Exploring the relation between obesity and urinary incontinence: Pathophysiology, clinical implications, and the effect of weight reduction, ICI-RS 2018.

AIMS: To evaluate the relationship between obesity and urinary incontinence (UI) and to determine the effect of weight reduction on the severity of incontinence. METHODS: This is a consensus report of the proceedings of a Research Proposal from the annual International Consultation on Incontinence-Research Society, 14 June to 16 June, 2018 (Bristol, UK): "What are the relationships between obesity and UI, and the effects of successful bariatric surgery?" RESULTS: Obesity is an increasing problem worldwide and is associated with many adverse effects on health and quality of life. From both translational and clinical studies, there is a strong relationship between obesity and the occurrence of UI. Both mechanical and metabolic factors seem to play an important role including systemic inflammation and oxidative stress due to the release of cytokines in visceral adipose tissue. The success rate of anti-incontinence surgery does not seem to be greatly affected by body mass index (BMI), although reliable data and long-term follow-up are currently lacking. Both weight reduction programs and bariatric surgery can result in amelioration of UI. Various studies have shown that weight loss (particularly that associated with bariatric surgery) can reduce incontinence, and the degree of weight loss is positively correlated with improvement in symptoms. CONCLUSIONS: Obesity is strongly associated with an increased prevalence of both stress and urgency UI. The treatment outcome does not seem to be highly dependent on BMI. Weight reduction is positively correlated with improvement of incontinence symptoms and therefore should be advocated in the management.

Path of translational discovery of urological complications of obesity and diabetes.

Diabetes mellitus (DM) is a prevalent chronic disease. Type 1 DM (T1DM) is a metabolic disorder that is characterized by hyperglycemia in the context of absolute lack of insulin, whereas type 2 DM (T2DM) is due to insulin resistance-related relative insulin deficiency. In comparison with T1DM, T2DM is more complex. The natural history of T2DM in most patients typically involves a course of obesity to impaired glucose tolerance, to insulin resistance, to hyperinsulinemia, to hyperglycemia, and finally to insulin deficiency. Obesity is a risk factor of T2DM. Diabetes causes some serious microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy, angiopathy and stroke. Urological complications of obesity and diabetes (UCOD) affect quality of life, but are not well investigated. The urological complications in T1DM and T2DM are different. In addition, obesity itself affects the lower urinary tract. The aim of this perspective is to review the available data, combined with the experience of our research teams, who have spent a good part of last decade on studies of association between DM and lower urinary tract symptoms (LUTS) with the aim of bringing more focus to the future scientific exploration of UCOD. We focus on the most commonly seen urological complications, urinary incontinence, bladder dysfunction, and LUTS, in obesity and diabetes. Knowledge of these associations will lead to a better understanding of the pathophysiology underlying UCOD and hopefully assist urologists in the clinical management of obese or diabetic patients with LUTS.

Are we justified in suggesting change to caffeine, alcohol, and carbonated drink intake in lower urinary tract disease? Report from the ICI-RS 2015.

AIMS: There is increasing evidence that diet may have a significant role in the development of lower urinary tract symptoms. While fluid intake is known to affect lower urinary tract function the effects of alcohol, caffeine, carbonated drinks, and artificial sweeteners are less well understood and evidence from epidemiological studies is mixed and sometimes contradictory. The aim of this paper is to appraise the available evidence on the effect of caffeine, alcohol, and carbonated drinks on lower urinary tract function and dysfunction in addition to suggesting proposals for further research. METHODS: Literature review based on a systematic search strategy using the terms "fluid intake," "caffeine," "alcohol," "carbonated" and "urinary incontinence," "detrusor overactivity," "Overactive Bladder," "OAB." RESULTS: In addition to fluid intake, there is some evidence to support a role of caffeine, alcohol, and carbonated beverages in the pathogenesis of OAB and lower urinary tract dysfunction. Although some findings are contradictory, others clearly show an association between the ingestion of caffeine, carbonated drinks, and alcohol with symptom severity. CONCLUSIONS Given the available evidence lifestyle interventions and fluid modification may have an important role in the primary prevention of lower urinary tract symptoms. However, more research is needed to determine the precise role of caffeine, carbonated drinks, and alcohol in the pathogenesis and management of these symptoms. The purpose of this paper is to stimulate that research. Neurourol. Urodynam. 36:876-881, 2017. © 2017 Wiley Periodicals, Inc.

Is testosterone important in LUT function in men and women? ICI-RS 2015.

AIM: This review article is a collaborative report based upon the Authors' presentations and Group discussion on the role of testosterone (T) in the male and female lower urinary tract (LUT) which took place at the 6th International Consultation on Incontinence Research Society's (ICI-RS) annual meeting, in Bristol, UK (September 8-10, 2015). METHODS: It comprises overviews and opinions on both the current state of knowledge of the role of T in LUT function and dysfunction in both sexes. RESULTS: Results from animal studies suggest that T treatment may be beneficial for disorders of the LUT in women including urinary incontinence and pelvic organ prolapse. The need for clinical studies to evaluate the effect of T treatment in peri- and post-menopausal women, taking into account the type of applied androgen, the application form, timing and dosage, is especially emphasized. In males, findings on the impact of T on the male external urethral sphincter underscores that there is still much to learn about its role in male LUT physiology. The important topic of the use of T therapy in the treatment of enuresis in the young, both sexes, is also discussed. The importance of understanding the steroidogenic pathways linking T with estradiol is discussed as being of paramount importance in researching the unique actions of T in the LUT. CONCLUSION: The overall conclusion is that further research into the role of T in LUT function and dysfunction across genders and age groups (young to old) is extremely important. Neurourol. Urodynam. 36:859-862, 2017. © 2017 Wiley Periodicals, Inc.

Psychological and Physical Environmental Factors in the Development of Incontinence in Adults and Children: A Comprehensive Review.

The aim of this review was to identify etiological environmental factors related to incontinence in children and adults. A variety of etiological environmental factors for the development of incontinence were identified. In children, these encompass stressful life events and trauma, family dysfunction, parental psychopathology, school-related stressors, toilet or "potty" training, fluid consumption habits, housing conditions, and the availability of toilets. In adults, physical exercise, obesity, working conditions, fluid intake, and the availability of toilets play a role. Intervening variables such as hormonal variations due to work shifts have also been identified as influencing the likelihood of incontinence. Current research suggests that environmental factors influence the development of incontinence in children and adults. The interactions between biological factors, the immediate environment, and intervening variables need to be explored in greater detail. Practical solutions to reduce barriers to adequate fluid intake and healthy toileting habits should be implemented in school and work settings.

Do we need to know more about the effects of hormones on lower urinary tract dysfunction? ICI-RS 2014.

This review article reflects the presentations and subsequent discussions during a think tank at the 5th International Consultation on Incontinence Research Society's annual meeting, held in Bristol, UK (September 22-24, 2014). It reviews the current state of knowledge on the role of hormones in lower urinary tract dysfunction (LUTD) and overactive bladder (OAB) and in particular: highlights some specific basic research findings from discussion participants; reviews future research topics; and discusses potential new therapeutic opportunities for LUTD and OAB. The role of the large conductance voltage- and Ca(2+) -activated K(+) (BK) channels, as novel therapeutic targets for OAB was discussed, in particular as recent studies on human detrusor smooth muscle suggest that estradiol exerts a direct non-genomic activation of the BK channels. Recent developments on the roles of sex hormones on diuresis, as well as the roles of melatonin and vitamin D on LUTD were also discussed. It was concluded that further basic science and translational studies are needed to better understand hormonal regulatory mechanisms of the lower urinary tract and the implications for novel treatment options for LUTD and OAB.

Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium.

AIMS: Botulinum neurotoxin serotype A (BoNT/A) has emerged as an effective treatment of urinary bladder overactivity. Intravesical lipotoxin (BoNT/A delivery using liposomes), which may target the urothelium, is effective in blocking acetic acid induced hyperactivity in animals. The objective of this study was to assess the possible site of toxin action within the urothelium. METHODS: We examined expression of the toxin receptor (SV2) and its cleavage targets (SNAP-25 and SNAP-23) within urothelium as well as effects of the toxin on mechanically evoked release of ATP from cultured rat urothelial cells. ATP release was measured using the luciferin-luciferase assay; we examined expression of SNAP-23 and -25 in urothelial cells and mucosa of rat and human bladders. RESULTS: BoNT/A (1.5 U; 1-3 hr) blocked hypotonic evoked release of urothelial ATP, without affecting morphology. The expression of protein targets for BoNT/A binding (SV2) was detected in human and rat bladder mucosa and catalytic action (SNAP-23, -25) in urothelial cells and mucosa (differed in intensity) from rat and human bladder. Incubation of cultured (rat) urothelial cells with BoNT/A decreased expression levels of both SNAP-23 (44%) and SNAP-25 (80%). CONCLUSIONS: Our findings reveal that the bladder urothelium expresses the intracellular targets and the binding protein for cellular uptake of BoNT/A; and that the toxin is able to suppress the levels of these targets as well as hypotonic-evoked ATP release. These data raise the possibility that intravesical treatment with BoNT/A suppresses bladder reflex and sensory mechanisms by affecting a number of urothelial functions including release of transmitters.

Urothelial mucosal signaling and the overactive bladder-ICI-RS 2013.

There is abundant evidence that the lower urinary tract (LUT) mucosal layer is involved both in mechanosensory functions that regulate bladder contractile activity and in urethral sensation. Changes to the mucosa can be associated with a number of bladder pathologies. For example, alterations of the urothelium and underlying lamina propria at both the molecular and structural levels have been reported in both patients and animals associated with disorders such as bladder pain syndrome and diabetic cystopathy. In contrast to the urinary bladder, much less is known about the urothelium/lamina propria of the bladder neck/proximal urethra. There are important gender differences in the outflow region both anatomically and with respect to innervation, hormonal sensitivity, and location of the external urethral sphincter. There is reasonable evidence to support the view that the mucosal signaling pathway in the proximal urethra is important for normal voiding, but it has also been speculated that the proximal urethra can initiate bladder overactivity. When dysfunctional, the proximal urethra may be an interesting target, for example, botulinum toxin injections aiming at eliminating both urgency and incontinence due to detrusor overactivity.

Pathophysiology of idiopathic overactive bladder and the success of treatment: a systematic review from ICI-RS 2013.

AIMS: To investigate the frequency of phenotype profiling of patients with idiopathic overactive bladder (OAB) syndrome, and to determine the effectiveness of treatment among individuals with different pathophysiologic profiles. METHODS: The electronic databases MEDLINE, EMBASE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and CINAHL were searched from January 1, 1980 to August 12, 2013 for interventional randomized controlled treatment trials (RCTs) of idiopathic OAB. Phenotying for pathophysiologies originating in the urothelial/mucosal layer of the bladder, the detrusor muscle cell layer, and the central nervous system were sought. Articles that analyzed urgency outcomes based on pathophysiologic profiling were selected. Due to the heterogeneity of the included interventions and outcome assessment measures, meta-analysis was not appropriate and a qualitative synthesis was undertaken. RESULTS: Of 239 original RCTs of idiopathic OAB, 48 (20%) profiled participants on underlying pathophysiology. Less than half of these (n = 20) reported treatment efficacy for urgency symptoms by pathophysiological sub-type. One examined the effect of botulinum A toxin on interstitial cell protein expression. Four compared treatment efficacy in OAB patients with and without involuntary detrusor contractions. Fifteen compared the effect of treatment on urgency reduction in patients with detrusor overactivity. There were no consistent trends in treatment efficacy according to pathophysiologic sub-type. No studies examined urothelial dysfunction or abnormal central processing of bladder afferent signaling in response to treatment. CONCLUSIONS: In order to advance the field of idiopathic OAB, more trials are needed that profile and test urgency outcomes in participants according to suspected underlying pathophysiology. Neurourol. Urodynam. 33:611-617, 2014. © 2014 Wiley Periodicals, Inc.

Do we understand any more about bladder interstitial cells?-ICI-RS 2013.

AIMS: To present a brief review on discussions from "Do we understand any more about lower urinary tract interstitial cells?" session at the 2013 International Consultation on Incontinence-Research Society (ICI-RS) meeting in Bristol, UK. METHODS: Discussion focused on bladder interstitial cell (IC) subtypes, their localization and characterization, and communication between themselves, the urothelium, and detrusor smooth muscle. The role of ICs in bladder pathologies and new methods for studying ICs were also addressed. RESULTS: ICs have been studied extensively in the lower urinary tract and have been characterized based on comparisons with ICs of Cajal in the gastro-intestinal tract. In fetal bladders it is believed that ICs drive intrinsic contractions to expel urine through the urachus. These contractions diminish postpartum as bladder innervation develops. Voiding in human neonates occurs when filling triggers a spinal cord reflex that contracts the detrusor; in rodents, maternal stimulation of the perineum triggers voiding. Following spinal cord injury, intrinsic contractions, and spinal micturition reflexes develop, similar to those seen during neonatal development. These enhanced contractions may stimulate nociceptive and mechanosensitive afferents contributing to neurogenic detrusor overactivity and incontinence. The IC-mediated activity is believed to be initiated in the lamina propria by responding to urothelial factors. These IC may act syncytially through gap junction coupling and modulate detrusor activity through unknown mechanisms. CONCLUSION: There has been a great deal of information discovered regarding bladder ICs, however, many of their (patho)physiological functions and mechanisms are still unclear and necessitates further research. Neurourol. Urodynam. 33:573-576, 2014. © 2014 Wiley Periodicals, Inc.

Impact of diabetes mellitus on bladder uroepithelial cells.

Diabetic bladder dysfunction (DBD), a prevalent complication of diabetes mellitus (DM), is characterized by a broad spectrum of symptoms including urinary urgency, frequency, and incontinence. As DBD is commonly diagnosed late, it is important to understand the chronic impact of DM on bladder tissues. While changes in bladder smooth muscle and innervation have been reported in diabetic patients, the impact of DM on the specialized epithelial lining of the urinary bladder, the urothelium (UT), is largely unknown. Quantitative polymerase chain reaction analysis and electron microscopy were used to evaluate UT gene expression and cell morphology 3, 9, and 20 wk following streptozotocin (STZ) induction of DM in female Sprague-Dawley rats compared with age-matched control tissue. Desquamation of superficial (umbrella) cells was noted at 9 wk DM, indicating a possible breach in barrier function. One causative factor may be metabolic burden due to chronic hyperglycemia, suggested by upregulation of the polyol pathway and glucose transport genes in DM UT. While superficial UT repopulation occurred by 20 wk DM, the phenotype was different, with significant upregulation of receptors associated with UT mechanosensation (transient receptor potential vanilloid subfamily member 1; TRPV1) and UT autocrine/paracrine signaling (acetylcholine receptors AChR-M2 and -M3, purinergic receptors P2X(2) and P2X(3)). Compromised barrier function and alterations in UT mechanosensitivity and cell signaling could contribute to bladder instability, hyperactivity, and altered bladder sensation by modulating activity of afferent nerve endings, which appose the urothelium. Our results show that DM impacts urothelial homeostasis and may contribute to the underlying mechanisms of DBD.

Sophisticated models and methods for studying neurogenic bladder dysfunction.

AIM: To describe how the use of new and established animal models and methods can generate vital and far reaching experimental data in the study of mechanism underlying neurogenic bladder overactivity. METHODS: Bladder and colonic irradiated mice and those with upper and lower motor neuron lesions were used to study neurogenic bladder overactivity. Methods included cystometry, tension measurements, afferent nerve recordings and optical mapping of action potentials and intracellular Ca(2+) transients. Recordings were made in a number of innovative preparations including in-line cultured cells, bladder-urethra sheets and cross-sections, spinal cord slices and the cerebral cortex. RESULTS: The animal models and methods used allow for the study of peripheral and central mechanisms of neurogenic overactivity. While colonic irradiation results in solely neurogenic dysfunction, spinal cord lesions also induce non-neural changes resulting in increased spontaneous detrusor contractions that can directly stimulate afferent nerves. Imaging of cultured bladder interstitial cells reveals spontaneous firing that could contribute to detrusor overactivity, while optical imaging of the spinal cord and brain could identify changes in central pathways that underlie lower urinary tract dysfunction. CONCLUSIONS: The animal models and methods described allow for the study of neurogenic overactivity at the peripheral, spinal and cortical levels. This may lead to greater understanding of sensory and motor mechanisms involved in incontinence, the contributions of interstitial cells and spontaneous detrusor contractions, and the involvement of the cortex.

Beyond neurons: Involvement of urothelial and glial cells in bladder function.

AIM: The urothelium, or epithelial lining of the lower urinary tract (LUT), is likely to play an important role in bladder function by actively communicating with bladder nerves, smooth muscle, and cells of the immune and inflammatory systems. Recent evidence supports the importance of non-neuronal cells that may extend to both the peripheral and central processes of the neurons that transmit normal and nociceptive signals from the urinary bladder. Using cats diagnosed with a naturally occurring syndrome termed feline interstitial cystitis (FIC), we investigated whether changes in physiologic parameters occur within 3 cell types associated with sensory transduction in the urinary bladder: 1) the urothelium, 2) identified bladder dorsal root ganglion (DRG) neurons and 3) grey matter astrocytes in the lumbosacral (S1) spinal cord. As estrogen fluctuations may modulate the severity of many chronic pelvic pain syndromes, we also examined whether 17beta-estradiol (E2) alters cell signaling in rat urothelial cells. RESULTS: We have identified an increase in nerve growth factor (NGF) and substance P (SP) in urothelium from FIC cats over that seen in urothelium from unaffected (control) bladders. The elevated NGF expression by FIC urothelium is a possible cause for the increased cell body size of DRG neurons from cats with FIC, reported in this study. At the level of the spinal cord, astrocytic GFAP immuno-intensity was significantly elevated and there was evidence for co-expression of the primitive intermediate filament, nestin (both indicative of a reactive state) in regions of the FIC S1 cord (superficial and deep dorsal horn, central canal and laminae V-VIl) that receive input from pelvic afferents. Finally, we find that E2 triggers an estrus-modifiable activation of p38 MAPK in rat urothelial cells. There were cyclic variations with E2-mediated elevation of p38 MAPK at both diestrus and estrus, and inhibition of p38 MAPK in proestrous urothelial cells. CONCLUSION: Though urothelial cells are often viewed as bystanders in the processing of visceral sensation, these and other findings support the view that these cells function as primary transducers of some physical and chemical stimuli. In addition, the pronounced activation of spinal cord astrocytes in an animal model for bladder pain syndrome (BPS) may play an important role in the pain syndrome and open up new potential approaches for drug intervention.

Diabetic bladder dysfunction: current translational knowledge.

PURPOSE: Diabetes mellitus, a metabolic disorder caused by an absolute or relative deficiency of insulin, is a debilitating and costly disease with multiple serious complications. Lower urinary tract complications are among the most common complications of diabetes mellitus. The most common, bothersome lower urinary tract complication of diabetes mellitus is diabetic cystopathy or diabetic bladder dysfunction. We reviewed the current translational knowledge of diabetic bladder dysfunction. MATERIALS AND METHODS: We performed a search of the English literature through PubMed. The key words used were diabetes and bladder dysfunction or cystopathy. Our data and perspective are provided for consideration of the future direction of research. RESULTS: Despite traditional recognition of diabetic bladder dysfunction as a voiding problem characterized by poor emptying and overflow incontinence, recent clinical and experimental evidence indicate storage problems such as urgency and urge incontinence in diabetes mellitus cases. Recent experimental evidence from studies of diabetic bladder dysfunction in small animal models of diabetes mellitus show a temporal effect on diabetic bladder dysfunction. Early phase diabetes mellitus causes compensated bladder function and the late phase causes decompensated bladder function. The temporal theory could plausibly provide the scientific road map to correlate clinical and experimental findings, and identify the role of mechanisms such as polyuria, hyperglycemia, oxidative stress, autonomic neuropathy and decompensation of the bladder contractile apparatus in the creation of clinical and experimental manifestations of diabetic bladder dysfunction. CONCLUSIONS: Diabetic bladder dysfunction includes time dependent manifestations of storage and emptying problems. Identifying mechanistic pathways would lead to the identification of therapeutic intervention.

New insights into the pharmacology of the bladder.

PURPOSE OF REVIEW: Pharmacotherapy of a number of bladder disorders has traditionally focused on targeting the 'sensory' component or bladder nerves and the smooth muscle. This review aims to provide an insight into recent (experimental and clinical) developments in mechanisms of existing therapies as well as novel targets. RECENT FINDINGS: Traditionally, sensory signaling in the urinary bladder has been attributed to activation of bladder afferents, but new findings have pointed to the urothelium and interstitial cells as key participants in the transduction of sensory events. Recent advances provide strong support for the development of subtype selective receptor agonists/antagonists, the modulation of signal transduction cascades and new and expanded uses for various neurotoxins. SUMMARY: The development of therapeutic options for the treatment of a number of bladder disorders is complicated, and most treatments are associated with an increased incidence of side effects or lack of specificity. Recent studies suggest that selective targeting of receptors/ion channels or a disease-specific (i.e. phosphorylated) form of the receptor may represent a viable therapeutic target. Though the mechanisms regulating ion channel expression under pathological conditions are not fully known, an increased understanding of these pathways has important implications for drug development.

Non-neuronal acetylcholine and urinary bladder urothelium.

Non-neuronal release of acetylcholine (ACh) has been proposed to play a role in urinary bladder function. These studies investigated the expression and function of the non-neuronal cholinergic system in cultured urothelial cells isolated from the rat urinary bladder. Our findings have revealed that urothelial cells express the high-affinity choline transporter (CHT1) and acetylcholine-synthesizing enzymes, choline acetyltransferase (ChAT) and carnitine acetyltransferase (CarAT). In contrast to neurons, urothelial cells do not express the vesicular acetylcholine transporter (VAChT) but do express OCT3, a subtype of polyspecific organic cation transporter (OCT) that is thought to be involved in the release of acetylcholine from non-neuronal cells. Following exposure of cultured urothelial cells to (3)H-choline, radioactivity was detected in the cells and increased release of radioactivity into the eternal media was evoked by mechanical stimulation (exposure of the cells to 50% hypotonic Krebs) or chemical stimulation of purinergic receptors by 100 muM ATP. The present experiments did not establish if the evoked release of radioactivity (termed (3)H-ACh release in this paper) was due to release of acetylcholine or choline. (3)H-ACh release was not evoked by application of acetylcholine alone, however pretreatment with the non-selective muscarinic receptor antagonist atropine prior to application of acetylcholine facilitated (3)H-ACh release, suggesting that the acetylcholine released from urothelial cells may participate in a negative feedback mechanism by acting on muscarinic receptors to inhibit its own release in the urothelium. Brefeldin, an agent which disrupts vesicular exocytosis, did not block hypotonic-evoked (3)H-ACh release. These observations indicate that acetylcholine release from urothelial cells is mediated by different mechanisms than those such as vesicular storage and exocytosis that underlie the release of neurotransmitters from nerves.

Effect of Polyuria on Bladder Function in Diabetics versus Non-Diabetics: An Article Review.

OBJECTIVES: To review studies that investigated the role of polyuria on bladder function. METHODS: We performed a search of the English literature through PubMed. We only included animal studies that assessed parameters of bladder function and had compared diabetic and non-diabetic polyuric animals. RESULTS: Fluid intake and urine output were increased in diabetic and polyuric animals; failure to appropriately gain weight was seen in diabetics only. All but 1 study reported increase in bladder weight in both groups. In cystometrograms, control mice showed reductions in basal bladder pressure over time, whereas diabetic and diuretic groups stabilized or increased. Both groups showed larger bladder capacity. Overall, many characteristic changes in cystometrographic studies in diabetic animals could be attributed to polyuria. In histological studies, bladder hypertrophy, increase in smooth muscle and urothelium, and increase in protein and DNA content per bladder were observed in diuretic and diabetic rats. Actual collagen cross-sectional area did not change during the progression of diabetes or diuresis but decreased over time in both groups as a percentage of total tissue area. Both groups expressed less type I collagen mRNA and TGF-beta-1 mRNA. CONCLUSIONS: Although lower urinary tract changes in anatomy and function in diabetic patients might arise from a number of causes, polyuria seems to play an important causative role.

Melatonin and Its Role in Lower Urinary Tract Function: An Article Review.

This article reviewed the results of studies done on animals that assessed effects of melatonin on bladder function. Melatonin does not change strip relaxation on its own. However, pre-treatment with melatonin decreases contractile responses induced by phenylephrine, acetylcholine, bethanechol and KCl in a dose-dependent manner. The contractile responses induced by the direct calcium channel openers are significantly decreased by melatonin pre-treatment. It also binds to Ca(2+)-activated calmodulin, and prevents it from activating myosin light-chain kinase. It may have direct effects on ion channels which are responsible for regulating bladder contraction. Its other mode of action on bladder occurs via the brain GABAA receptor. Melatonin is an antioxidant. In bladder, treatment with melatonin prevents elevations in malondialdehyde levels, reverses changes in glutathione levels, and decreases myeloperoxidase levels compared with oxidative injury. It can normalize age induced bladder dysfunction through its antioxidant effects, inhibiting smooth muscle contractility directly and restoring impaired contractility via normalization of Ca(2+) handling and sensitizations pathways. It attenuates the severity of cystitis and inflammation. Mast cell proliferation and activation are increased in cystitis, but decrease by melatonin treatment. Also, there is a decrease in expression levels of pro-inflammatory cytokines after melatonin treatment.

Corticotropin-releasing factor family peptide signaling in feline bladder urothelial cells.

Corticotropin-releasing factor (CRF) plays a central role in the orchestration of behavioral and neuroendocrine responses to stress. The family of CRF-related peptides (CRF and paralogs: urocortin (Ucn)-I, -II, and -III) and associated receptors (CRFR1 and CRFR2) are also expressed in peripheral tissues such as the skin and gastrointestinal tract. Local signaling may exert multiple effects of stress-induced exacerbation of many complex syndromes, including psoriasis and visceral hypersensitivity. Interstitial cystitis/painful bladder syndrome (IC/PBS), a chronic visceral pain syndrome characterized by urinary frequency, urgency, and pelvic pain, is reported to be exacerbated by stress. Functional changes in the epithelial lining of the bladder, a vital blood-urine barrier called the urothelium, may play a role in IC/PBS. This study investigated the expression and functional activity of CRF-related peptides in the urothelium of normal cats and cats with feline interstitial cystitis (FIC), a chronic idiopathic cystitis exhibiting similarities to humans diagnosed with IC/PBS. Western blots analysis showed urothelial (UT) expression of CRFR1 and CRFR2. Enzyme immunoassay revealed release of endogenous ligands (CRF and Ucn) by UT cells in culture. Evidence of functional activation of CRFR1 and CRFR2 by receptor-selective agonists (CRF and UCN3 respectively) was shown by i) the measurement of ATP release using the luciferin-luciferase assay and ii) the use of membrane-impermeant fluorescent dyes (FM dyes) for fluorescence microscopy to assess membrane exocytotic responses in real time. Our findings show evidence of CRF-related peptide signaling in the urothelium. Differences in functional responses between FIC and normal UT indicate that this system is altered in IC/PBS.