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Context: Current literature suggests that several pathophysiological factors and mechanisms might be responsible for the nonspecific symptom complex of overactive bladder (OAB)., Objective: To provide a comprehensive analysis of the potential pathophysiology underlying detrusor overactivity (DO) and OAB., Evidence Acquisition: A PubMed-based literature search was conducted in April 2018, to identify randomised controlled trials, prospective and retrospective series, animal model studies, and reviews., Evidence Synthesis: OAB is a nonspecific storage symptom complex with poorly defined pathophysiology. OAB was historically thought to be caused by DO, which was either "myogenic" (urgency initiated from autonomous contraction of the detrusor muscle) or "neurogenic" (urgency signalled from the central nervous system, which initiates a detrusor contraction). Patients with OAB are often found to not have objective evidence of DO on urodynamic studies; therefore, alternative mechanisms for the development of OAB have been postulated. Increasing evidence on the role of urothelium/suburothelium and bladder afferent signalling arose in the early 2000s, emphasising an afferent "urotheliogenic" hypothesis, namely, that urgency is initiated from the urothelium/suburothelium. The urethra has also recently been regarded as a possible afferent origin of OAB-the "urethrogenic" hypothesis. Several other pathophysiological factors have been implicated, including metabolic syndrome, affective disorders, sex hormone deficiency, urinary microbiota, gastrointestinal functional disorders, and subclinical autonomic nervous system dysfunctions. These various possible mechanisms should be considered as contributing to diagnostic and treatment algorithms., Conclusions: There is a temptation to label OAB as "idiopathic" without obvious causation, given the poorly understood nature of its pathophysiology. OAB should be seen as a complex, multifactorial symptom syndrome, resulting from multiple potential pathophysiological mechanisms. Identification of the underlying causes on an individual basis may lead to the definition of OAB phenotypes, paving the way for personalised medical care., Patient Summary: Overactive bladder (OAB) is a storage symptom syndrome with multiple possible causes. Identification of the mechanisms causing a patient to experience OAB symptoms may help tailor treatment to individual patients and improve outcomes., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Storage phase bladder activity is a counter-intuitive observation of spontaneous contractions. They are potentially an intrinsic feature of the smooth muscle, but interstitial cells in the mucosa and the detrusor itself, as well as other muscular elements in the mucosa may substantially influence them. They are identified in several models explaining lower urinary tract dysfunction., Methods: A consensus meeting at the International Consultation on Incontinence Research Society (ICI-RS) 2017 congress considered the origins and relevance of spontaneous bladder contractions by debating which cell type(s) modulate bladder spontaneous activity, whether the methodologies are sufficiently robust, and implications for healthy and abnormal lower urinary tract function., Results: The identified research priorities reflect a wide range of unknown aspects. Cellular contributions to spontaneous contractions in detrusor smooth muscle are still uncertain. Accordingly, insight into the cellular physiology of the bladder wall, particularly smooth muscle cells, interstitial cells, and urothelium, remains important. Upstream influences, such as innervation, endocrine, and paracrine factors, are particularly important. The cellular interactions represent the key understanding to derive the integrative physiology of organ function, notably the nature of signalling between mucosa and detrusor layers. Indeed, it is still not clear to what extent spontaneous contractions generated in isolated preparations mirror their normal and pathological counterparts in the intact bladder. Improved models of how spontaneous contractions influence pressure generation and sensory nerve function are also needed., Conclusions: Deriving approaches to robust evaluation of spontaneous contractions and their influences for experimental and clinical use could yield considerable progress in functional urology., (© 2018 Wiley Periodicals, Inc.)

The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium-derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor and cyclooxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD 2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD 2 was found to have an inhibitory influence on nerve-induced contractions in guinea pig urinary bladder and on spontaneous contractions in the out-flow region. An altered release of excitatory and inhibitory factors is likely to play an important part in bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Aims: There are some reports that bladder C-fibers are partially involved in detrusor overactivity in patients with brain lesions. We investigated the contribution of bladder C-fiber to decreased bladder capacity in rats with cerebral infarction., Methods: Cerebral infarction was induced under halothane anesthesia by left middle cerebral artery occlusion with 4-0 nylon thread in female Sprague-Dawley rats. Intramural amounts of ATP and prostaglandin E 2 , in vivo and in vitro ATP, NGF, and prostaglandin E 2 release from the distended bladder urothelium, and changes in mRNA expressions of sensor molecules and receptors were monitored 6 h after the occlusion. Cystometry was performed in rats with or without resiniferatoxin pretreatment., Results: Overexpression of sensor molecule, transient receptor potential vanilloid-type channel 1, acid-sensing ion channel 2, purinergic receptors P2X 3 , and M 2 /M 3 muscarinic receptors was found in the bladder. These changes were accompanied by increases in ATP and NGF release from the urothelium. In contrast, when bladder C-fibers were desensitized by resiniferatoxin, no increase in NGF release from the urothelium was found either in vivo or in vitro. There was no difference in the percentage decrease in bladder capacity between cerebral infarction rats pretreated with resiniferatoxin and cerebral infarction rats without pretreatment., Conclusions: Results indicate that expression of sensor molecules in the bladder is altered by distant infarction in the brain. ATP and NGF release from the urothelium also increased. NGF release was related to activation of bladder C-fibers. Bladder C-fibers might not contribute much to decreased bladder capacity caused by cerebral infarction., (© 2016 Wiley Periodicals, Inc.)

Storage dysfunction of the urinary bladder, specifically overactive bladder syndrome, is a condition that occurs frequently in the general population. Historically, pathophysiological and treatment concepts related to overactive bladder have focused on smooth muscle cells. Although these are the central effector, numerous anatomic structures are involved in their regulation, including the urothelium, afferent and efferent nerves, and the central nervous system. Each of these structures involves receptors for—and the urothelium itself also releases—many mediators. Moreover, hypoperfusion, hypertrophy, and fibrosis can affect bladder function. Established treatments such as muscarinic antagonists, β-adrenoceptor agonists, and onabotulinumtoxinA each work in part through their effects on the urothelium and afferent nerves, as do α1-adrenoceptor antagonists in the treatment of voiding dysfunction associated with benign prostatic hyperplasia; however, none of these treatments are specifically targeted to the urothelium and afferent nerves. It remains to be explored whether future treatments that specifically act at one of these structures will provide a therapeutic advantage.

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., (© 2014 Wiley Periodicals, Inc.)

Aim: It is known that physiopathological changes in diabetes affect the function of the bladder. In this study, we aimed to demonstrate the possible effects of diabetes on the urothelium during this physiopathological process., Methods: Diabetes was induced in rats by tail vein injection of 35 mg/kg streptozotocin. Eight weeks later, intact and denuded bladder strips were prepared from these rats. Electrical field stimulation (EFS; 0.5-32 Hz), carbachol (10(-8)-10(-3) mol/L; cumulative dosage-response curves) and KCl (120 mmol/L) were used for the evaluation of the contractile responses. All responses were expressed as mg tension developed per mg of bladder tissue. Weights of rats and of their bladders, blood glucose levels, and frequency- and concentration-response curves were compared using anova, the paired t-test and the independent t-test. Differences were considered significant at P<0.05., Results: Although no differences related to the weight of bladders of the control and diabetic groups were observed, there were differences in blood glucose levels and body weights between the two groups. Similarly, although there were no differences between the data obtained with EFS and KCl from tissues with intact and denuded strips in the control group, carbachol responses significantly differed between intact and denuded strips in the non-diabetic group. These differences were not observed in the diabetic group. In the control groups, in the presence of additional strips with intact urothelium placed in the medium containing denuded tissue, the differences in contractile responses between the intact control strip and the denuded strip disappeared., Conclusions: Diabetes possibly changes the interaction between the relaxant factors that are released from urothelium and muscarinic stimulation, but these interactions are not completely understood yet. Consequently, the response of the bladder to contractile stimulants is also affected. Further studies are required to reveal the mechanism by which diabetes influences the urothelium.

Purpose: Stimulating muscarinic receptors in pig bladder urothelium causes the release of a diffusable factor that inhibits contractions of the underlying detrusor muscle. We investigated whether the contractions of human detrusor strips elicited by the muscarinic agonist carbachol, electrical field stimulation, KCl or the neurokinin receptor agonist neurokinin A are affected by the urothelium., Materials and Methods: Paired intact and urothelium denuded muscle strips were placed in modified gassed Tyrode's solution at 37C. Cumulative concentration-response curves to carbachol or KCl were constructed. In other tissues the strips were stimulated electrically (1 to 40 Hz) with trains of square wave pulses 20 seconds in duration at 5-minute intervals., Results: Cholinergic contractions evoked by electrical field stimulation at 10 and 30 Hz or by carbachol were significantly inhibited in the presence of an intact urothelium. Contractions elicited by KCl and by 10 microM neurokinin A were not modified by the urothelium. The urothelium mediated inhibition of contractions induced by carbachol was not affected by 300 microM L-NG-nitroarginine, 1 microM ODQ (1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one), 1 microM propranolol or 5 microM indomethacin., Conclusions: Muscarinic agonists stimulate the release of an inhibitory factor from the human urothelium. The factor is distinct from nitric oxide and it persists in the presence beta-adrenoceptor blockade or cyclooxygenase inhibition.