Youko Ikeda

The role of anticholinergics in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: a systematic review and meta-analysis.

Authors from the UK present a systematic review of publications on the safety and efficacy of anticholinergics in men with LUTS; they found them to be safe, but suggested that further studies are required to establish precisely their efficacy.

Modulation of bladder myofibroblast activity: implications for bladder function.

Bladder suburothelial myofibroblasts may modulate both sensory responses from the bladder wall and spontaneous activity. This study aimed to characterize further these cells in their response to exogenous agents implicated in mediating the above activity. Detrusor strips, with or without mucosa, and isolated suburothelial myofibroblasts were prepared from guinea pig bladders. Isometric tension, intracellular Ca2+, and membrane current were recorded. Cell pairs were formed by pushing two cells together. Tension, intracellular Ca2+, and membrane potential were also recorded from bladder sheets using normal or spinal cord-transected (SCT) rats. Spontaneous contractions were greater in detrusor strips with an intact mucosa and were augmented by 10 μM UTP. ATP, UTP, or reduced extracellular pH elicited Ca2+ transients and inward currents (Erev −30 mV) in isolated cells. Capsaicin (5–30 μM) reduced membrane current (37 ± 12% of control) with minor effects on Ca2+ transients: sodium nitroprusside reduced membrane currents (40 ± 21% of control). Cell pair formation, without an increase in cell capacitance, augmented ATP and pH responses (180 ± 58% of control) and reduced the threshold to ATP and acidosis. Glivec (20–50 μM) reversibly blocked the augmentation and also reduced spontaneous activity in bladder sheets from SCT, but not normal, rats. Glivec also disrupted the spread of Ca2+ waves in SCT sheets, generating patterns similar to normal bladders. Suburothelial myofibroblasts respond to exogenous agents implicated in modulating bladder sensory responses; responses augmented by physical intercellular contact. The action of glivec and its selective suppression of spontaneous activity in SCT rats identifies a possible pathway to attenuate bladder overactivity.

Botulinum Neurotoxin Serotype A Suppresses Neurotransmitter Release from Afferent as Well as Efferent Nerves in the Urinary Bladder

BACKGROUND Botulinum neurotoxin A (BoNTA), which alleviates overactive bladder symptoms, is thought to act predominantly via the inhibition of transmitter release from parasympathetic nerves. However, actions at other sites such as afferent nerve terminals are possible. OBJECTIVE To evaluate the effects of BoNTA on bladder afferent neuropeptide release and firing. DESIGN, SETTING, AND PARTICIPANTS One side of the bladder of control and chronic (1-2 wk) spinal cord transected (SCT; T(8)-T(9)) adult female mice was injected with BoNTA (0.5 U/5 μl saline). After 48 h, bladders with L(6)-S(2) spinal nerves were prepared for in vitro recordings. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS In bladder preparations, tension and optical mapping of Ca(2+) transients were used to measure intrinsic contractions, those evoked by capsaicin or the electrical stimulation of spinal nerves. Afferent firing was evoked by stretch or intrinsic bladder contractions. The numbers of responding units and firing rates were measured. Animal numbers were used to detect moderate to large between-group differences based on Cohens criteria. Two-way analysis of variance was used to test spatial/temporal differences in Ca(2+) signals as mean plus or minus standard deviation. Differences between data sets were tested with the student t test and skewed data sets with a Mann-Whitney U test (significant when p<0.05). RESULTS AND LIMITATIONS In control and SCT bladders, BoNTA treatment decreased the contractions evoked by electrical stimulation of spinal nerves without altering intrinsic contractions. Afferent firing on untreated sides in response to stretch/intrinsic contractions was increased in SCTs versus controls. On BoNTA-treated sides, afferent firing rates were greatly attenuated in response to mechanical stimulation as were the capsaicin-evoked optical signals mediated by neuropeptide release. CONCLUSIONS SCT caused an increased sensitivity of afferent nerves to mechanical stimulation that was reduced by BoNTA treatment. Increased intrinsic activity after SCT was unaffected by the toxin. Thus BoNTA suppresses neurogenic detrusor overactivity by targeting afferent as well as efferent pathways in the bladder.

Researching bladder afferents—determining the effects of β3‐adrenergic receptor agonists and botulinum toxin type‐A

A substantial portion of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated, enhanced and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source for drug targets. Established drug therapies such as muscarinic receptor antagonists, and two emerging therapies, β3‐adrenergic receptor agonists and botulinum toxin type‐A, may act partly through afferent mechanisms. This review focuses on these two new principles and new and established methods for determining their sites of action. It also provides brief information on the innervation of the bladder, afferent receptors and transmitters and how these may communicate with the urothelium, interstitial cells and detrusor smooth muscle to regulate micturition. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms and urgency sensations are also covered. This work is the result from ‘Think Tank’ presentations, and the lengthy discussions that followed, at the 2010 International Consultation on Incontinence Research Society meeting in Bristol, UK. Neurourol. Urodynam. Neurourol. Urodynam. 30:684–691, 2011.

Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists

Spinal cord transection (SCT) leads to an increase in spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase in interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders, and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP, and UTP. We have investigated the hypothesis that these agents underlie the increase in spontaneous activity. Rats underwent lower thoracic spinal cord transection, and their bladder sheets or strips, with intact mucosa except where specified, were used for experiments. Isometric tension was recorded and propagating Ca(2+) and membrane potential (E(m)) waves were recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9 ± 0.4/min); ADP, UTP, and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y(6)-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca(2+)/E(m) waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca(2+)/E(m) waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space.

Mechanisms of action of botulinum neurotoxins, β3‐adrenergic receptor agonists, and PDE5 inhibitors in modulating detrusor function in overactive bladders: ICI‐RS 2011

Botulinum neurotoxins type A (BoNT/A), β3‐adrenergic receptor agonists, and phosphodiesterase type 5 (PDE5) inhibitors are promising agents that mitigate lower urinary tract symptoms by attenuating the sensory system. However, whether they act directly on afferent nerves or indirectly through the other cell types is unclear.

Mucosal Muscarinic Receptors Enhance Bladder Activity in Cats With Feline Interstitial Cystitis

PURPOSE Interstitial cystitis is a chronic pelvic pain syndrome of which the origin and mechanisms involved remain unclear. In this study Ca(2+) transients in the bladder wall of domestic cats diagnosed with naturally occurring feline interstitial cystitis were examined. MATERIALS AND METHODS Cross-sections of full-thickness bladder strips from normal cats and cats with feline interstitial cystitis were examined by optically mapping Ca(2+) transients and recording tension. Responses of Ca(2+) activity and detrusor contractions to pharmacological interventions were compared. In addition, pharmacological responses were compared in mucosa denuded preparations. RESULTS Optical mapping showed that feline interstitial cystitis bladders had significantly more spontaneous Ca(2+) transients in the mucosal layer than control bladders. Optical mapping also demonstrated that feline interstitial cystitis bladders were hypersensitive to a low dose (50 nM) of the muscarinic receptor agonist arecaidine when the mucosal layer was intact. This hypersensitivity was markedly decreased in mucosa denuded bladder strips. CONCLUSIONS In feline interstitial cystitis cat bladders there is increased Ca(2+) activity and sensitivity of muscarinic receptors in the mucosal layer, which can enhance smooth muscle spontaneous contractions.

The potential role of unregulated autonomous bladder micromotions in urinary storage and voiding dysfunction; overactive bladder and detrusor underactivity

The isolated bladder shows autonomous micromotions, which increase with bladder distension, generate sensory nerve activity, and are altered in models of urinary dysfunction. Intravesical pressure resulting from autonomous activity putatively reflects three key variables; the extent of micromotion initiation, distances over which micromotions propagate, and overall bladder tone. In vivo, these variables are subordinate to the efferent drive of the central nervous system. In the micturition cycle storage phase, efferent inhibition keeps autonomous activity generally at a low level, where it may signal ‘state of fullness’, whilst maintaining compliance. In the voiding phase, mass efferent excitation elicits generalised contraction (global motility initiation). In lower urinary tract dysfunction, efferent control of the bladder can be impaired, for example due to peripheral ‘patchy’ denervation. In this case, loss of efferent inhibition may enable unregulated micromotility, and afferent stimulation, predisposing to urinary urgency. If denervation is relatively slight, the detrimental impact on voiding may be low, as the adjacent innervated areas may be able to initiate micromotility synchronous with the efferent nerve drive, so that even denervated areas can contribute to the voiding contraction. This would become increasingly inefficient the more severe the denervation, such that ability of triggered micromotility to propagate sufficiently to engage the denervated areas in voiding declines, so the voiding contraction increasingly develops the characteristics of underactivity. In summary, reduced peripheral coverage by the dual efferent innervation (inhibitory and excitatory) impairs regulation of micromotility initiation and propagation, potentially allowing emergence of overactive bladder and, with progression, detrusor underactivity.

Recent advances in detrusor muscle function

Contractile activation of detrusor smooth muscle is initiated by the release of transmitters from motor nerves. Acetylcholine is a ubiquitous transmitter, as also is adenosine triphosphate (ATP) in many animal bladders and in people from several patient groups with pathological bladder function. In recent years there has been progress in explaining several cellular mechanisms that link transmitter release to contraction and these will be considered. The lifetime of ATP in the neuromuscular junction is finite and broken down ultimately to adenosine, which can exert modulatory control of contractile activation. Adenosine depresses nerve-mediated contractions and two sites of action have been proposed: an action on the motor nerves via A[Formula: See Text] receptors to depress further transmitter release and a less well-defined depressant effect on the detrusor muscle. The Ca[Formula: See Text] ions that activate the contractile proteins are derived from intracellular stores, which releases their content via IP[Formula: See Text] receptor activation and Ca[Formula: See Text]-induced Ca[Formula: See Text] release. Filling of the stores in the rest interval is mediated via transmembrane flux of Ca[Formula: See Text] through Ca[Formula: See Text] channels. Activation of the channels is regulated by the level of the intracellular [Ca[Formula: See Text]], via activation and inactivation of Ca[Formula: See Text]-sensitive K[Formula: See Text] channels. Thus, Ca store filling is regulated by intracellular [Ca[Formula: See Text]] via a negative feedback process. The presence and physiological function of spontaneous contractions in detrusor remain contentious and little is known about their origin. One possibility is that they originate from random Ca[Formula: See Text] sparks, i.e. localized transient increases of [Ca[Formula: See Text]] that may eventually progress to generate a cellular Ca[Formula: See Text] transient. Observations by confocal microscopy have revealed the presence of such sparks, especially near the cell membrane, and thus provide a cellular basis for spontaneous contractions. Finally, the questions arises as to whether detrusor smooth muscle is a functional syncitium. The demonstration of small gap junctions by electron microscopy and the demonstration of the gap junction protein connexin45 indicate that the muscle mass may indeed be functionally connected. The implications regarding the spread of excitation are discussed.

Sophisticated models and methods for studying neurogenic bladder dysfunction

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.