Pathophysiology Of Overactive Bladder Research Articles

Diabetes mellitus and female urinary incontinence: a time for change

Diabetes mellitus (DM), a chronic metabolic disease, is becoming a global health problem with increasing prevalence. The incidence of type I DM is fairly constant but that of type II DM is on the rise, most likely as a consequence of the contemporary changes in lifestyle, increasing obesity rates, and aging of the female population. DM is considered an independent risk factor for female urinary incontinence (UI); in a pooled analysis of 71,650 women aged 37–79 years, Danforth et al. [1] showed a 20 % increased odds of UI in women with DM [odds ratio (OR) 1.2, 95 % confidence interval (CI) 1.0– 1.3, p00.01)] This was largely because of urgency UI with no apparent association with stress or mixed UI. In a study of the Turkish population, Izci et al. [2] has shown a 2.5-fold increase in prevalence of UI in diabetic women, mainly of mixed UI. Similar results were shown in studies from Taiwanese, Chinese, and South American female populations. Despite this evidence, the management of incontinent diabetic women has been relatively neglected by the urogynecology community. This is partly because the etiology of DM is not well understood and partly due to lack of training in diabetic medicine in most urogynecology training programs. Traditionally, diabetic bladder dysfunction has been described as a triad of decreased sensation, increased capacity, and poor emptying causing a broad spectrum of symptoms including overactive bladder (OAB), voiding dysfunction, and urinary retention [3]. The role of DM in the pathophysiology of OAB and urgency UI is well described as a result of glycosuria, recurrent urinary tract infections (UTI), diabetic autonomic neuropathy, and diabetic cystopathy [4–6]. Hyperglycemia will often cause glycosuria and consequently osmotic diuresis leading to polyuria and increased frequency of micturition in diabetic women [7]. Autonomic neuropathy is a late complication of DM with a cumulative increase in prevalence over time [8]. Liu et al. [9] have recently shown that the prevalence of lower urinary tract symptoms is directly related to duration of DMwith 2.4and 4.2-fold increase with DM duration >10 years and age>50 years, respectively. The cause of diabetic neuropathy is multifocal and includes ischemia, superoxide-induced free radical formation, impaired axonal transport, and metabolic derangement of the Schwann cell resulting in segmental demyelination and impairment of nerve conduction [9]. Animal and research data suggest that diabetic cystopathy is caused by ultrastructural and microvascular damage to the detrusor muscle with alteration in its neural component ultimately resulting in alterations in detrusor muscle function [10]. Diabetic cystopathy affects up to 40–80 % of diabetic patients, is slowly progressive, and clinically characterized by decreased bladder sensation and either impaired or unstable detrusor contractions [8]. The metabolic syndrome associated with DM and characterized by dyslipidemia and hypertension can further decrease the blood flow to the detrusor muscle and compromise bladder function. Liu et al. [9] have shown that patients with DM and metabolic syndrome showed a higher trend for developing urgency UI. These studies provide an explanation for the fact that OAB is the main clinical feature of diabetic cystopathy which can also be associated with increased post-void residual M. Abdel-fattah Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK

Pathophysiology of Overactive Bladder.

Overactive bladder syndrome (OAB), characterized by urinary frequency, nocturia and urgency with or without incontinence, is a widespread medical condition with significant impact on quality of life. Three main factors have been proposed regarding the cause of OAB: myogenic, neurogenic and urotheliogenic. Disturbance of any of the three factors or a combination of these factors can attribute to OAB. Metabolic derangement, bladder outlet obstruction and inflammation can increase the excitability of nerve, detrusor muscle and alter the sensory and barrier functions of the urothelium. The detection of proteins in the urine such as NGF, PGE2, and proinflammatory chemokines may advance our understanding of the pathophysiology of OAB and offer novel diagnostic biomarkers of OAB.

Pathophysiology of overactive bladder

Overactive bladder (OAB) is a common disorder that negatively affects the quality of life of our patients and carries a large socioeconomic burden. According to the International Continence Society, it is characterized as urinary urgency, with or without urge incontinence, usually, with frequency and nocturia in the absence of causative infection. The pathophysiology of this disease entity varies between neurogenic, myogenic, or idiopathic factors. This paper provides a review of the contemporary theories behind the pathophysiology of OAB.

Biomarkers in Overactive Bladder

Overactive bladder (OAB) remains a remarkably common urologic condition and results in significant clinical and economic sequelae. Although likely underestimated, the overall prevalence of OAB is projected to be between 15% and 38%. The diverse etiologies of this symptom complex have limited attempts to develop reproducible biological markers of disease. Recent advances in bladder and urothelial physiology have dramatically expanded our repertoire of potential markers for use in diagnosis and to monitor treatment. Herein we present an overview of several emerging options for OAB diagnosis and review the available literature regarding these prospective biomarkers. Despite intensive awareness into OAB diagnostics, we are witness to the genesis of exploration on detrusor function and urothelial biology that will guide interventions in the coming decades. Immense opportunity exists for future evaluation of OAB pathophysiology to advance our knowledge regarding management of this multifactorial urologic disorder and define biomarkers of the disease process.

Pharmacotherapy of overactive bladder: epidemiology and pathophysiology of overactive bladder

Introduction: Overactive bladder (OAB) describes complex symptoms, comprising of urinary urgency, with or without urinary incontinence, often with increased daytime frequency and nocturia in the absence of infection or other obvious etiology. OAB is highly prevalent and affects physical and mental health, activities of daily life and the quality of life of millions of adults. The pathophysiology of OAB and detrusor overactivity is still not completely known, but is most probably multifactorial.Areas covered: The epidemiology and pathophysiology of OAB is reviewed. A literature search using PubMed from 2000 to 2010 was undertaken for this review with pertinent older papers referenced as needed to gain a clearer understanding of the epidemiology of OAB and related bladder pathophysiology, which it is hoped will lead to more effective and better-tolerated treatments for OAB.Expert opinion: With recent advances in our understanding of the basic science of OAB, it is becoming clear that the control of bladder function is far more complex than previously believed. Recent research has highlighted several potential targets for the treatment of OAB, particularly within the mechanosensory pathways.

Future Directions in Overactive Bladder Treatment

Overactive bladder (OAB) remains a remarkably common urologic condition resulting in significant clinical and economic sequelae. Although likely underestimated, the overall prevalence of overactive bladder is projected to be between 15% and 38%. The mainstay of therapy for decades has revolved around anticholinergic pharmaceuticals. However, recent advances in bladder and urothelial physiology have dramatically expanded the treatment options available for OAB management. Herein we present an overview of several emerging options for OAB therapy and review the available literature regarding these therapies. Despite substantial investment into OAB treatment, we are witness to but the genesis of research on detrusor function and urothelial biology that will guide practitioner interventions in the coming decades. Immense opportunity exists for future evaluation of OAB pathophysiology to advance our knowledge regarding management of this multifactorial urologic disorder.

The Overactive Bladder: New Concepts of Etiology and Treatment

Overactive bladder (OAB) is a disorder characterized by urinary urgency. In the past, the pathophysiology and treatment of OAB focused on the parasympathetic efferent innervation of detrusor smooth muscle cells. However, recent evidence has provided a clearer understanding of the neurological, chemical, and functional physiology of the bladder and how it relates to the pathophysiology of OAB. Urothelial cells, sensory neurons, and interstitial cells of Cajal have secretory and receptor functions that play an important role in bladder function and dysfunction. As we learn more about bladder function and the mechanism of current OAB treatments, newer forms of therapy are emerging. These include neuromodulation, botulinum toxin, and the development of new drugs based on the pathophysiology of OAB.

1526 SERUM NOX LEVELS ASSOCIATED WITH THE VOIDED VOLUME IN COMMUNITY-DWELLING WOMEN WITH OVERACTIVE BLADDER

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Non-Neurogenic Voiding Dysfunction I1 Apr 20101526 SERUM NOX LEVELS ASSOCIATED WITH THE VOIDED VOLUME IN COMMUNITY-DWELLING WOMEN WITH OVERACTIVE BLADDER Hisashi Honjo, Masahiro Nakao, Jun Ueyama, Takaaki Kondo, Osamu Ukimura, Akihiro Kawauchi, Hiroshi Kitakoji, Nobuyuki Hamajima, and Tsuneharu Miki Hisashi HonjoHisashi Honjo Nantan, Japan More articles by this author , Masahiro NakaoMasahiro Nakao Nantan, Japan More articles by this author , Jun UeyamaJun Ueyama Nagoya, Japan More articles by this author , Takaaki KondoTakaaki Kondo Nagoya, Japan More articles by this author , Osamu UkimuraOsamu Ukimura Kyoto, Japan More articles by this author , Akihiro KawauchiAkihiro Kawauchi Kyoto, Japan More articles by this author , Hiroshi KitakojiHiroshi Kitakoji Nantan, Japan More articles by this author , Nobuyuki HamajimaNobuyuki Hamajima Nagoya, Japan More articles by this author , and Tsuneharu MikiTsuneharu Miki Kyoto, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1277AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have reported that the serum adiponectin level, which is a metabolic syndrome serum biomarker, in overactive bladder (OAB) women with that syndrome, was significantly lower than that in healthy women, and the serum adiponectin level in OAB with urge urinary incontinence (UUI) women had significant linear correlation with the average voided volume (AVV) (AUA 2009, #1869). On the other hand, nitric oxide (NO) has been recognized as an important neurotransmitter in the lower urinary tract. However, the relationships between these factors and OAB symptoms remain unclear. The aims of this study are to assess whether the serum NOx levels are related to OAB symptoms and the variables obtained from bladder diaries in community-dwelling women of 40 yrs of age or older in Japan. METHODS In total, 345 women (mean 63 years of age, range 40 to 84) were asked to complete 3-day bladder diaries and questionnaires to assess OAB (OABSS) (Urology, 68: 318, 2006.). OAB syndrome was defined using standardized symptom indicators. Serum NOx levels were measured using a commercial EIA kit. RESULTS Of the 345 women, 92 (26.6%) had OAB symptoms, including 55 (15.9%) without urge incontinence (OAB-Dry), and 37 (10.7%) with urge incontinence (OAB-Wet). The serum NOx levels significantly increased with age in all subjects. As for the bladder diary parameters in the OAB-Dry women, the serum NOx levels had significant linear correlation to the average voided volume (r=0.40, p<0.001). Out of 55 women with OAB-Dry, there were significant differences in the serum NOx levels between the women with AVV<200 ml and those with AVV≥200 ml (p=0.01) (28.1 vs. 44.2 Emol/l, respectively). The serum NOx levels of the women in the OAB-Dry group (41.2 Emol/l) were significantly lower than those in the OAB-Wet group (55.4 Emol/l) (p<0.05). CONCLUSIONS This study suggests significant linear correlation between the average voided volume and the serum NOx level, and also shows significantly lower serum NOx levels in OAB-Dry group women in comparison to OAB-Wet group women. Evaluation of the serum NOx levels could contribute as a biomarker that represents an earlier stage in the pathophysiology of OAB. Serum NOx levels are a potential novel target for the prevention and/or treatment of OAB. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e588-e589 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hisashi Honjo Nantan, Japan More articles by this author Masahiro Nakao Nantan, Japan More articles by this author Jun Ueyama Nagoya, Japan More articles by this author Takaaki Kondo Nagoya, Japan More articles by this author Osamu Ukimura Kyoto, Japan More articles by this author Akihiro Kawauchi Kyoto, Japan More articles by this author Hiroshi Kitakoji Nantan, Japan More articles by this author Nobuyuki Hamajima Nagoya, Japan More articles by this author Tsuneharu Miki Kyoto, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1671 STRETCH-INIDUCED EXPRESSION OF HIF-1α HIF-2α AND VEGF IN BLADDER UROTHELIAL CELLS (BUC) FROM SUBJECTS WITH OVERACTIVE BLADDER (OAB)

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Female Urology II1 Apr 20101671 STRETCH-INIDUCED EXPRESSION OF HIF-1α HIF-2α AND VEGF IN BLADDER UROTHELIAL CELLS (BUC) FROM SUBJECTS WITH OVERACTIVE BLADDER (OAB) Charlotte E. Christiaansen, Yan Sun, Yuchao Hsu, and Toby C. Chai Charlotte E. ChristiaansenCharlotte E. Christiaansen Rotterdam, Netherlands More articles by this author , Yan SunYan Sun Baltimore, MD More articles by this author , Yuchao HsuYuchao Hsu Baltimore, MD More articles by this author , and Toby C. ChaiToby C. Chai Baltimore, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1495AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Previous studies have shown that hypoxia can change the working conditions of the bladder and negatively affects its acute and long-term function. It is also known that abnormalities of BUC may play a role in OAB pathophysiology. We hypothesized that OAB may increases bladder oxygen demands due to increased bladder activity (urinary frequency and/or detrusor overactivity) which results in increased stretch of the bladder. We investigated whether OAB BUC react differently than normal BUC when subjected to stretch by measuring expression of angiogenesis factors: hypoxia-inducible factor 1, alpha subunit (HIF-1α), hypoxia-inducible factor 2, alpha subunit (HIF-2α) and vascular endothelial growth factor (VEGF). METHODS Human BUC were cultured from cystoscopic urothelial biopsies. Normal and OAB BUC were stretched using an in vitro stretch device, the Flexcell. HIF-1α, HIF-2α and VEGF mRNA expression were analyzed using quantitative real-time PCR. Fluorescence activated cell sorting (FACS) was used to determine HIF-1α, HIF-2α, and VEGF protein expression. Furthermore, because VEGF is a known cytokine released by cells, quantitation of VEGF level in the supernatant of OAB and normal BUC after stretching was determined with ELISA. RESULTS mRNA levels for HIF-1α, HIF-2α and VEGF were significantly higher in the stretched OAB BUC compared to stretched normal BUC (HIF-1α, p = 0.023; HIF-2α, p = 0.027; VEGF, p = 0.00017). FACS analysis of protein expression of HIF-2α in stretched OAB BUC showed significantly higher levels than in the non-stretched OAB BUC (p= 0.01). The protein expression of HIF-1α and VEGF in stretched OAB BUC were not different compared to non-stretched OAB BUC. During stretch, OAB BUC released significantly greater VEGF than stretched normal BUC at 8hr (p = 0.031), 24 hr (p = 0.031), and 48 hr (p = 0.043) time points respectively. As a control experiment, stretched OAB BUC released significantly more VEGF compared to non-stretched OAB BUC at 48hr (p = 0.007) and 96hr (p = 0.021) time points respectively. CONCLUSIONS These results demonstrated that OAB BUC responded differently compared to normal BUC to stretch by increased expression of mRNA for HIF-1α, HIF-2α and VEGF. Furthermore, OAB BUC secreted more VEGF in response to stretch. These results showed that OAB BUC responded to stretch as if they were in hypoxic conditions. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e645 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Charlotte E. Christiaansen Rotterdam, Netherlands More articles by this author Yan Sun Baltimore, MD More articles by this author Yuchao Hsu Baltimore, MD More articles by this author Toby C. Chai Baltimore, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

Overactive bladder (OAB) syndrome, which is characterized by a complex of storage symptoms (urinary urgency, frequency, nocturia, and urgency incontinence) is highly prevalent within the general population, causing major distress to patients in terms of their psychosocial and physical functioning. Muscarinic receptors of bladder smooth muscles are involved in both normal and disturbed bladder contraction. The muscarinic receptor functions may change in bladder disorders associated with OAB, implying that mechanisms, which normally have little clinical importance, may be up-regulated and contribute to the pathophysiology of OAB. In addition, several reports have suggested that various stimulations release many substances, including adenosine triphosphate, prostaglandins, nitric oxide, and acetylcholine, from bladder urothelium, which contribute to pathophysiology of the increased bladder sensation, OAB symptoms, and detrusor overactivity. Bladder urothelium possesses a non-neuronal cholinergic system and high density of muscarinic receptors. The roles and functions of the non-neuronal cholinergic system in OAB are now being evaluated. In the pharmacotherapy of OAB, antimuscarinic agents are the first choice drugs. Furthermore, new therapeutic targets at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain are proposed. In this review, the pathophysiology of OAB, especially the role of non-neuronal acetylcholine, is discussed. In addition, new drugs with new action mechanisms will be introduced.

Update on the Pharmacologic Management of Overactive Bladder: The Present and the Future

Overactive bladder (OAB) is a common condition, affecting approximately 17% of females and males 40 years of age and older. Historically, oxybutynin was the only medication approved for use in the management of OAB. Over the past decade, several new antimuscarinics have been approved for the treatment of OAB. Although all are deemed to be effective in improving the bothersome symptoms of OAB, they differ in their molecular properties, metabolism, and tolerability/side effect profile. A greater understanding of the pathophysiology of OAB has led to approved and investigative therapies to treat refractory OAB, such as neuromodulation and intravesical injection of Botulinum toxin, respectively. A variety of pharmacologic agents are in clinical trials for OAB that target different components of bladder function, such as the urothelium, the afferent sensory nerve pathways, and the central nervous system. It is the intent of this article to highlight these aspects of OAB management.

Pelvic organ prolapse and overactive bladder

In this review we try to shed light on the following questions: *How frequently are symptoms of overactive bladder (OAB) and is detrusor overactivity (DO) present in patients with pelvic organ prolapse (POP) and is there a difference from women without POP? *Does the presence of OAB symptoms depend on the prolapsed compartment and/or stage of the prolapse? *What is the possible pathophysiology of OAB in POP? *Do OAB symptoms and DO change after conservative or surgical treatment of POP? We searched on Medline and Embase for relevant studies. We only included studies in which actual data about OAB symptoms were available. All data for prolapse surgery were without the results of concomitant stress urinary incontinence (SUI) surgery. Community- and hospital-based studies showed that the prevalence of OAB symptoms was greater in patients with POP than without POP. No evidence was found for a relationship between the compartment or stage of the prolapse and the presence of OAB symptoms. All treatments for POP (surgery, pessaries) resulted in an improvement in OAB symptoms. It is unclear what predicts whether OAB symptoms disappear or not. When there is concomitant DO and POP, following POP surgery DO disappear in a proportion of the patients. Bladder outlet obstruction is likely to be the most important mechanism by which POP induces OAB symptoms and DO signs. However, several other mechanisms might also play a role. There are strong indications that there is a causal relationship between OAB and POP.

Perspectives on overactive bladder in the elderly population

Overactive bladder (OAB) represents a disruption in the storage function of the lower urinary tract. This bothersome condition occurs more commonly in the elderly. Since population forecasts predict a worldwide increase in the proportion of people aged over 65 years, it is reasonable to expect that the healthcare burden associated with OAB will also increase. The pathophysiology of OAB in the elderly is thought to be multifactorial, with an abnormality occurring in the nervous supply and/or the structure/function of the urothelium or bladder smooth muscle, leading to bladder hypersensitivity, abnormalities in bladder sensation (urgency) and involuntary detrusor contraction. A review of some of the key aspects relating to management of this growing population was undertaken. The potential for an elderly patient to present with a number of concomitant conditions means that careful characterization of their overall status is required before deciding on the most appropriate management option for their urinary tract pathology. Lifestyle interventions and pharmacological agents have shown success in treating OAB in the elderly, but as this patient group often has many concomitant conditions they are more likely to be seen by a non-urology specialist. It is therefore important to raise awareness of the condition and an appreciation of its impact among healthcare professionals to ensure the most appropriate care.

Overactive bladder in males.

The prevalence of overactive bladder (OAB) symptoms is considerable in both men and women and the impact on quality of life (QOL) is equally substantial. Ironically, despite nearly equal prevalence, OAB symptoms in men are infrequently treated, and often with medical therapies aimed at bladder outlet obstruction (BOO). In this review, we examine the pathophysiology of OAB and its evaluation in the context of benign prostatic hypertrophy and concomitant BOO. We then consider the efficacy and safety of individual therapeutic options for lower urinary tract symptoms in men, focusing on the mainstays of medical therapy: α-adrenergic blockers, 5-α reductase inhibitors, and antimuscarinic agents. Finally, we aim to comment on new therapeutic strategies and targets that may one day be available for the treatment of male OAB.

Preclinical compounds for the treatment of overactive bladder

Background: Overactive bladder is a prevalent and bothersome condition. Existing pharmacotherapy with antimuscarinics improves symptoms and quality of life but there are certain limitations in efficacy and tolerability. Objective: To review novel, recently patented compounds for the treatment of overactive bladder. Methods: The European Patent Office database was searched for compounds that emerged in the last 3 years. Results/conclusion: Overactive bladder pathophysiology and treatment is an active field of research. Molecules that modulate/inhibit afferent nerve pathways are the focus of interest and the most promising field of overactive bladder drug development.

Emerging drugs for treatment of overactive bladder and detrusor overactivity

Background: Overactive bladder (OAB) signifies the presence of urinary urgency and can have major effects on quality of life and social functioning. Standard antimuscarinic drugs have good initial response rates but substantial adverse effects and long-term compliance problems. Objectives: To review the complexities of the mechanisms underlying OAB and the current drugs available for treating its symptoms. Methods: The literature was reviewed to define current therapies and drugs in clinical trials. Articles were identified by means of a computerised PubMed and Cochrane Library search (using the following keywords: overactive bladder, detrusor overactivity, urgency and bladder), supported by a search of the PharmaProjects database. Conclusions: New drug classes, such as beta-3 adrenergic agonists, may work by reducing contractility or excitability of bladder muscle. Moderation of afferent activity may allow improved OAB symptoms, with lower risk of affecting voiding function. Agents acting on the CNS could influence OAB favourably, but target selection and adverse effects are an issue. The recognition of the functional contribution of the urothelium and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of OAB pathophysiology.

Physiologic and Pathophysiologic Functions of Purinoceptors in Voiding Reflex

Purinergic neurotransmission has been regarded as major component of non-adrenergic, noncholinergic (NANC) contraction in detrusor smooth muscle. Although in normal human detrusor, this contraction seems to be small, the importance of the NANC component for detrusor contraction in disease conditions such as detrusor overactivity remains to be established. Based on many evidences for purinergic contributions in lower urinary tract, ATP and purinoceptors has been suggested to be involved in both efferent and afferent mechanism in voiding reflex. ATP signaling via P2X1 receptors plays an important role in efferent neural control of urinary bladder function, although to varying degrees across species from experimental animals to men. The efferent function of purinoceptors may be enhanced in detrusor overactivity and aging. ATP also suggested being involved in mechanosensory transmission, via activation of P2X3 and P2X2/3 receptors on sensory afferent nerves. The afferent function of purinoceptors may be related with pathophysiology of overactive bladder or interstitial cystitis, mediating bladder hyperexicitability. These results suggest that the selective antagonists for the purinoceptors may offer better relief of sensory and motor symptoms for overactive bladder or interstitial cystitis patients in the future. (J Korean Continence Soc 2008;12:93-8)

Differential modulation by Ca 2+ ‐sensitive K + channels in longitudinal and transverse bladder strip contractions: implications in age‐related over‐active bladder symptoms

Over-active bladder (OAB) is affecting up to one-third of middle-aged adults worldwide. Physiological changes to the detrusor portion of the bladder are often associated with OAB symptoms. In the detrusor, smooth muscle cells (SMCs) are oriented both longitudinally and transversely. Evidence has pointed to the disparity in contractile responses between longitudinal SMCs (LSMCs) and transverse SMCs (TSMCs) in old adult rat bladders. The differences in contractility between LSMCs and TSMCs may also exist in young bladders, however only to be exacerbated during the aging process. Differences in the modulation of LSMC and TSMC contractility were hereby identified in the young adult rat detrusor. Detrusor strips of identical sizes were mounted on a myograph system where contractions were measured from SMCs in both orientations, i.e. LSMC- and TSMC-oriented. A single application of the muscarinic agonist carbachol (CCh, 0.01-50 micromol/L) yielded no differences in contractions between TSMC- and LSMC-oriented strips. However, blockade of KCa with tetraethylammonium (0.1–30 mmol/L) in TSMC-oriented strips showed more prominent contractions than the LSMC-oriented ones. The present findings indicated that young adult rat bladder strip contractions are modulated by KCa to different extents, depending on the SMC orientation. It is of interests to determine which KCa subtype(s) and if other types of K+ channels contribute to the observed differential LSMC and TSMC contractility. The K+ channel-associated differences in LSMC and TSMC contractions may have implications in the initiation and progression of OAB accompanied with aging. Thus, future studies examining bladders from a wider age group of rats will provide more insights into the pathophysiology of OAB.

Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder

1. The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2. Muscarinic M3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3. Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4. This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.

The puzzle of overactive bladder: controversies, inconsistencies, and insights

Overactive bladder (OAB) affects millions of individuals and may severely impair the quality of life of those affected. The contribution of human behavior to manifestations of this symptom complex remains poorly understood. Continued evolution of our understanding of the pathophysiology of OAB has identified contributory mechanisms, which in turn may open new therapeutic avenues. Recent improvements in drug delivery systems represent advances in the management of OAB. However, more complete symptom control with greater tolerability is desirable; this awaits the development of agents specific for newly emerging and as yet unidentified pathophysiologic pathways. Importantly, as understanding of outcomes assessment in OAB matures, refined assessments of disease severity, response to intervention, and patient preference should be possible.