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Purpose: The relative roles of urinary sphincter damage, aging, and childbirth in stress urinary incontinence (SUI), have not been established. This study was performed to elucidate the roles of these factors.Methods: The study included: (1) 8 female cynomolgus monkeys (17–19 years of age and 7–8 vaginal births each); (2) six 5-yearold nulliparous monkeys with surgically created chronic urinary sphincter dysfunction; and (3) six 5-year-old, nulliparous, nosurgery controls. Sedated abdominal leak point pressure (ALPP) and maximum urethral sphincter pressures (MUP) were measured. Sphincters, bladders, and pelvic support muscles were quantified for collagen content. Additionally, bladders were analyzed for collagen fiber thickness, length, and angle using CT-FIRE analysis of Picrosirius red-stained tissues.Results: Resting MUP values were similar in the controls and older multiparous monkeys (P>0.05). However, aging and multiple births reduced pudendal nerve-stimulated increases in MUP (P0.05 vs. young groups). Bladder collagen content was greater, and muscle content less, in the old multiparous monkeys (P

The aim of this review is to discuss how to link lower urinary tract symptoms (LUTS) and oxidative stress (OS) and to define relevant targets for therapeutic intervention. Narrative review based on published literature. Many of the multifactorial pathophysiological mechanisms behind LUTS can initiate reactive oxygen species (ROS) generation. Assuming that OS is a consequence rather than a primary cause of LUTS it seems reasonable to identify both the disease mechanism initiating LUTS, and the source of ROS involved. There are many possible sources of ROS overproduction, but the NADPH oxidase (NOX) family of enzymes is the primary source; NOX activation in turn, may result in the activation of secondary ROS sources, i.e., ROS-dependent ROS production. Selective NOX inhibition therefore seems an attractive therapeutic strategy in LUTS treatment. The finding of NOX2 localization to centers in the brain associated with micturition control, opens up for further studies of NOX involvement in the central control of micturition, normally and in disease. Further information on the localization of the different isoforms of NOX in the LUT e.g., the bladder wall and its components and the prostate, is desirable. To optimize treatment, the pathophysiological mechanism initiating LUTS, and the activated isoform of NOX, should be identified. Unfortunately, in most cases of LUTS this is currently not possible. Even if selective NOX inhibitors have entered the clinical trial stage for treatment of disorders other than LUT dysfunction, their efficacy for LUTS treatment has to be demonstrated. If this can be achieved, an attractive approach would be combination of selective NOX inhibition with established drug therapies.

Aims: Rodent cystometry has provided valuable insights into the impact of the disease, injury, and aging on the cellular and molecular pathways, neurologic processes, and biomechanics of lower urinary tract function. The purpose of this white paper is to highlight the benefits and shortcomings of different experimental methods and strategies and to provide guidance on the proper interpretation of results. Methods: Literature search, selection of articles, and conclusions based on discussions among a panel of workers in the field. Results: A range of cystometric tests and techniques used to explore biological phenomena relevant to the lower urinary tract are described, the advantages and disadvantages of various experimental conditions are discussed, and guidance on the practical aspects of experimental execution and proper interpretation of results are provided. Conclusions: Cystometric evaluation of rodents comprises an extensive collection of functional tests that can be performed under a variety of experimental conditions. Decisions regarding which approaches to choose should be determined by the specific questions to be addressed and implementation of the test should follow standardized procedures. (Less)

Aims Two phase 1 trials were performed in healthy women with the overactive bladder (OAB) syndrome and urodynamically demonstrated detrusor overactivity (DO), with the aim to demonstrate the safety and potential efficacy of URO‐902, which comprises a gene therapy plasmid vector expressing the human big potassium channel α subunit. Methods ION‐02 (intravesical instillation) and ION‐03 (direct injection) were double‐blind, placebo‐controlled, multicenter studies without overlap in enrollment between studies. Active doses were administered and evaluated sequentially (lowest dose first) for safety. ION‐02 participants received either 5000 µg or 10 000 µg URO‐902, or placebo. ION‐03 participants received either 16 000 or 24 000 µg URO‐902, or placebo, injected directly into the bladder wall using cystoscopy. Primary outcome variables were safety parameters occurring subsequent to URO‐902 administration; secondary efficacy variables also were evaluated. Results Among the safety outcomes, there were no dose‐limiting toxicities or significant adverse events (AEs) preventing dose escalation during either trial, and no participants withdrew due to AEs. For efficacy, in ION‐02 (N = 21), involuntary detrusor contractions on urodynamics at 24 weeks in patients receiving URO‐902 (P

Purpose of review Update on recent regenerative medicine approaches to the treatment of stress urinary incontinence (SUI) caused by intrinsic sphincter deficiency (ISD). Recent findings In the treatment of female SUI/ISD, results using different types of cellular therapy have been disappointing, and new approaches are desirable. To advance our regenerative medicine approaches to SUI/ISD, it is critical to utilize animal models that best parallel the pathophysiology of this disease in women. Many current animal models mimic acute SUI/ISD. However, SUI/ISD in women is usually a chronic condition resulting from previous muscle and nerve sphincter damage during parturition or muscle loss during aging. Similar to women, a nonhuman primate (NHP) model of chronic SUI/ISD has demonstrated only modest response to cell therapy. However, treatment with stromal cell-derived factor 1 (SDF1), also known as C-X-C motif chemokine 12 (CXCL12) restored continence in this model. Summary As a potential therapeutic approach, the use of a well characterized chemokine, such as CXCL12, may by-pass the lengthy and expensive process of cell isolation, expansion, and injection. Recent findings in this new NHP model of chronic SUI/ISD may open up the field for noncell-based treatments.

Objective: To perform a descriptive microscopic study of prostatectomy specimens from 19 patients which anatomically characterizes the distributions of periprostatic nerve qualities, and to visualize these using diffusion tensor imaging (DTI). Materials and Methods: Serial whole-mounted sections were stained for cholinergic (neuronal nitric oxide synthase), adrenergic (tyrosine hydroxylase) and sensory (calcitonin gene-related peptide) nerves. Extracapsular stained nerves were counted by prostate surface sector, and classified by diameter. Stain-related relative density was calculated, and distribution patterns were evaluated. To better visualize the reported neuronal structures and independently confirm our findings, nerve concordance in five male volunteers was investigated using a 3-Tesla magnetic resonance imaging-DTI system. Results: At the base, cholinergic nerves were distributed from the anterolateral to posterior sectors, continuing posterolaterally (mid-section) into the posterolateral-posterior sector toward the apex. Adrenergic nerves were distributed across the anterolateral-posterior sectors at the base, with the course narrowing to the posterolateral-posterior sectors at the mid- and apical levels. Sensory fibres were found posterolaterally posteriorly at the base, continuing posterolaterally over the mid- and apical levels. Although it was not possible to determine the different nerve qualities, DTI confirmed histological findings from the base to the apex. Conclusions: Different types of nerve fibres were found to vary in distribution. When linked to possible functional aspects of the different nerve types, this morphological evidence may be of importance to further protect function after radical prostatectomy (RP). To our knowledge, this is the first time that DTI has confirmed reported histological findings in nerve-sparing RPs. DTI could be an important tool with which to correlate nerves to tumour for better preoperative planning and to incorporate imaging into treatment.

Purpose A major question remaining in approaches to tissue engineering and organ replacement is the role of native mobilized native cells in the regeneration process of damaged tissues and organs. The goal of this study was to compare the cell mobilizing effects of the chemokine CXCL12 and cell therapy on the urinary sphincter of nonhuman primates (NHP) with chronic intrinsic urinary sphincter dysfunction. Methods Either autologous lenti-M-cherry labeled skeletal muscle precursor cells (skMPCs) or CXCL12 were injected directly into the sphincter complex of female NHPs with or without surgery-induced chronic urinary sphincter dysfunction (n=4/treatment condition). All monkeys had partial bone marrow transplantation with autologous lenti-green fluorescent protein (GFP) bone marrow cells prior to treatment. Labeled cells were identified, characterized and quantified using computer-assisted immunohistochemistry 6 months posttreatment. Results GFP-labeled bone marrow cells (BMCs) were identified in the bone marrow and both BMCs and skMPCs were found in the urinary sphincter at 6-month postinjection. BMCs and skMPCs were present in the striated muscle, smooth muscle, and lamina propria/urothelium of the sphincter tissue. Sphincter injury increased the sphincter content of BMCs when analyzed 6-month postinjection. CXCL12 treatment, but not skMPCs, increased the number of BMCs in all layers of the sphincter complex (P

Aim: To discuss animal models of lower urinary tract disorders (LUTD) and their translational impact. Methods: Report of discussions based on presented literature-search based reviews relevant for the purpose. Results: Animal models can be used to investigate fundamental biological mechanisms, but also as tools to elucidate aspects of the pathogenesis of disease and to provide early evidence of any safety risk. Several different models may be required to obtain information that can have a translational impact. The term “translational research” covers not only the process of directly transferring knowledge from basic sciences to human trials to produce new drugs, devices, and treatment options for patients (T1 type translation) but also the implementation of early clinical research findings (phases I-III) into practice to improve care for patients (T2 type). Direct transfer of animal data to T2 is rarely possible, and the process often does not continue after the first trials in humans (phase I). It should be emphasized that many preclinical observations do not have (and do not need to have) immediate translational impact. Conclusions: No single animal model can mimic the complexity of the human disease. Still, animal models can be useful for gaining information on LUT function in humans, for elucidating pathophysiological mechanisms, and for the definition of targets for future drugs to treat LUT disorders. (Less)

Several studies indicate that pelvic ischemia and oxidative stress may play a significant role in lower urinary tract dysfunction (LUTD), including detrusor overactivity (DO)/overactive bladder (OAB) and detrusor underactivity (DU)/underactive bladder (UAB). The present article addresses proposal 1: "Are oxidative stress and ischemia significant causes of bladder damage leading to LUTD?" from the 2019 International Consultation on Incontinence-Research Society (ICI-RS) meeting. Bladder ischemia in animals and humans is briefly described, along with the proposed progression from ischemia to LUTD. Bladder ischemia is compared with ischemia of other organs, and the ongoing development of pelvic ischemia animal models is discussed. In addition, the distribution of blood within the bladder during filling and voiding and the challenges of quantification of blood flow in vivo are described. Furthermore, oxidative stress, including potential biomarkers and treatments, and challenges regarding antioxidant therapy for the treatment of LUTD are discussed. Finally, seven critical research questions and proposed studies to answer those questions were identified as priorities that would lead to major advances in the understanding and treatment of lower urinary tract symptoms (LUTS)/LUTD associated with pelvic ischemia and oxidative stress.

AIM: To review evidence for novel drug targets that can manage overactive bladder (OAB) symptoms.METHODS: A think tank considered evidence from the literature and their own research experience to propose new drug targets in the urinary bladder to characterize their use to treat OAB.RESULTS: Five classes of agents or cellular pathways were considered. (a) Cyclic nucleotide-dependent (cyclic adenosine monophosphate and cyclic guanosine monophosphate) pathways that modulate adenosine triphosphate release from motor nerves and urothelium. (b) Novel targets for β3 agonists, including the bladder wall vasculature and muscularis mucosa. (c) Several TRP channels (TRPV1 , TRPV4 , TRPA1 , and TRPM4 ) and their modulators in affecting detrusor overactivity. (d) Small conductance Ca2+ -activated K+ channels and their influence on spontaneous contractions. (e) Antifibrosis agents that act to modulate directly or indirectly the TGF-β pathway-the canonical fibrosis pathway.CONCLUSIONS: The specificity of action remains a consideration if particular classes of agents can be considered for future development as receptors or pathways that mediate actions of the above mentioned potential agents are distributed among most organ systems. The tasks are to determine more detail of the pathological changes that occur in the OAB and how the specificity of potential drugs may be directed to bladder pathological changes. An important conclusion was that the storage, not the voiding, phase in the micturition cycle should be investigated and potential targets lie in the whole range of tissue in the bladder wall and not just detrusor.

Objectives To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). Materials and methods In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. Results LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 μg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10 μg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. Conclusion A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.

AIMS To explore whether autophagy plays a role in the remodeling of bladder smooth muscle cells (SMCs) in children with neurogenic lower urinary tract dysfunction (NLUTD), we investigated the effect of autophagy in NLUTD in the paediatric population. METHODS Bladder biopsies were taken from children with NLUTD and healthy donors as controls. Samples were labeled with the SMC markers calponin, smoothelin, and the autophagy proteins LC3, ATG5, and Beclin1. The contractile ability of bladder derived SMCs was investigated. RESULTS ATG5 gene and protein was upregulated in NLUTD muscle tissue compared to normal bladder. NLUTD muscle exhibited a punctated immunostaining pattern for LC3 in a subset of the SMCs, confirming the accumulation of autophagosomes. Pronounced elevation of ATG5 in the SMC in NLUTD tissue was associated with a downregulation of the key contractile proteins smoothelin and calponin. Pharmacological blocking of autophagy completely stopped the cells growth in normal bladder SMCs. Inhibition of autophagy in the NLUTD SMCs, with already elevated levels of ATG5, resulted in a reduction of ATG5 protein expression to the basal level found in normal controls. CONCLUSIONS Our study suggests that autophagy is an important factor affecting the remodeling of SMCs and the alteration of functionality in bladder smooth muscle tissue in the NLUTD. Since autophagy can be influenced by oral medication, this finding might lead to novel strategies preventing the deterioration of NLUTD muscle.

The acontractile bladder (AcB) is a urodynamic-based diagnosis wherein the bladder is unable to demonstrate any contraction during a pressure flow study. Although it is often grouped with underactive bladder, it is a unique phenomenon and should be investigated independently. The purpose of the present review was to examine the current literature on AcB regarding its pathology, diagnosis, current management guidelines, and future developments. We performed a review of the PubMed database, classifying the evidence for AcB pathology, diagnosis, treatment, and potential future treatments. Over the 67 years covered in our review period, 42 studies were identified that met our criteria. Studies were largely poor quality and mainly consisted of retrospective review or animal models. The underlying pathology of AcB is variable with both neurological and myogenic aetiologies. Treatment is largely tailored for renal preservation and reduction of infection. Although future developments may allow more functional restorative treatments, current treatments mainly focus on bladder drainage. AcB is a unique and understudied bladder phenomenon. Treatment is largely based on symptoms and presentation. While cellular therapy and neuromodulation may hold promise, further research is needed into the underlying neuro-urological pathophysiology of this disease so that we may better develop future treatments.

Objectives To explore if the mechanism of the voiding dysfunction caused by spinal cord injury in rats can be improved by intravenous administration of the 5-HT2A/2C receptor agonist, DOI, and discuss whether it can be ascribed to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons. Materials and Methods Female Sprague-Dawley rats were used, which were divided into two groups (Spinal cord injury group VS Normal control group). Under urethane anesthesia, cystometry was performed to examine the variation of urodynamic parameters before and after successive intrathecal administration of various doses of DOI into the lumbosacral cord. Additionally, the changes of serotonin 2A and 2C receptors in the lumbosacral cord were investigated by immunohistochemical staining and Western blot. Results Compared to controls, spinal cord injured rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After spinal cord injury, DOI improved voiding efficiency likely via affecting external urethral sphincter activity. Immunohistochemical staining and Western blot analysis showed that serotonin 2A and 2C receptors were up-regulated in lumbosacral cord motoneurons. Conclusion In rats with spinal cord injury, DOI can improve voiding efficiency, and this may be due to serotonin 2A and 2C receptor up-regulation in lumbosacral cord motoneurons controlling external urethral sphincter activity. This article is protected by copyright. All rights reserved.

The overactive bladder (OAB) syndrome, characterized by urinary urgency with or without urgency urinary incontinence (UUI) and usually associated with increased daytime frequency and nocturia (1), is a common condition worldwide. Independent of the methodology used (telephone survey, postal survey) several epidemiologic studies in Europe, Canada, the United States, and Japan have shown the OAB syndrome to be present in 8.0% to 16.5% of adults, with similar rates between men and women (2,3).

Purpose: Mixed efficacy results of autologous skeletal muscle precursor cell therapy in women with chronic intrinsic urinary sphincter deficiency have increased interest in the therapeutic value of alternative regenerative medicine approaches. The goal of this study was to compare the effects of the cell homing chemokine CXCL12 (C-X-C motif chemokine 12) and skeletal muscle precursor cells on chronic urinary sphincter regeneration in chronic intrinsic urinary sphincter deficiency.Materials and Methods: Five million autologous skeletal muscle precursor cells or 100 ng CXCL12 were injected in the urinary sphincter complex of adult female cynomolgus monkeys with chronic (6-month history) intrinsic urinary sphincter deficiency. These treatment groups of 3 monkeys per group were compared to a group of 3 with no intrinsic urinary sphincter deficiency and no injection, and a group of 3 with intrinsic urinary sphincter deficiency plus vehicle injection. Maximal urethral pressure was measured at rest, during stimu...

We summarize the current state of knowledge regarding cell therapy for stress urinary incontinence and introduce new approaches of using regenerative pharmacology as an adjunct or replacement for cell therapy.We reviewed the literature by searching PubMed®, Ovid and Biological Abstracts. The period searched was 1975 to December 2015. The inclusion terms separately or in combination were stress urinary incontinence, cell therapy, chemokine, vascularization, innervation, secretome and/or animal models. Epublished articles were not included. We did not exclude articles based on impact factor.Cell therapy is currently proposed to restore functional muscle cells and aid in closure of the sphincter in women with sphincter associated incontinence. Clinical trials have included small numbers of patients and results have varied depending on the patient cohorts and the cells used. Results of preclinical studies have also varied but show a more favorable outcome. This difference was most likely explained by the fact that animal modeling is not directly translatable to the human condition. However, preclinical studies have identified an exciting new approach to regeneration of the urinary sphincter using the components of cells (secretomes) or chemokines that home reparative cells to sites of injury.Cell therapy will continue to be explored. However, a regenerative pharmacological approach to the treatment of stress urinary incontinence holds the promise of bypassing the lengthy and expensive process of cell isolation and also increasing the availability of treatment in many clinical settings. This approach requires careful preclinical modeling and attention to its health benefit-to-risk ratio.

Purpose: Bladder outflow obstruction (BOO) is common in the elderly and can result in bladder voiding dysfunction (BVD) due to severe bladder muscle damage. The goal of this research was to evaluate the use of adult stem cells for the treatment of BVD due to decreased muscle contractility in a rat model. Materials and methods: Adipose-derived stem cells (ADSCs) and muscle precursor cells (MPCs) were harvested from male Lewis rats and expanded in culture. BOO was induced by tying a suture around the urethra. Six weeks after obstruction, the development of BVD was confirmed by cystometric analysis in conscious rats, histology and molecular investigations. Injection of ADSCs or MPCs into the bladder wall and synchronous deligation was performed 6weeks after the obstruction. After stem-cell treatment, morphological and functional changes were assessed. Age-matched rats and animals without cellular therapy but deligation-only served as controls. Results: Voiding pressures decreased progressively 6weeks after obstruction with increased bladder capacities. Structural changes of the detrusor muscle occurred during the time of obstruction with an increased connective tissue-to-smooth muscle ratio and decreased SMA/smoothelin expression. After stem-cell injection, improved voiding pressures and voiding volumes were observed together with recovered tissue architecture. RT-PCR and Western blotting showed an up-regulation of important contractile proteins. Conclusions: We established a reliable model for BVD and demonstrated that ADSCs and MPCs can prevent pathophysiological remodelling and provide regenerated bladder tissue and function.

Item does not contain fulltext CONTEXT: Several drugs are approved and available for the treatment of lower urinary tract symptoms (LUTS) in men and women. However, the vast majority of available data, upon which the approval and recommendation in guidelines are based, considered only the role of the monotherapies and did not evaluate possible combination therapies. OBJECTIVE: This systematic review analyzes the efficacy and adverse events of combination therapies for male and female LUTS. EVIDENCE ACQUISITION: A systematic literature search in the PubMed/Medline, Web of Science, and Cochrane databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement to identify clinical trials, randomized controlled trials, meta-analyses, and guidelines on male and female LUTS combination therapy published from March 2012 to December 2017 for men (in order to update a previous men-focused work) and from January 1988 to December 2017 for women. A total of 58 papers were identified. EVIDENCE SYNTHESIS: The most studied combination therapy for the treatment of male LUTS is the alpha1-adrenoceptor antagonist/5alpha-reductase inhibitor combination. This combination seems to be more efficacious in terms of several outcome variables, in particular in men who have moderate-to-severe LUTS and are at risk of disease progression. Also in terms of nocturia improvements, this combination is significantly more effective than the monotherapy. The other often studied combination treatment, in both male and female patients with LUTS, was the combination of antimuscarinics (in particular solifenacin) and mirabegron. This combination seems to be more effective in comparison with the monotherapies with respect to urinary incontinence and urgency urinary incontinence episodes and several other objective and subjective parameters, without relevant increase of adverse events. The combination of hormone therapy and antimuscarinics in women with LUTS does not seem to be useful. CONCLUSIONS: For the treatment of LUTS in men and women, combination therapy appears to be a promising option to optimize the efficacy of the available drugs for those who do not experience sufficient benefit with monotherapy. This add-on scenario offers the possibility to have a more tailored approach to the management of LUTS, always seeking the optimal balance between efficacy and tolerability for a given patient. PATIENT SUMMARY: Some combination of drugs may offer advantages over monotherapies for the treatment of voiding and storage complaints in men and women.

We aimed to investigate the association between nocturia and serum metabolites identified using metabolomics analysis. This study enrolled 66 men aged 65–80 years, recruited from the outpatient department of a university hospital. The participants were stratified as follows: Nocturia group [45 men with any total international prostate symptom score (IPSS) and an average of 3 nights ≥ 1.5 micturitions/night] and Control group (21 men with total IPSS

Introduction Endoscopic surgical treatment represents the gold standard in patients with lower urinary tract symptoms (LUTS) when medical treatment fails. In the past years there has been a growing interest in intraprostatic injections which represent a minimally invasive alternative for those patients not suitable for surgery. Aim of our study is to systematically review all the available data on intraprostatic injections for the treatment of LUTS patients with benign prostatic enlargement (BPE). Evidence acquisition A systematic review of the literature using the Medline, Scopus and Web of Science databases for relevant articles published until June 2018 was performed using both the Medical Subjects Heading and free test protocols. The MeSH search was conducted by combining the following terms: "Intraprostatic Injections," "Botulinum Toxin A," "Onabotulinum," "Ethanol," "Lower Urinary tract Symptoms," "Benign prostatic enlargement," "Benign Prostatic Hyperplasia," "NX1207," "PRX302." Each article's title and abstract were reviewed for their appropriateness and their relevance with regards to the relationship to intraprostatic injections. Evidence synthesis Intraprostatic injections for the treatment of LUTS/BPE patients may be performed using different products as: ethanol, onabotulinum toxin A, NX1207 and PRX 302. Ethanol, the first agent for intraprostatic use, showed promising results in prospective trials, however, the rare but serious adverse events associated with extraprostatic diffusion of ethanol stopped its use. Many studies on onabotulinum toxin A (BotoxR) have been performed, however, two large randomized clinical trials showed no differences in terms of symptoms improvements and flow improvements when compared to placebo. Two new promising drugs NX 1207 and PRX 302 have been developped in the past years. NX 1207 showed lack of efficacy in the two large European phase III RCT. PRX 302 showed promising results in phase I and II studies, however, definitive results from a large phase III randomized controlled trial (RCT) are awaited before drawing any definitive conclusions. Conclusions Intraprostatic injections are still to be considered investigational for the minimally invasive management of LUTS/BPE patients. Emerging data suggest a possible role of new agents in the near future when definitive data of ongoing RCTs will be available.

Introduction Tramadol exhibits an effect profile similar to that of opioid agonists, and tramadol abuse seems to be a problem for a number of countries. The relationship between tramadol and sexual function appears to be controversial. Men with premature ejaculation (PE) may benefit from taking tramadol off label; however, these patients live “on a knife's edge” and are exquisitely sensitive to develop other sexual dysfunctions. Aim To review the literature regarding the problem of tramadol abuse and its relationship with sexual function. Methods We searched electronic databases from 1977 to September 2015, including PubMed MEDLINE, EMBASE, EBCSO Academic Search Complete, Cochrane Systematic Reviews Database, and GoogleScholar using the following key words: tramadol, sexual functions, and sexual dysfunction. Main Outcome Measure To define the supposed benefits and the potential risks of tramadol on different sexual functions including ejaculation, orgasm, erection, desire, and testosterone levels. Results Although tramadol is thought to have low abuse and dependence potentials worldwide, its abuse has become a serious problem in many countries, particularly in the Middle East, Africa, and West Asia. The benefit of tramadol in PE was reported in 11 clinical trials, evaluated by 6 systematic reviews, 3 of which pooled data in a meta-analysis. The evidence base on erectile dysfunction, decreased libido, hypogonadism, anorgasmia, and risky sexual behaviors in patients abusing tramadol is inadequate. Conclusions Tramadol may offer a useful intervention for treating PE. As all primary studies had suffered from selection, allocation, performance, or assessment bias, additional rigorous well-designed controlled trials are warranted to further investigate the potential long-term risks of tramadol and to determine the safe and the effective minimum daily dose. Clinical research on drug abuse and sexual dysfunction is an emerging field. To date, small numbers of studies have been performed and further studies are warranted.

Aims The pathophysiologies of nocturia (NOC) and nocturnal polyuria (NP) are multifactorial and their etiologies remain unclear in a large number of patients. Clock genes exist in most cells and organs, and the products of Clock regulate circadian rhythms as representative clock genes. Clock genes regulate lower urinary tract function, and a newly suggested concept is that abnormalities in clock genes cause lower urinary tract symptoms. In the present study, we investigated the voiding behavior of Clock mutant (ClockΔ19/Δ19) mice in order to determine the effects of clock genes on NOC/NP. Methods Male C57BL/6 mice aged 8–12 weeks (WT) and male C57BL/6 ClockΔ19/Δ19 mice aged 8 weeks were used. They were bred under 12 hr light/dark conditions for 2 weeks and voiding behavior was investigated by measuring water intake volume, urine volume, urine volume/void, and voiding frequency in metabolic cages in the dark and light periods. Results No significant differences were observed in behavior patterns between ClockΔ19/Δ19 and WT mice. ClockΔ19/Δ19 mice showed greater voiding frequencies and urine volumes during the sleep phase than WT mice. The diurnal change in urine volume/void between the dark and light periods in WT mice was absent in ClockΔ19/Δ19 mice. Additionally, functional bladder capacity was significantly lower in ClockΔ19/Δ19 mice than in WT mice. Conclusions We demonstrated that ClockΔ19/Δ19 mice showed the phenotype of NOC/NP. The ClockΔ19/Δ19 mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. © 2016 Wiley Periodicals, Inc.

This article describes a number of changes in lower urinary tract (LUT) function that occurs in the aging population as well as in animal models. Age-related LUT dysfunctions result from complex processes controlled by multiple genetic, epigenetic and environmental factors and accounts for high costs of healthcare. While the underlying factors that contribute to patient symptoms are not known, this article will discuss a number of risk factors that may play a role in age- related LUT dysfunction. In addition, while limited data is available using animal models of aging, there is evidence that many of the structural and functional changes observed in these studies appear to be similar to those observed in humans. A better understanding of factors and mechanisms underlying LUTS in the older population may lead to therapeutic interventions which may be used to reduce these dysfunctions.

Objective Persistent urinary incontinence (UI) and/or erectile dysfunction (ED) occur in 30-50% of post-radical prostatectomy patients regardless of nerve sparing approaches. Identification of potential treatment options for these patients will require testing in an animal model that develops these chronic conditions. The objective was to characterize a nonhuman primate (NHP) model of persistent post-prostatectomy ED and UI and then test the feasibility of periurethral injection of the chemokine CXCL-12. Methods Ten adult male cynomolgus monkeys were used. Two were used for study of normal male nonhuman primate genitourinary anatomy. Five were used for measures of sexual behavior, peak intra-corporal pressure (ICP), abdominal leak point pressures (ALPP) 3 and 6-months post open radical prostatectomy (ORP). Three additional ORP animals received ultrasound-guided peri-urethral injection of chemokine CXCL12 6 weeks after ORP, and UI/ED evaluated for up to 3 months. Results The anatomy, innervation, and vascular supply to the prostate and surrounding tissues of these male NHPs are substantially similar to those of human beings. ORP resulted in complete removal of the prostate gland along with both neurovascular bundles and seminal vesicles while permitting stable restoration of vesico-urethral patency. ORP produced sustained (6 months) decreases in ALPP, ICP's, and sexual function. Transurethral injection of chemokine CXCL12 was feasible and had beneficial effects on erectile and urinary function. Conclusions ORP in NHPs produced persistent erectile and urinary tract dysfunction. Periurethral injection of CXCL-12 was feasible and improved both urinary incontinence and erectile dysfunction and suggests that this model can be used to test new approaches for both conditions.

Aims. Most benign bladder pathologies are associated with an increase of extracellular matrix (ECM – fibrosis) and may progress from formation of stiffer matrix to a more compliant structure. The aims were to summarise current knowledge of the origins of bladder fibrosis and consequences in bladder function. Methods. A meeting at the International Consultation on Incontinence Research Society 2017 congress discussed the above aims and considered paradigms to reduce the extent of fibrosis. Discussants based their arguments on the basis of their own expertise, supplemented by review of the literature through PubMed. Proposals for future work were derived from the discussionResults. Altered urodynamic compliance when ECM deposition is increased is mirrored by changes in the elastic modulus of isolated tissue, whether compliance is decreased or increased. No changes to compliance or fibrosis have been reported after botulinum toxin injections. Several paracrine and autocrine agents increase ECM deposition, the role of TGF-β was particularly emphasised. None of these agents has a net long-term effect on detrusor contractility and the reduction of contractile performance with increased ECM is due solely to a loss of detrusor mass. Several strategies to reduce fibrosis were described, ranging from potential therapeutic roles for vitamin-D or endostatin, manipulation of intracellular pathways that mediate myofibroblast differentiation and the potential role of the anti-fibrotic hormone relaxin. An understanding of epigenetic regulation of ECM deposition was also considered.Conclusions. The conclusion that reduced bladder contractile function with increased fibrosis is due largely to the replacement of detrusor with ECM offers a way forward for future research to consider approaches that will restore bladder function by reducing ECM deposition.

Urgency is the prevalent and most bothersome symptom of overactive bladder (OAB) and the treatment of urgency is the primary objective in the management of OAB. Urgency has a major impact on other symptoms of OAB and culminates in an increased frequency of micturition and reduced volume voided, which may contribute to shorter intervals between the need to void. Antimuscarinic agents and mirabegron, a β3-adrenoceptor agonist, constitute the main oral pharmacotherapeutic options for the treatment of urgency and other OAB symptoms. The reduction of urgency and other OAB symptoms significantly improve health-related quality of life. This review will explore the distinct mechanisms of action and effects of antimuscarinic agents and mirabegron, in relation to their effect on the pathophysiology of urgency. The review will also provide an overview of the various validated measurements of urgency and the numerous clinical trials regarding antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin. A narrative review of the literature relating to pathophysiology of urgency, the validated measurements of urgency, and clinical trials relating to the pharmacological treatment of urgency. Antimuscarinic agent monotherapy, mirabegron monotherapy, or combination treatment with mirabegron added on to the antimuscarinic agent solifenacin statistically significantly reduce the symptoms of urgency compared with placebo. Combination therapy with mirabegron added on to solifenacin also statistically significantly reduces the symptoms of severe urgency compared with antimuscarinic agent monotherapy. A critique of the clinical benefits of combination therapy is also provided. Combination therapy provides an alternative treatment in patients with OAB that includes urgency who respond poorly to first-line monotherapy and who may otherwise often move on to more invasive treatments.

Aims: Update on some molecular targets for new drugs to improve lower urinary tract (LUT) dysfunction. Methods: Using PubMed, a search for literature on molecular targets in the LUT was performed to identify relevant clinical and animal studies. Keywords were entered as Medical Subject Headings (MeSH) or as text words. The Mesh terms were used in various combinations and usually included the terms lower urinary AND pharmacology. Other Mesh term included: bladder, urethra, CNS, physiology, afferent activity, ATP, prostanoids, cannabinoids, fibrosis. Search results were assessed for their overall relevance to this review. Results: In a normal bladder, ATP contributes little to detrusor contraction, but in a diseased bladder ATP may contribute to OAB. Selective decrease of ATP release via adenosine A1 receptor stimulation offers a potential treatment possibility. Candidates for relaxation of the smooth muscle of the urethra can be found among, for example, the receptor subtypes of PGE2, and PGD2. Drugs for relaxation of the striated sphincter can target the muscle directly or the spinal sphincter control. Fibrosis is a major problem in LUT dysfunction and agents with an inhibitory effect on the TGFβ pathway, for example relaxin and BMP7, may be promising avenues. Available drugs with a CNS site of action are often limited by low efficacy or adverse effects. Inhibitors of the glycine receptor Gly-T2 or antagonists of the adenosine A2 receptor may be new alternatives. Conclusion: New molecular targets for drugs aiming at improvement of voiding function can be identified, but their translational impact remains to be established.

Oxidative stress is considered to reflect an imbalance between the systemic manifestation of reactive oxygen and nitrogen species (RONS) and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. RONS are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. They are normally generated as by-products of oxygen metabolism; however, environmental stressors (i.e., UV, ionizing radiations, pollutants, heavy metal, and xenobiotics) contribute to greatly increase RONS production. Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, but so far, none has been approved for any indication because they have not met the criteria of efficacy for drug approval. The present review discusses the concept of oxidative stress, how to measure it, how to prevent it, and its occurrence in different organ systems with special reference to the lower urinary tract. This article is protected by copyright. All rights reserved.

PURPOSE OF REVIEW: To assess current pharmacological principles used for treatment of nocturia/nocturnal polyuria.RECENT FINDINGS: The pathophysiology of nocturia is often multifactorial, but two main mechanisms have been identified, occurring alone or in combination: low functional bladder capacity and nocturnal polyuria. The multifactorial pathophysiology not only implies several possible targets for therapeutic intervention but also means that it is unlikely that one treatment modality including drugs will be successful in all patients. Drugs approved for the treatment of male LUTS and male and female OAB are known to be far more effective for treatment of the daytime symptoms than for nocturia. Several pharmacological principles have been tested with varying success. The treatment of choice should depend upon the main underlying cause, thus aiming primarily to increase bladder capacity by counteracting detrusor overactivity and/or reducing nocturnal polyuria. Using current available agents, effective, personalized treatment should be designed taking into account gender, co-morbidities, and identified etiological factors. However, there is a medical need for new, approved drugs for treatments for patients with nocturia.

The 6th International Consultation on Incontinence met between September 13-15th 2016 in Tokyo and was organised by the International Consultation on Urological Diseases and the International Continence Society (ICS), in order to develop consensus statements and recommendations for the diagnosis, evaluation and treatment of urinary incontinence, faecal incontinence, pelvic organ prolapse and bladder pain syndrome.The consensus statements are evidence based following a thorough review of the available literature and the global subjective opinion of recognised experts serving on focused committees. The individual committee reports were developed and peer reviewed by open presentation and comment. The Scientific Committee, consisting of the Chairs of all the committees then refined the final consensus statements. These consensus statements published in 2017 will be periodically reevaluated in the light of clinical experience, technological progressand research.

Chronic pelvic pain (CPP) is a common condition involving multiple, organ-specific medical specialties, each with its own approach to diagnosis and treatment. Management requires knowledge of the interplay between pelvic organ function and neuro-functional anatomy, and of the neurologic and psychological aspects of CPP, but no current specialty fully encompasses this approach. Neuropelveology is an emerging discipline focusing on pathologies of the pelvic nervous system on a cross-disciplinary basis. It involves a neurological/neurosurgical approach, combining the knowledge required for a proper neurologic diagnosis, confirmation by transvaginal/transrectal examination of the pelvic nerves, and advanced laparoscopic surgery in selected cases of CPP. The management of CPP requires multidisciplinary contributions, and neuropelveology may offer an educational framework for the interdisciplinary exchange of knowledge between clinical physicians and basic researchers.

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains elusive and may involve multiple causes. To better understand its pathophysiology, many efforts have been made to create IC/BPS models. Most existing models of IC/BPS strive to recreate bladder-related features by applying noxious intravesical or systemic stimuli to healthy animals. These models are useful to help understand various mechanisms; however, they are limited to demonstrating how the bladder and nervous system respond to noxious stimuli, and are not representative of the complex interactions and pathophysiology of IC/BPS. To study the various factors that may be relevant for IC/BPS, at least 3 different types of animal models are commonly used: (1) bladder-centric models, (2) models with complex mechanisms, and (3) psychological and physical stressors/natural disease models. It is obvious that all aspects of the human disease cannot be mimicked by a single model. It may be the case that several models, each contributing to a piece of the puzzle, are required to recreate a reasonable picture of the pathophysiology and time course of the disease(s) diagnosed as IC/BPS, and thus to identify reasonable targets for treatment.

Objectives To examine the effects of the serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) on micturition in rats with diabetes mellitus (DM). Methods Female Sprague–Dawley rats (n = 16) were divided into two groups: rats with Type 1 DM and age-matched control rats. DM was induced by i.p. injection of streptozotocin (65 mg/kg) and detailed cystometrogram (CMG) studies were performed 8 weeks post-injection in all rats under urethane anaesthesia. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose–response curve was plotted. All drugs were administered i.v. Results Compared with controls, comprehensive urodynamic studies showed that DM rats had a higher bladder capacity and post-void residual urine volume (PVR), and a markedly lower voiding efficiency. In DM rats, DOI (0.01–0.3 mg/kg) induced significant dose-dependent increases in micturition volume and reductions in PVR, resulting in greater voiding efficiency. CMG measurements showed a dose-dependent increase in high-frequency oscillation (HFO) activity, evidenced by an increased duration of HFOs per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI-induced changes. Conclusions The HFOs observed in the present study seem to correlate with external urethral sphincter bursting activity during voiding. Bladder voiding efficiency was reduced in DM rats. The 5-HT2A receptor agonist can enhance HFO activity and improves voiding efficiency, and so may represent a new strategy to improve voiding efficiency after DM in experimental studies.

Purpose of review The purpose of this study is to review and discuss recently published (2013-2014) experimental and clinical studies of intraprostatic injection therapy as an alternative treatment of lower urinary tract symptoms (LUTS). Recent findings Recent focus has been on intraprostatic injection of botulinum toxin both with regard to mechanism of action and efficacy. In contrast to the promising findings in several previous studies, a recent large, randomized, placebo-controlled trial found no differences between onabotulinumtoxin A treatment and placebo. There is little new information on the use of anhydrous ethanol and agents such as NX-1207 and PRX302, which previously have been reported to have promising effects. Summary Intraprostatic injection of different agents as a minimally invasive surgical therapy for LUTS associated with benign prostatic hyperplasia seems attractive and may have a potential as a treatment alternative, but so far, available results are not convincing. Further studies on the mechanisms of action of novel agents, and controlled clinical trials documenting their efficacy and side-effects when injected into the prostate are needed before their place in the treatment of benign prostatic hyperplasia/LUTS can be properly assessed.

The incidence of lower urinary tract symptoms, including overactive bladder (OAB), is continuing to rise, and is associated with a negative impact on quality of life and a heavy economic burden. A major risk factor for OAB is advancing age. The etiology of OAB is multifactorial and appears to involve myogenic, neurogenic, and urotheliogenic factors. In this article, we review the strengthening preclinical evidence supporting the contribution of chronic pelvic ischemia to the pathogenesis of OAB. In animal models, chronic ischemia induced by arterial injury and a high-fat diet upregulates markers of oxidative stress and proinflammatory cytokines in the urothelium and lamina propria, and leads to increased expression of nerve growth factor. These processes result in increased afferent activity and an increased frequency of micturition, reflecting a state of bladder hyperactivity. In severe, prolonged cases, bladder overactivity may develop into underactivity. Antimuscarinic therapies are the mainstay of OAB treatment, but their usefulness is limited by modest efficacy and troublesome side-effects. Our increasing understanding of the contribution of chronic ischemia to OAB is leading toward novel therapeutic options targeting chronic pelvic ischemia and its morphological, functional, and oxidative consequences. Preclinical trials have demonstrated encouraging results with α1 -adrenoreceptor blockade, phosphodiesterase type 5 inhibition, β3 -adrenoreceptor agonism, free radical scavenging, and stem cell therapy, in preventing morphological, biochemical and functional changes induced by chronic bladder ischemia.

Purpose of review To summarize recent data on the medical treatment of men with incontinence due to overactive bladder or to stress urinary incontinence published in peer-reviewed journals. Recent findings Previous randomized controlled trials have shown that both antimuscarinic drugs and α1-adrenoceptor blockers can be useful for treatment of male lower urinary tract symptoms, including the overactive bladder syndrome, and that combination of the two principles may offer additional benefits over monotherapy with either agent. This has been further confirmed in several recent studies. There seems to be an associated increase in postvoid residual urine volume by the combinations, but not a significantly increased risk of retention. The efficacy of other combinations, for example, α1-adrenoceptor blocker and 5α-reductase inhibitor, has also been further documented. Recent evidence supports the use of mirabegron, alone or in combination with solifenacin, as a treatment alternative of male overactive bladder syndrome. Monotherapy with phosphodiesterase 5 inhibitors seems to be as effective as α1-adrenoceptor blockers in male lower urinary tract symptoms. Only a few recent studies have been performed on the pharmacological treatment of male stress urinary incontinence, confirming that duloxetine had a modest positive effect in men with postprostatectomy incontinence. Summary For treatment of storage symptoms in men with lower urinary tract symptoms, combinations of antimuscarinics and α1-adrenoceptor blockers have produced the most promising results. Duloxetine exerts only modest relief of male stress urinary incontinence, but may be recommended in some patients.

Chronic bladder ischemia is potentially a common cause of lower urinary tract symptoms in the elderly. Epidemiological studies have shown a close association between lower urinary tract symptoms and vascular risk factors for atherosclerosis, and investigations using transrectal color Doppler ultrasonography have shown a negative correlation between decreased lower urinary tract perfusion and International Prostate Symptom Score in elderly patients with lower urinary tract symptoms. Bladder blood flow is also known to decrease in men with bladder outlet obstruction as a result of benign prostatic hyperplasia. Studies in animal models suggest that chronic bladder ischemia and repeated ischemia/reperfusion during a micturition cycle might produce oxidative stress, leading to denervation of the bladder and the expression of tissue-damaging molecules in the bladder wall, which could be responsible for the development of bladder hyperactivity progressing to bladder underactivity. The effects of drugs with different mechanisms of action; for example, α1-adrenoceptor antagonists, phosphodiesterase type 5 inhibitors, free radical scavengers and β3-adrenoceptor agonist, have been studied in animal models of chronic bladder ischemia. The drugs, representing different treatment principles for increasing blood flow and decreasing oxidative stress, showed protective effects not only on urodynamic parameters, but also on negative effects on muscle contractility and on detrimental structural bladder wall changes. Improvement of lower urinary tract perfusion and control of oxidative stress can be considered new therapeutic strategies for treatment of bladder dysfunction induced by chronic ischemia.

BACKGROUND The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. METHODS Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. RESULTS Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. CONCLUSIONS In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be prevented by treatment with the PDE5 inhibitor, tadalafil, suggesting an involvement of cyclic guanosine monophosphate (cGMP). Prostate 75:233–241, 2015. © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

We investigated the characteristics of bladder mechanosensitive single-unit afferent activities (SAAs) in rats with a bladder outlet obstruction (BOO) and their relationship with bladder microcontractions. Male Wistar rats were divided into Sham and BOO groups. Four or 10 days after the surgery, rats were anesthetized with urethane. The SAAs of Aδ- or C-fibers from the L6 dorsal roots were recorded during bladder filling. The BOO group showed a higher number of microcontractions and lower SAAs of Aδ-fibers compared with those of the Sham group. These findings were significant at day 10 post-operatively. In contrast, SAAs of C-fibers were not significantly different between the groups at either day 4 or 10. In the BOO group at day 10, the SAAs of both Aδ- and C-fibers at the “ascending” phase of microcontractions were significantly higher than those at the other phases (descending or stationary), and a similar tendency was also observed at day 4. Taken together, during bladder filling, the bladder mechanosensitive SAAs of Aδ-fibers were attenuated, but SAAs of both Aδ- and C-fibers were intermittently enhanced by propagation of microcontractions.

Toll-like receptor 7 (TLR7) is associated with the pathophysiology of systemic lupus erythematosus and Sjo "gren syndrome, wellknown diseases accompanying interstitial cystitis (IC). We studied TLR7 expression in the bladder of patients with Hunner-type IC (HIC) and its functional roles in bladder inflammation and nociception using mice. Bladder biopsy specimens were obtained from patients with HIC. Specimens from the noncancerous portion of the bladder of patients with bladder cancer served as controls. The specimens were examined by immunohistochemistry and real-time polymerase chain reaction of TLR7. Loxoribine (LX), a TLR7 agonist, was instilled in the bladder of C57BL/6N female mice, and TLR7-mRNA expression and histological changes of the bladder, bladder pain-like licking behavior, voiding behavior, cystometry, and bladder afferent nerve activities were investigated. The effects of hydroxychloroquine, a TLR7 antagonist, on the LX-induced changes on cystometry and voiding behavior were studied. The number of TLR7 immuno-reactive cells and the mRNA expression of TLR7 were significantly increased in HIC specimens. Intravesical instillation of LX induced edema, congestion, inflammation, and significantly increased TLR7-mRNA expression in the mouse bladder. Loxoribine-instillation also significantly increased licking behavior, voiding frequency, and afferent nerve activities associated with decreased single-voided volume and intercontraction interval of micturitions. Hydroxychloroquine reversed the LXinduced cystometric and voiding behavioral changes. Toll-like receptor 7 was up-regulated in the bladder mucosa of patients with HIC, and activation of TLR7 in the mouse bladder induced cystitis with sensory hyperactivity of the bladder. Blocking the TLR7 pathway may be an innovative treatment target of HIC.

The selective blockade of α1-adrenoceptors (ARs) is now a well-accepted and widely used treatment for patients presenting with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and bladder outlet obstruction. The sites of action of the currently used α1-AR antagonists when relieving LUTS have not yet been established, but it seems clear that effects on prostatic as well as non-prostatic tissues are important. α1-ARs in the bladder, urethra, and vas deferens, on ganglia and nerve terminals, and in the central nervous system (CNS) may all influence LUTS and the clinical effects of α1-AR antagonists. The relevance of α1-AR subtype selectivity for the clinical usefulness of existing drug therapy has still not been clarified, but it cannot be dismissed that blockading both α1A- and α1D-ARs is necessary for optimal clinical effect. Despite the above uncertainties, there seems to be a consensus that clinically available α1-AR antagonists provide a safe, effective and generally well-tolerated therapy for patients with LUTS.

The clinical success of mirabegron as the first a3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of a3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of a3-AR stimulation have still not been established. The recent demonstration of a3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that a3-ARs can be found these structures. However, recent studies suggest that the a3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that a3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.