glycosaminoglycan (GAG) protective layer and a high number of activated bladder mast cells. There is no effective therapy even through intravesical administration of dimethylsulfoxide (DMSO) or oral pentosanpolysulfate (PPS) have had variable success. A dietary supplement, CystoProtek, was formulated with the natural GAG components chondroitin sulfate and sodium hyaluronate to provide urothelial cytoprotection, together with the flavonoid quercetin that has anti-inflammatory properties and inhibits activation of mast cells. Thirty-seven female patients diagnosed by the NIDDK criteria who had failed all forms of therapy took six softgel CystoProtek capsules per day for 6 months. Global assessment scale was reduced from 9.0 +/- 2.9 to 4.3 +/- 2.1 (p < 0.05); moreover, the O'Leary/Sant Symptom Index decreased from 15.3 +/- 3.1 to 6.9 +/- 4.2 (p < 0.05) and the Problem Index from 13.1 +/- 3.7 to 5.4 +/- 4.0 (p <0.05). These results are very promising and warrant a larger study that may permit further analyses with respect to other, especially atopic, comorbid diseases.

Adult↗