Search

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.

Background: Cell therapy for intrinsic urinary sphincter deficiency (ISD) in women has been moderately effective, and improvements are needed. To improve treatment efficacy, it is important to better understand determinates of cell efficacy in the different patient cohorts. We have reported that in nonhuman primates the chronicity of ISD may affect cell efficacy, but additional factors (age, psychosocial stress, hormone status, body weight) can be associated with many disease/treatment outcomes in women -and these factors are the focus of this study.Methods: Adult female cynomolgus monkeys were divided into groups: (1) younger (n = 10, 5-8 years of age) versus older (n = 10, 13-18 years of age); (2) age-matched/socially subordinate (n = 15) versus socially dominant (n = 15); and (3) age-matched lower body weight (n = 6) versus higher body weight (n = 6). Autologous skeletal muscle precursor cells (skMPCs, 5 million) were injected into the urinary sphincter 6 weeks after a surgically induced ISD procedure. Resting and pudendal nerve-stimulated maximal urethral pressures (MUP) were measured before, and 3 and 6 months post-skMPC treatment and urinary sphincter muscle/collagen content within the sphincter complex was measured by quantitative histology 6 months posttreatment.Results: Efficacy of skMPCs on MUP and sphincter muscle/collagen ratios are affected by age (average 40% reduction in efficacy, p Conclusion: Multiple factors (age, stress-induced dysmenorrhea, and body weight) affect the efficacy of cell therapy to restore structure and function in the urinary sphincter complex in NHPs with ISD. Consideration of, and alternatives for, these patient cohorts should be considered.

During the last 30 years, a number of treatments and management algorithms have been developed and applied in the treatment of patients with Interstitial Cystitis/Bladder Painful Syndrome (IC/BPS), and many behavioral, dietary, interventional, pharmacologic and surgical therapies have been developed in the attempt to control the disease and to offer substantial benefits to the affected patients. Nevertheless, the complexity of the disease in terms of aetiology and pathogenesis still has made it difficult to induce significant and long-lasting benefits for any kind of these treatments. In addition, few well designed, randomised controlled trials have been conducted until now on different treatment modalities, and this still precludes the development of evidence-based management strategies. Indeed, the majority of pharmacological agents used to treat patients with IC/BPS are still off label. In this respect, the Interstitial Cystitis Data Base study noted >180 treatment modalities for IC/BPS, with poor results in the majority of cases [1]. To date, there is general agreement on the use of some agents, orally or intravesically administered, as indicated by the EAU guidelines on chronic pelvic pain [2] and the AUA Guidelines for the Diagnosis and Treatment of Interstitial Cystitis/ Bladder Pain Syndrome [3].

Context Lower urinary tract symptoms (LUTSs) and erectile dysfunction (ED) are substantial health concerns with a significant impact on the overall male quality of life. Objective To evaluate the available evidence of the association between LUTSs and ED in patients with benign prostatic hyperplasia (BPH), and discuss possible clinical implications for the management of LUTS/BPH. Evidence acquisition A systematic review of the existing literature published between 1997 and June 2017 and available in the Medline, Scopus, and Web of Science databases was conducted using both the Medical Subject Heading (MeSH) and free-text protocols. The MeSH search was conducted by combining the following terms: "lower urinary tract symptoms," "LUTS," "benign prostatic hyperplasia," "BPH," "erectile dysfunction," "sexual dysfunction," "BPE," and "benign prostatic enlargement." The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. Evidence synthesis Several community-based studies in different geographical areas have provided strong evidence of an age-independent association between LUTSs and ED. Several biological mechanisms have been proposed to explain this association, but further research is required to better understand the molecular pathways involved. It is necessary to evaluate the possible impact of the metabolic syndrome treatment on LUTS/ED management. Considering the possible relationship between LUTSs and ED, their impact on the quality of life, and the possible adverse effects associated with LUTS medical treatment, clinicians should always evaluate ED in patients with LUTSs and take the opportunity to evaluate patients reporting ED for LUTSs. Conclusions Data from the peer-reviewed literature suggest the existence of an association between LUTS/BPH and ED, although their casual relationship has not been established yet. Emerging data also suggest that pathophysiological mechanisms involved in the metabolic syndrome are key factors in both disorders. Considering the association, it is also recommended that men presenting with LUTSs or ED should be evaluated for both disorders. A better understanding of the molecular pathways behind this association may also help identify new possible targets and develop novel therapeutic approaches to manage LUTSs and ED. Patient summary In this manuscript, we report on all the available evidence linking erectile dysfunction and lower urinary tract symptoms. Our findings suggest the existence of a strong relationship between these two conditions. On the basis of these findings, we recommend that clinicians always explore both conditions in male patients presenting with either of symptoms.

Aims To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO). Methods Fifty-six male Sprague–Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization. Results Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P

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.

The objectives of this study were to examine the expression of various cellular proteins within the urothelium (UT) and lamina propria (LP) following chronic bladder ischemia in the rat urinary bladder.Urinary bladders were removed from adult Sprague-Dawley rats 8 weeks after creation of bladder ischemia and from sham controls. Immunocytochemistry was used to examine distribution of LP-vimentin-immunoreactive (IR) cells and connexins (Cx26; Cx43), and western immunoblotting or ELISA for proteins involved in UT barrier and sensory functions.Ischemia was associated with a significant increase in LP-vimentin-IR cells and increased expression of the gap junction proteins Cx26 and Cx43 within the bladder UT as compared to sham control. Ischemia also resulted in an increased (p 0.05) expression level of the junctional marker (ZO-1) and non-significantly increased expressions of the trophic factor nerve growth factor as well as norepinephrine.Our findings reveal that chronic ischemia alters a number of proteins within the UT and underlying LP. These proteins are involved in barrier function, remodeling, repair as well as intercellular communication. The increased expression of LP-vimentin-IR cells suggests that changes in cell-cell interactions could play a role in ischemia-induced changes in bladder activity.

Nocturia, awaking from sleep to void, has a negative impact on health and well-being. Nocturia affects men and women and is more prevalent among the elderly. More than two nocturnal voids is considered to be a clinically meaningful threshold associated with significant negative outcomes for health and well-being, and the timing of awakening has a significant bearing on the negative consequences of nocturia. Several serious underlying pathophysiologic conditions may be associated with nocturia. A thorough history and assessment of number and times of voids, void volume, and fluid intake is essential for determining the etiology of a patient's nocturia. With data obtained from the frequency-volume chart (FVC), which is used to collect quantitative voiding data, a patient's nocturia may be classified as global polyuria, nocturnal polyuria, reduced bladder capacity, or a combination of these categories. Global polyuria is defined as 24-hr urinary output that exceeds 40 ml/kg body weight and results in increased 24-hr urinary frequency. Nocturnal polyuria is defined as more than 20% of daily urine output at night in young patients and more than 33% in elderly patients. Reduced bladder capacity may be a result of idiopathic or neurogenic detrusor overactivity, bladder outlet obstruction, or reduced nocturnal bladder capacity. The pathophysiology underlying the findings of the FVC falls into five main categories: global polyuria, nocturnal polyuria, reduced bladder capacity, sleep disorders, and circadian clock disorders. This review discusses the epidemiology, etiology, and pathophysiology of nocturia.

Cellular therapy induced transient urodynamic improvement in a rat model of Parkinson disease in which bladder dysfunction was noted after unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. We sought to prolong the effect by injecting allogeneic rat bone marrow mesenchymal stromal cells before and after microencapsulation into the substantia nigra pars compacta.Female rats underwent unilateral stereotactic injection of 6-hydroxydopamine in the medial forebrain bundle. Injection was performed in the ipsilateral substantia nigra pars compacta using vehicle alone or vehicle with nonmicroencapsulated or microencapsulated rat bone marrow derived mesenchymal stromal cells. Rats were evaluated by cystometry 7, 14, 28 and 42 days after treatment. Brains were extracted for immunostaining.At 42 days the nonmicroencapsulated group had lower threshold and intermicturition pressure, spontaneous activity and AUC than vehicle treated animals. Rats that received microencapsulated cells had lower threshold pressure at 28 days and lower spontaneous activity at 42 days than vehicle treated rats. Microencapsulated and nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells were noted in the substantia nigra pars compacta up to 42 days after transplantation. At 42 days tyrosine hydroxylase positive neurons were more numerous in the substantia nigra pars compacta of the nonmicroencapsulated group, followed by the microencapsulated and vehicle treated groups.Urodynamic effects of the 6-hydroxydopamine lesion persisted up to 42 days after vehicle injection. Transplantation of nonmicroencapsulated rat bone marrow derived mesenchymal stromal cells improved urodynamic pressure by 42 days after treatment more markedly than microencapsulated cells. This was associated with more tyrosine hydroxylase positive neurons in the treated substantia nigra pars compacta of the nonmicroencapsulated group, suggesting that functional improvement requires a juxtacrine effect.

We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome.This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg).At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea.The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome.

BackgroundIn early fetal life, the bladder is merely a conduit allowing urine to pass through freely into the amniotic cavity. As the striated external urethral sphincter evolves, the bladder acquires its reservoir and voiding functions. We characterized the myogenic and neurogenic contractions of the normal fetal porcine bladder from midterm until close to full-term gestation.MethodsContractile responses were measured in vitro using bladder strips from fetuses at 60 (N=23) and 100 days (N=21) of gestation. Spontaneous activity, and the responses to potassium chloride (KCl) solution, electrical field stimulation (EFS), and receptor activation were recorded. The smooth muscle content was evaluated histologically.ResultsHistological studies revealed that the fractional content of smooth muscle doubled between the two time points, and passive tension was adjusted to take that into account. Spontaneous activity was regular at 60 days, changing toward an irregular pattern at 100 days. Contractile force elicited by KCl and carbachol increased significantly with gestational age, while contractions to the purinergic agonist, α-β-methylene adenosine 5'-triphosphate did not. The responses to EFS were almost completely blocked by atropine.ConclusionSpontaneous myogenic contractions become irregular and contractile responses to muscarinic receptor stimulation increase during gestation, as the bladder reservoir and voiding functions develop.Pediatric Research advance online publication, 4 October 2017; doi:10.1038/pr.2017.181.

This review focuses on the current status of research that utilizes the application of pharmacological sciences to accelerate, optimize and characterize the development, maturation and function of bioengineered and regenerating tissues. These regenerative pharmacologic approaches have been applied to diseases of the urogenital tract, the heart, the brain, the musculoskeletal system and diabetes. Approaches have included the use of growth factors (such as VEGF and chemokines (stromal-derived factor – CXCL12) to mobilize cell to the sights of tissue loss or damage. The promise of this approach is to bypass the lengthy and expensive processes of cell isolation and implant fabrication to stimulate the body to heal itself with its own tissue regenerative pathways.

Background Many factors may influence the efficacy of cell therapy for intrinsic urinary sphincter deficiency (ISD), including the route of administration of the cells and the condition of the sphincter. The goal of this study was to compare local versus intravenous administration of autologous skeletal muscle precursor cells (skMPCs) when administered to nonhuman primates (NHPs) with either acute or chronic ISD. Methods Thirty-two adult female monkeys were divided into eight groups (n = 4/group): (1) control; (2) surgically induced ISD/no treatment; (3) acute ISD (6-week duration)/local vehicle only; (4) acute ISD/local skMPC injection; (5) acute ISD/systemic skMPC; (6) chronic ISD (6-month duration)/local vehicle; (7) chronic ISD/local skMPC; (8) chronic ISD/systemic skMPC. Maximal urethral pressures (MUP) were measured prior to ISD, prior to treatment and at 3 and 6 months following treatment. Quantitative histology was used to measure muscle/collagen content, somatic innervation, and vascularity of the sphincter complexes. Results In NHPs with acute ISD both systemic and local administration of skMPCs increased resting MUP values and sphincter muscle content (p p > 0.05). In NHPs with chronic ISD local skMPC administration had reduced (compared to NHPs with acute ISD) effects on MUP and sphincter muscle values (p p Conclusions Both the chronicity of ISD and the route of cell injection influence the efficacy of cell therapy in monkey models of ISD. This may be related to the relative ability of cells to stimulate vascularization and re-innervation in these different treatment conditions.

Objective To evaluate bladder function in an established cannabinoid type 1 (CB1) receptor knockout (KO) mouse model via organ-bath (in vitro) and urodynamic (cystometric; in vivo) experiments. Materials and Methods In all, 20 8-week-old female wildtype (WT) mice (C57BL/6) and 20 age-matched CB1 KO mice were used. Six mice from each group were used for the organ-bath experiments, where the contractile responses of bladder tissue strips after carbachol exposure (carbachol concentration response curve [CCRC]; myogenic contraction) and during electrical field stimulation (EFS; neurogenic contraction) were assessed. In all, 14 mice per group were used for cystometric experiments without any anaesthesia, in which standard urodynamic variables were assessed 3 days after bladder catheterisation. Results The CCRCs of bladder strips from CB1 KO mice were similar to those of WT mice. However, during EFS the bladder strips from the CB1 KO mice had significantly lower contractile responses than WT preparations, indicating that in CB1 KO mice the neuronal component of bladder contraction was different. In cystometric experiments the CB1 KO mice had a higher micturition frequency (shorter mean [sem] inter-micturition interval of 3.24 [0.29] vs 7.32 [0.5] min), a lower bladder capacity (0.09 [0.01] vs 0.18 [0.01] mL) and micturition volume (0.07 [0.01] vs 0.14 [0.01] mL), a lower bladder compliance (0.007 [0.001] vs 0.02 [0.002] mL/cmH2O), and higher spontaneous bladder activity (5.1 [0.5] vs 2.6 [0.6] cmH2O) than WT mice (all P < 0.05, Student's t-test). In WT mice, systemic administration of rimonabant (SR141716), a CB1 receptor antagonist, resulted in urodynamic changes similar to those seen in the CB1 KO mice. Conclusions In vitro, bladder strips from CB1 KO mice responded to muscarinic receptor stimulation similarly as the WT controls, but were less responsive to electrical stimulation of nerves. In vivo, CB1 KO mice had a higher micturition frequency and more spontaneous activity than WT mice. The present findings suggest that CB1 receptors are involved in peripheral and central nervous control of micturition.

The pathophysiology of lower urinary tract symptoms (LUTS), particularly in the elderly, seems to be multifactorial. One of the factors involved may be chronic ischemia of the bladder caused by bladder outflow obstruction (male) or atherosclerosis (male/female). The mechanisms by which chronic ischemia initiates and causes LUTS and progressive bladder dysfunction, and the time course of the effects, are incompletely known. Bladder ischemia and repeated ischemia/reperfusion during a micturition cycle may produce oxidative stress, leading to denervation of the bladder and the expression of tissue damaging molecules in the bladder wall. This may be responsible for the development of detrusor overactivity progressing to detrusor underactivity and inability to empty the bladder. The extent of bladder dysfunction in chronic bladder ischemia may depend on the degree and duration of ischemia. To prevent chronic bladder ischemia caused by atherosclerosis and to treat its consequences, more pathophysiological knowledge is needed. Several animal models of atherosclerosis-induced chronic bladder ischemia are available and should be useful tools for further research.

We measured the long-term efficacy of autologous muscle precursor cell therapy in premenopausal female nonhuman primates with sustained urinary sphincter deficiency.Urinary sphincter deficiency was created in adult premenopausal female cynomolgus monkeys by selectively cauterizing and then transecting the pudendal innervation to the sphincter complex. The monkeys were then treated (18) or not treated (18) with intra-urinary sphincter injections of 5 million autologous green fluorescent protein labeled skeletal muscle precursor cells. Four untreated, uninjured monkeys served as controls. Maximal urethral pressure measurement and corresponding histological analysis of the structural and cellular components of the sphincter complex were performed up to 12 months after injection.Cell treatment produced sustained (12 months) increases in resting, somatic nerve stimulated and adrenergic nerve stimulated maximal urethral pressure, and a greater percent of sphincter area occupied by muscle as well as a decrease in the sphincter area occupied by collagen compared to the untreated group (each p0.05). These results were within control values (each p0.05). By 3 months after injection green fluorescent protein positive cells were found in the skeletal muscle layer, expressing desmin and connexin-43, and in the smooth muscle layer, expressing α-smooth muscle actin and connexin-43, and they were incorporated into the subendothelial vasculature, expressing Von Willebrand factor. Cell injected sphincter tissue contained a mixture of green fluorescent protein positive cells and predominantly green fluorescent protein negative cells.Injected skeletal muscle progenitor cells incorporated into the injured sphincter complex resulted in long-term structural and functional restoration of the injured sphincter complex in this nonhuman primate model.

Background The pathophysiology of male lower urinary tract symptoms (LUTS) is highly complex and multifactorial. The shift in perception that LUTS are not sex or organ specific has not been followed by significant innovations regarding the available drug classes. Objective To review pathophysiologic mechanisms and clinical and experimental data related to the development of new pharmacologic treatments for male LUTS. Evidence acquisition The PubMed database was used to identify articles describing experimental and clinical studies of pathophysiologic mechanisms contributing to male LUTS and, supported by them, new pharmacotherapies with clinical or experimental evidence in the field. Evidence synthesis Several pathologic processes (eg, androgen signaling, inflammation, and metabolic factors) and targets (eg, the urothelium, prostate, interstitial cells, detrusor, neurotransmitters, neuromodulators, and receptors) have been implicated in male LUTS. Some newly introduced drugs, such as phosphodiesterase type 5 inhibitors and β3-adrenergic agonists, have just started broad use in clinical practice. Drugs with potential benefit, such as vitamin D3 receptor analogs, gonadotropin-releasing hormone antagonists, cannabinoids, and drugs injected into the prostate, have been evaluated in experimental studies and have progressed to clinical trials. However, safety and efficacy data for these drugs are still scarce. Some compounds with interesting profiles have only been tested in experimental settings (eg, transient receptor potential channel blockers, Rho-kinase inhibitors, purinergic receptor blockers, and endothelin-converting enzyme inhibitors). Conclusions New pathophysiologic mechanisms of male LUTS are described that lead to the continuous development of new pharmacotherapies. To date, few drugs have been added to the current armamentarium, and several are in various phases of clinical or experimental investigation.

Purpose: The bladder effects of isoprenaline, and selective β1 and β2-adrenoceptor agonists reported in early studies suggest that bladder β-adrenoceptors are atypical. Since there is a lack of alternatives to antimuscarinics in the treatment of overactive bladder symptoms, there has been an intensive search for new drug targets. Discovery of the β3-adrenoceptor with high expression in the bladder suggested that this receptor, which mediates detrusor relaxation, could be a target for overactive bladder symptoms.Materials and Methods: An overview of the published literature on β-adrenoceptor and the bladder was performed using MEDLINE®. The United States Food and Drug Administration website, clinicaltrials.gov and controlled-trials.com online trial registries were searched for English language articles containing the terms β3-adrenoceptors and β3-adrenoceptor agonists. In addition, abstracts from recent international scientific meetings were searched for randomized, controlled trials of β3-adrenoceptor ago...

Aims To better understand the effects of the selective 5-HT7 receptor agonist 4-[2-(Methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide hydrochloride (LP44) on micturition in spinal cord injury (SCI) rats. Methods Female Sprague-Dawley rats weighing 200–275 g were used. SCI was produced in 8 of the 16 rats by transection at the T10 level; cystometric study occurred 8–12 weeks post-transection. Intravesical pressure was monitored in urethane-anesthetized animals via a transvesical catheter. The selective 5-HT7 antagonist (R)-3-[2-[2-(4-Methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl] phenol hydrochloride (SB-269970) was administered after each LP44 dose–response curve (all drugs were administered intravenously, i.v). Results Compared to controls, SCI rats had a higher bladder capacity and residual volume, and a lower voiding efficiency. In SCI rats, LP44 (0.003–0.3 mg/kg, i.v) induced significant dose-dependent increases in micturition volume, significant dose-dependent decreases in residual volume, resulting in significant increases in voiding efficiency. CMG measurements showed a dose-dependent increase of the high-frequency oscillation (HFO) activity, including the number of small oscillation per voiding. This was correlated with the improved voiding efficiency. SB-269970 (0.1 mg/kg, i.v) partially or completely reversed all LP44-induced changes. Conclusions HFOs seems to be correlated with external urethral sphincter (EUS) bursting activity during voiding. Both the bladder voiding efficiency and the periodic EUS activity were decreased in SCI rats. 5-HT7 receptor agonist can enhance HFO activity, thereby improving voiding efficiency. Whether or not these results may have implications for the future treatment of voiding dysfunction in SCI patients remains to be studied. Neurourol. Urodynam. 33:1165–1170, 2014. © 2013 Wiley Periodicals, Inc.

The bladder mucosa consists of the urothelium, basement membrane, and lamina propria (LP). Although the urothelium has been given much attention, it may be regarded as one part of a signaling system involving another equally important component of the bladder mucosa, namely, the LP. The LP lies between the basement membrane of the mucosa and the detrusor muscle and is composed of an extracellular matrix containing several types of cells, including fibroblasts, adipocytes, interstitial cells, and afferent and efferent nerve endings. In addition, the LP contains a rich vascular network, lymphatic vessels, elastic fibers, and smooth muscle fascicles (muscularis mucosae). The roles of the LP and its components in bladder function have not been definitively established, though it has been suggested to be the capacitance layer of the bladder, determining bladder compliance and enabling adaptive changes to increasing volumes. However, the bladder LP may also serve as a communication center, with an important integrative role in signal transduction to the central nervous system (nociception, mechanosensation). The LP may also, by means of its different components, make it possible for the urothelium to transmit information to other components of the bladder wall, contributing to activation of the detrusor muscle. In addition, the LP may serve as a source for production of factors influencing the growth of both the overlying urothelium and the underlying detrusor muscle.

Aims The contribution of individual CB receptors (CB1R and CB2R) to normal micturition has not been clearly defined. Our goal was to study if differences in urodynamic parameters or in vitro bladder contractility can be demonstrated between CB2R knockout (CB2RKO) and C57BL/6J control (wild type, WT) mice. Methods Female WT and CB2RKO mice underwent bladder catheterization and cystometry was performed after 2 and 3 days. Cystometric evaluations were performed in awake animals without drug administration, and WT were also given HU-308 (CB2R agonist) followed by AM630 (CB2R antagonist). Bladders were removed for in vitro assessment of contractile responses to carbachol and electrical field stimulation (EFS). Results CB2RKO mice had significantly higher intercontraction intervals (ICIs), bladder capacity (BC) and compliance (Bcom) than WT controls (P

The pathophysiology of urinary sphincter deficiency in women remains incompletely understood and current treatment options have limitations. Female nonhuman primates may represent a relevant animal model for studies of pathophysiology and treatment interventions because of their human-like reproductive and age associated stages of life (premenopause, perimenopause and postmenopause), lower urinary tract structure and bipedal posture. We developed and characterized a nonhuman primate model of defined injury to the urethral sphincter complex.We used 22 adult female cynomolgus monkeys in which injury to the sphincter complex was created by cauterizing and then transecting its pudendal innervation. Urodynamic studies were performed before and during pudendal and hypogastric nerve stimulation at baseline, and 3, 6 and 12 months after injury. We also analyzed sphincter structure in vivo by cystourethrography, and ex vivo by quantitative histology and immunohistochemistry at these time points.Injury produced a 47% to 50% decrease in maximal urethral pressure (vs baseline p0.05). It also abolished the increase in maximal urethral pressure in response to pudendal and hypogastric nerve stimulation (vs baseline p0.05), which persisted more than 12 months after injury. Urodynamic changes were consistent with decreased skeletal and smooth muscle content, decreased nerve responses and an associated decrease in somatic and adrenergic innervation in the sphincter complex.These structural and urodynamic changes are consistent with those in patients with stress urinary incontinence. They support the usefulness of nonhuman primates as translatable surrogates for pathophysiological studies of urinary sphincter deficiency and testing novel therapies for that condition.

We examined the effects of the 5-HT2A/2C receptor agonist DOI on micturition in chronic spinal cord injured rats.Female Sprague-Dawley® rats were used. Spinal cord injury was produced by transection at the T10 level. A cystometric study was performed 8 to 12 weeks after transection. Cystometrograms were done using urethane anesthesia in all rats. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose-response curve. All drugs were administered intravenously.Compared to controls, spinal cord injured rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. In spinal cord injured rats DOI (0.01 to 0.3 mg/kg) induced significant dose dependent increases in micturition volume and decreases in residual volume, resulting in increased voiding efficiency. Cystometrogram measurements showed a dose dependent increase in high frequency oscillation activity, evident as an increased number of small oscillation per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI induced changes.High frequency oscillation seems to reflect external urethral sphincter burst activity during voiding. Bladder voiding efficiency and high frequency oscillation activity were decreased in spinal cord injured rats. High frequency oscillation activity can be enhanced by 5-HT2A receptor agonism, improving voiding efficiency. To our knowledge it remains to be studied whether these results may have implications for the future treatment of voiding dysfunction in patients with spinal cord injury.

Phosphodiesterase-5-Inhibitoren (PDE5-Inhibitoren) wie Sildenafil, Tadalafil und Vardenafil sind Therapie der Wahl bei Mannern mit erektiler Dysfunktion (ED). PDE5-Inhibitoren steigern die intrazellulare Konzentration an cGMP uber eine Hemmung der PDE5, woraus eine Relaxation glatter Muskulatur im Schwellkorper entsteht. Dieser Mechanismus wird ebenfalls fur die glatte Muskulatur des unteren Harntraktes angenommen. In randomisierten kontrollierten Studien wurde bei Mannern mit benignem Prostatasyndrom (BPS) eine Verbesserung von Symptomen des unteren Harntraktes (LUTS) gezeigt. Zusatzlich konnte durch Tadalafil, welches vor kurzem fur die Therapie von Patienten mit BPS zugelassen wurde, eine signifikante Verbesserung des maximalen Harnstrahls beobachtet werden.

Aims To describe the morphological and functional consequences for bladder development and function when nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is lacking or reduced. Methods The Bloated Bladder (Blad) mouse, lacking Nmnat2, and heterozygotes were utilized for this investigation. Morphology and development of the bladder were studied using immunohistochemistry against urothelial, smooth muscle, and nerve markers. Functional effects were assessed by organ bath experiments and cystometry. Results Homozygote mutants were malformed and died at birth, whereas heterozygotes survived and morphologically did not differ from wild-type controls. Morphological bladder changes appeared in the Blad mutants as early as embryonic day 15.5 (E15.5) with an extremely distended bladder at E18.5. Staining revealed that all the bladder layers were present and expressed mature markers in all three genotypes. No nerves could be demonstrated by immunohistochemistry in the Blad mutant bladder at E18.5. Organ bath analysis showed that bladders from Blad mutant showed signs of denervation supersensitivity in response to carbachol, and no response to electrical stimulation of nerves at E18.5. Adult heterozygotes, which have a reduced expression of Nmnat2 at E18.5, showed decreased responses to carbachol and electrical stimulation compared to wild-type controls. The latter also retained their ability to empty their bladders, but showed increased micturition pressures compared to controls. Conclusions Complete loss of Nmnat2 leads to a mature but distended bladder in utero and is not compatible with survival. Moderate loss of Nmnat2 has no effect on bladder development, survival, and has only modest effects on bladder function later in life. Neurourol. Urodynam. 32:1130–1136, 2013. © 2013 Wiley Periodicals, Inc.

What's known on the subject? and What does the study add? There are many studies showing melatonin's potent endogenous free radical scavenging and antioxidative properties, which protect against oxidative insult, but there is no information about the effect of chronic treatment with melatonin on oxidative-stress-related bladder dysfunction caused by chronic ischaemia. The model used in this study shows that functional and morphological changes caused by chronic bladder ischaemia and oxidative stress were protected by chronic treatment with melatonin, resulting in improvement of bladder hyperactivity. Objective To investigate the potential therapeutic benefit of melatonin for chronic ischaemia-related bladder dysfunction. Materials and Methods Adult male Sprague–Dawley rats were divided into control, arterial injury (AI), AI with low-dose melatonin treatment (AI-ML) and AI with high-dose melatonin treatment (AI-MH) groups. The AI, AI-ML and AI-MH groups underwent a procedure to induce endothelial injury of the iliac arteries and received a 2% cholesterol diet after AI. The rats in the AI-ML and AI-MH groups were treated with melatonin 2.5 or 20 mg/kg/day orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, urodynamic investigations were performed. Bladder tissues and iliac arteries were processed for pharmacological studies, and for immunohistochemical and histological examination. Results Iliac arteries from AI, AI-ML and AI-MH rats displayed neo-intimal formation and luminal occlusion. In the AI group, the micturition interval was significantly shorter, and bladder capacity and voided volume were lower than in the controls. Contractile responses of bladder strips to KCl, electrical field stimulation and carbachol were significantly lower after AI than in the controls. The AI bladders were found to have a significantly increased collagen ratio, oxidative stress and inducible nitric oxide synthase (NOS) expression, and decreased constitutive NOS expression compared with the controls. In the AI-ML and AI-MH groups, neo-intimal formation was not prevented, but there were beneficial effects on bladder function and morphology. In the AI-ML group, the beneficial effects failed to reach statistical significance. In the AI-MH group, melatonin significantly improved oxidative stress and NOS expression, and there were significant improvements in all the functional and morphological variables compared with the AI group. Conclusions Arterial occlusive disease may lead to chronic bladder ischaemia and bladder hyperactivity associated with oxidative stress. In the model used, chronic treatment with melatonin protected bladder function and morphology, probably through its free radical scavenging and antioxidative properties. Melatonin may prevent oxidative damage and improve ischaemia-related bladder dysfunction.

β(3)-Adrenoceptors are major players in detrusor relaxation and have been suggested as a new putative target for the treatment of overactive bladder syndrome. We determined the effects of mirabegron (YM178), a novel β(3)-adrenoceptor agonist, on carbachol-induced tone in isolated human detrusor preparations from patients with bladder outflow obstruction (BOO) with and without detrusor overactivity (DO), and from patients with normal bladder function. We compared the effects to those of isoprenaline, a non-selective β-adrenoceptor agonist. Detrusor specimens were obtained from patients with benign prostatic hyperplasia undergoing cystoscopy and from patients undergoing radical prostatectomy/cystectomy (in total 33 donors). Detrusor contractility was evaluated by organ bath studies and strips were incubated with carbachol (1μM) to induce and enhance tension. Both mirabegron and isoprenaline reduced carbachol-induced tone in tissues from all groups. Isoprenaline decreased tension with higher potency than mirabegron in normal, BOO and BOO+DO detrusor strips with pIC(50) values of 7.49 ± 0.16 vs. 6.23 ± 0.26 (P=0.0002), 6.89 ± 0.34 vs. 6.04 ± 0.31 (P=0.01), and 6.57 ± 0.20 vs. 5.41 ± 0.08 (P0.05), respectively. Mirabegron and isoprenaline reduced carbachol-induced tone in both normal bladders and obstructed bladder with and without DO. Isoprenaline had higher potency than mirabegron, but the efficacy of mirabegron effect was the same as that of isoprenaline.

The autonomic nervous system plays an important role in the regulation of the urinary bladder function. Under physiological circumstances, noradrenaline, acting mainly on β(3) -adrenoceptors in the detrusor and on α(1) (A) -adrenoceptors in the bladder outflow tract, promotes urine storage, whereas neuronally released acetylcholine acting mainly on M(3) receptors promotes bladder emptying. Under pathophysiological conditions, however, this system may change in several ways. Firstly, there may be plasticity at the levels of innervation and receptor expression and function. Secondly, non-neuronal acetylcholine synthesis and release from the urothelium may occur during the storage phase, leading to a concomitant exposure of detrusor smooth muscle, urothelium and afferent nerves to acetylcholine and noradrenaline. This can cause interactions between the adrenergic and cholinergic system, which have been studied mostly at the post-junctional smooth muscle level until now. The implications of such plasticity are being discussed.

Historically, α(1)-adrenoceptors have been classified into three subtypes (α(1)(A), α(1)(B) and α(1)(D)) that are widely distributed in various organs. Research on the α(1)(D)-adrenoceptors in the bladder, urethra and prostate has focused on the relationship between expression levels and symptoms of bladder outlet obstruction, and the implications and functional roles of α(1)(D)-adrenoceptors subtypes in these organs. The α(1)(D)-adrenoceptor messenger ribonucleic acid and protein seem to be increased in obstructed bladders or small capacity bladders. In contrast, α(1)(D)-adrenoceptor subtype knock-out mice have been found to have a prolonged voiding interval. Interestingly, an α(1)(D)-adrenoceptor antagonist was found to inhibit the facilitation of afferent nerve activity for the micturition reflex induced by intravesical infusion of acetic acid. Clinically, patients who felt urgency at low filling volumes and had a small bladder capacity were found to have more α(1)(D)-adrenoceptor messenger ribonucleic acid in their bladder mucosa than patients who felt urgency at high filling volumes and had a large bladder capacity. An α(1)(D)-adrenoceptor antagonist was found to increase the first desired volume and the maximum desired volume while decreasing detrusor overactivity in pressure flow studies. Thus, α(1)(D)-adrenoceptors in the lower urinary tract might play an important role in the pathophysiology of lower urinary tract disorders.

The overactive bladder syndrome and detrusor overactivity are conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are still first-line treatment. These drugs often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium/suburothelium, the autonomous detrusor muscle activity during bladder filling and the diversity of nerve transmitters involved has sparked interest in both peripheral and central modulation of overactive bladder syndrome/detrusor overactivity pathophysiology. Three drugs recently approved for treatment of overactive bladder syndrome/detrusor overactivity (mirabegron, tadalafil and onabotulinum toxin A), representing different pharmacological mechanisms; that is, β-adrenoceptor agonism, phosphodiesterase type 5 inhibition, and inhibition of nerve release of efferent and afferent transmitters, all seem to have one effect in common: inhibition of the afferent nervous activity generated by the bladder during filling. In the present review, the different mechanisms forming the pharmacological basis for the use of these drugs are discussed.

The currently recommended first-line treatments of erectile dysfunction (ED), phosphodiesterase type 5 inhibitors (PDE5i), for example sildenafil, are efficacious in many patients with ED of vascular origin, but this therapy is insufficient in approximately 30–40% of men with ED where there is also a neuronal affection. There is a demand of novel approaches to treat the condition. We review the possibility of modulating the dopaminergic pathways to improve erectile function. Dopamine D1 (D1, D5)- and D2 (D2–D4)-like receptors in the paraventricular area, the medial pre-optic area, the spinal cord, and in the erectile tissue are involved in erection, and several agonists developed for the treatment of Parkinson's disease are associated with increased libido. A therapeutic window for the treatment of ED was found by sublingual administration of the general dopamine receptor agonist apomorphine, but it failed mainly due to less efficacy on erectile function compared with PDE5i. To avoid the dose-limiting side effects mediated by D2 receptors, nausea and emesis, dopamine D4 receptor agonists were developed, and they induce erection in rodents, but these drugs were never introduced clinically. The β-lactamase inhibitor clavulanic acid increases dopamine and serotonin and was found to increase sexual arousal and erections, but the dose–response curve is bell-shaped. Bupropion has selectivity for inhibition of the dopamine reuptake transporter and can be used to alleviate sexual symptoms caused by other antidepressant medication, hence providing an interesting approach to treat ED. In summary, modulation of the dopaminergic pathways provides a possibility to improve the treatment of ED.

We evaluated aging related bladder dysfunctions and biological changes in the bladder and dorsal root ganglia in rats. We also investigated whether long-term caloric restriction may have preventive effects on these changes.Male Fischer 344 rats were divided into a young group (age 6 months) and an old group (age 25 to 28 months), each with free access to normal food, and an old group (age 25 to 28 months) with food restricted to 3 days per week. Conscious cystometry, cDNA microarray analysis, immunohistochemistry and oxidative stress measurements of the bladder and dorsal root ganglia were performed.The old group with free access to normal food showed higher threshold pressure, more nonvoiding contractions and lower bladder compliance than the young group with free access to food. Old rats with free access showed greater post-void residual volume and lower voiding efficiency than old rats with caloric restriction and young rats. In the old group with free access 83 genes in the bladder and 48 in the L6 dorsal root ganglia were up-regulated compared with old rats with caloric restriction and young rats. These genes were mostly related to immune and inflammatory responses. Immunohistochemistry showed stronger expression of the immune response protease Gzm (granzyme) B and the collagenase Mmp13 (matrix metalloproteinase-13) in the bladder of old rats with free access vs old rats with caloric restriction and young rats. The level of malondialdehyde, an oxidative stress marker, was higher in the bladder of old rats with free access than in young rats but there was no difference between old rats with caloric restriction and young rats with free access to food.In rats aging leads to storage and voiding dysfunctions associated with immune and inflammatory related responses in the bladder and dorsal root ganglia, and with increased oxidative stress in the bladder. Caloric restriction reduced these aging related changes.

Half of the female population over age 50 years will experience pelvic organ prolapse. We suggest a new approach based on tissue engineering principles to functionally reconstruct the anatomical structures of the pelvic floor. The aim of this study is to investigate the mechanical performance and effect on collagen and elastin production of a degradable mesh releasing basic fibroblast growth factor (bFGF). Implantation of biodegradable mesh with or without bFGF in their core has been conducted in 40 rats in an abdominal wall defect model. Samples were explanted after 4, 8, and 24 weeks, and tested for mechanical properties and the composition of connective tissue. The study showed an increase in mRNA expression for collagen-I (p = 0.0060) and collagen-III (p = 0.0086) in the 4 weeks group with bFGF. The difference was equalized at 8 and 24 weeks. No difference was found at any time for protein amount for collagen-I, collagen-III, and fibronectin. The amount of collagen decreased from 4 to 24 weeks but the fraction of collagen increased. The maximal load of the newly formed tissue showed no effect of bFGF at any time. Exclusively, histology showed a limited ingrowth of collagen fibers after 4 weeks with bFGF but signs of elastin fibers were seen at 24 weeks. The investigation showed that a biodegradable mesh promotes tissue formation with a promising strength. The mesh with bFGF did not represent any advantage on either long or short term in comparison to the mesh without bFGF. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 680-688, 2018.

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 (ClockMale C57BL/6 mice aged 8-12 weeks (WT) and male C57BL/6 ClockNo significant differences were observed in behavior patterns between ClockWe demonstrated that Clock

INTRODUCTION AND OBJECTIVES: Melatonin is a powerful antioxidant and a scavenger of free radicals. Recently it is reported that adenosine could be used to downregulate cellular metabolism to achieve prolonged survival under hypoxic conditions. The aim of this study is to evaluate the effect of melatonin and cladribine (adenosine-based purine, pyrimidine nucleoside analogue) on apoptosis and changes its related proteins induced by ischemia/ reperfusion injury in rat bladder. METHODS: One hundred male SpragueDawley rats were divided into 5 groups: control group (sham operation), I/R (ischemia/ reperfusion) group, I/R plus melatonin treated (I/R+M) group, I/R plus cladribine treated (I/R+C) group and I/R plus melatonin and cladribine treated (I/R+M&C) group. Melatonin (10 mg/kg) and cladribine (10 mg/kg) were injected intraperitoneally 3 times/week for 2 weeks after ischemic injury of bladder. On post-op 14th day, tissue samples were obtained by cystectomy. TUNEL assay, mRNA and protein expressions associated with apoptosis were evaluated using RT-PCR and immunoblots. RESULTS: In TUNEL assay, section of group I/R tissue exhibits a significant increase in the number of TUNEL positive cells than the control group. I/R+M&C group showed significant decreased apoptosis than the other groups. I/R+M&C group was more activated cytokine related apoptosis pathway such as Jnk1, P38, Akt1 and Sphk1 than I/R group on mRNA and protein expression. Also expression of Caspase 3 and Sphk1 showed similar patterns between I/R+C and I/R+M&C group on protein expression. Synergy of combined therapy was not proved. But melatonin might directly suppress the expression of HIF-1a, whereas cladribine might increase expression of Sphk1 and consecutively SphK1 suppressed HIF-1a. CONCLUSIONS: These results show that melatonin is one of the most potent protectors against ischemia/ reperfusion injury of bladder and cladribine may have benefits in the treatment of ischemia/ reperfusion injury to the biochemical and histopathologic parameters.

The prevalence of lower urinary tract (LUT) symptoms increases with age but the etiology is unknown. This article aims to identify research directions that clarify the basis of this association. The initial question is whether biological age is the variable of interest or a time-dependent accumulation of factors that impact on LUT function at rates that differ between individuals. In particular, the accumulation of conditions or agents due to inflammatory states or tissue ischemia is important. Much of the above has been concerned with changes to bladder function and morphology. However, the outflow tract function is also affected, in particular changes to the function of external sphincter skeletal muscle and associated sacral motor nerve control. Nocturia is a cardinal symptom of LUT dysfunction and is more prevalent with aging. Urine production is determined by diurnal changes to the production of certain hormones as well as arterial blood pressure and such diurnal rhythms are blunted in subjects with nocturia, but the causal links remain to be elucidated. Changes to the central nervous control of LUT function with age are also increasingly recognized, whether in mid-brain/brainstem regions that directly affect LUT function or in higher centers that determine psycho-social and emotional factors impinging on the LUT. In particular, the linkage between increasing white matter hyperintensities and LUT dysfunction during aging is recognized but not understood. Overall, a more rational approach is being developed to link LUT dysfunction with factors that accumulate with age, however, the precise causal pathways remain to be characterized. Neurourol. Urodynam. 36:854-858, 2017. © 2017 Wiley Periodicals, Inc.

Context Several preclinical reports, randomized controlled trials, systematic reviews, and posthoc analyses corroborate the role of phosphodiesterase type 5 inhibitors (PDE5-Is) in the treatment of men with lower urinary tract symptoms (LUTS) associated with benign prostatic enlargement (BPE). Objective Update of the latest evidence on the mechanisms of action, evaluate the current meta-analyses, and emphasize the results of pooled data analyses of PDE5-Is in LUTS/BPE. Evidence acquisition Literature analysis of basic researches on PDE5-Is, systematic literature search in PubMed and Scopus until May 2015 on reviews of trials on PDE5-Is, and collection of pooled data available on tadalafil 5mg. Evidence synthesis Latest evidences on the pathophysiology of LUTS/BPE has provided the rationale for use of PDE5-Is: (1) improvement of LUT oxygenation, (2) smooth muscle relaxation, (3) negative regulation of proliferation and transdifferentiation of LUT stroma, (4) reduction of bladder afferent nerve activity, and (5) down-regulation of prostate inflammation are the proven mechanisms of action of PDE5-Is. Data from eight systematic reviews demonstrated that PDE5-Is allow to improve LUTS (International Prostate Symptom Score mean difference vs placebo: 2.35–4.21) and erectile function (International Index of Erectile Function mean difference vs placebo: 2.25–5.66), with negligible change in flow rate (Q max mean difference vs placebo: 0.01–1.43). Pooled data analyses revealed that tadalafil 5mg once daily allows the clinically-meaningful improvement of LUTS and nocturnal voiding frequency independent of both erectile dysfunction severity and improvement. Conclusions PDE5-Is are safe and effective in improving both LUTS and erectile function in appropriately selected men with LUTS/BPE. Data on the reduction of disease progression, long-term outcomes, and cost-effectiveness analyses are still lacking. Patient summary We reviewed recent literature on phosphodiesterase type 5 inhibitors in men with lower urinary tract symptoms associated with prostatic enlargement. We found evidence to confirm that phosphodiesterase type 5 inhibitors are a valid treatment option for men affected by bothersome urinary symptoms with or without erectile dysfunction.

Objective The aim of this study was to evaluate if levels of gonadotropic and sex steroidal hormones influence the efficacy of mirabegron in the treatment of overactive bladder. Methods We included 58 female participants who received treatment with mirabegron 50 mg once daily and provided a blood sample for hormone profiling before treatment was initiated. Serum hormone concentrations for estradiol, progesterone, testosterone, FSH, LH, TSH, and T4 were analyzed. Urinary Distress Inventory (UDI), (overactive bladder domain: UDIOAB), and the short form Pelvic Floor Impact Questionnaire (PFIQ-7) were used to assess subjective outcomes. Results There were significant overall improvements in UDI, UDIOAB, and the PFIQ from baseline to the 2 months of follow-up (P = 0.001, 0.001, and 0.008, respectively). The magnitude of the mean difference of improvements was similar between pre- and postmenopausal women. Estrogen levels were nonsignificantly lower in participants who experienced an improvement in UDI and UDIOAB at 2 months of follow-up as compared with those that did not (P = 0.7). There were no other clinically relevant differences in hormone levels in relation to improvements in UDI, UDIOAB, or PFIQ. In logistic regression analysis there were no associations between UDIOAB outcomes and age, previous use of anticholinergic drugs, parity, menopause, and local estrogen treatment. Conclusions Estradiol, gonadotropic hormones, thyroid hormones, and testosterone levels did not influence the clinical effects of mirabegron in women with overactive bladder. Menopause status should not be a determinant for mirabegron treatment.

Aims We determined if transient receptor potential melastatin 8 (TRPM8) channels are involved in the detrusor overactivity induced by menthol, or exposure to low temperature (LT). Methods Two days prior to cystometric investigation, the bladders of 10-week-old Sprague–Dawley rats were cannulated to measure bladder pressure. After a 20 min baseline cystometry period, the TRPM8 channel antagonist, N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC), or vehicle, was administered through a jugular vein catheter (n = 6). A 90% menthol solution was sprayed onto bare leg skin once every 5 min for 20 min, and then cystometric measurements were repeated. After a 30-min recovery period, the rats were intravenously administered 0.1 µmol/kg BCTC. Five minutes later, they were again sprayed and cystometry recorded. In separate experiments, cannulated rats were intravenously administered 0.001, 0.01, or 0.1 µmol/kg BCTC (n = 6 each dose). Five minutes later, they were exposed to LT (4 ± 2°C) for 20 min of cystometry. Results Menthol spray decreased voiding interval, micturition volume, and bladder capacity in the BCTC-free rats. However after BCTC administration, these effects were prevented. Exposure to LT elicited detrusor overactivity that caused decreased voiding interval, micturition volume, and bladder capacity. However, at 0.01 and 0.1 µmol/kg, BCTC inhibited this cold stress-induced detrusor overactivity. Conclusions Since the TRPM8 channel agonist, BCTC, inhibited detrusor overactivity in rats sprayed with the TRPM8 channel agonist, menthol, and the drug also inhibited cold stress-induced detrusor overactivity, we conclude that TRPM8 channels mediate, at least partially, detrusor overactivity elicited by exposure to LT. Neurourol. Urodynam. 32: 500–504, 2013. © 2012 Wiley Periodicals, Inc.

Increased gap junctions contribute to bladder overactivity but the factors and mechanisms involved in gap junction regulation in the bladder are not well established. We examined whether and how platelet derived growth factor regulates connexin43 in bladder smooth muscle cells.Cultured rat bladder smooth muscle cells were treated with growth factors with or without agents that interfere with phosphatidylinositol 3-kinase, mitogen activated protein kinase and β-catenin signaling pathways. Connexin43 expression was examined by Western and Northern blot, and immunochemistry. Functional gap junctions were evaluated by scrape-loading dye transfer assay. Bladder smooth muscle cell contraction was measured by collagen gel contraction.1) Platelet derived growth factor induced phosphatidylinositol 3-kinase and mitogen activated protein kinase dependent accumulation of nuclear β-catenin. This was followed by increased connexin43 expression. 2) Down-regulation of β-catenin by specific siRNA abolished the connexin43 increasing effect of platelet derived growth factor while β-catenin stimulation due to glycogen synthase kinase inhibition mimicked that effect. 3) Basic fibroblast growth factor and epidermal growth factor also induced connexin43 expression. Their effects were potentiated by platelet derived growth factor. 4) Gap junction inhibition attenuated the bladder smooth muscle cell contraction induced by platelet derived growth factor. Consistently fibroblasts from connexin43 knockout (Cx43-/-) mice showed a much weaker contractile response to platelet derived growth factor than cells from connexin43-wild (Cx43+/+) litter mates.Platelet derived growth factor induces connexin43 expression and bladder smooth muscle cell contraction by activating β-catenin signaling. As a convergence point for many signal pathways, β-catenin may be targeted to treat bladder overactivity.

BACKGROUND AND PURPOSE α(1) -Adrenoceptor-induced contraction of prostate smooth muscle is mediated by calcium- and Rho kinase-dependent mechanisms. In addition, other mechanisms, such as activation of c-jun N-terminal kinase (JNK) may be involved. Here, we investigated whether JNK participates in α(1)-adrenoceptor-induced contraction of human prostate smooth muscle. EXPERIMENTAL APPROACH Prostate tissue was obtained from patients undergoing radical prostatectomy. Effects of the JNK inhibitors SP600125 (50 µM) and BI-78D3 (30 µM) on contractions induced by phenylephrine, noradrenaline and electric field stimulation (EFS) were studied in myographic measurements. JNK activation by noradrenaline (30 µM) and phenylephrine (10 µM), and the effects of JNK inhibitors of c-Jun phosphorylation were assessed by Western blot analyses with phospho-specific antibodies. Expression of JNK was studied by immunohistochemistry and fluorescence double staining. KEY RESULTS The JNK inhibitors SP600125 and BI-78D3 reduced phenylephrine- and noradrenaline-induced contractions of human prostate strips. In addition, SP600125 reduced EFS-induced contraction of prostate strips. Stimulation of prostate tissue with noradrenaline or phenylephrine in vitro resulted in activation of JNK. Incubation of prostate tissue with SP600125 or BI-78D3 reduced the phosphorylation state of c-Jun. Immunohistochemical staining demonstrated the expression of JNK in smooth muscle cells of human prostate tissue. Fluorescence staining showed that α(1A)-adrenoceptors and JNK are expressed in the same cells. CONCLUSIONS AND IMPLICATIONS Activation of JNK is involved in α(1)-adrenoceptor-induced prostate smooth muscle contraction. Models of α(1)-adrenoceptor-mediated prostate smooth muscle contraction should include this JNK-dependent mechanism.

In animal models of partial urethral obstruction (PUO), altered smooth muscle function/contractility may be linked to changes in molecules that regulate calcium signaling/sensitization. PUO was created in male rats, and urodynamic studies were conducted 2 and 6 wk post-PUO. Cystometric recordings were analyzed for the presence or absence of nonvoiding contractions [i.e., detrusor overactivity (DO)]. RT-PCR and Western blots were performed on a subpopulation of rats to study the relationship between the expression of RhoA, L-type Ca2+ channels, Rho kinase-1, Rho kinase-2, inositol 1,4,5-trisphosphate, ryanodine receptor, sarco(endo)plasmic reticulum Ca2+-ATPase 2 and protein kinase C (PKC)-potentiated phosphatase inhibitor of 17 kDa, and urodynamic findings in the same animal. Animals displayed DO at 2 (38%) and 6 wk (43%) post-PUO, increases were seen in in vivo pressures at 2 wk, and residual volume at 6 wk. Statistical analysis of RT-PCR and Western blot data at 2 wk, during the compensatory phase of detrusor hypertrophy, documented that expression of molecules that regulate calcium signaling and sensitization was consistently lower in obstructed rats without DO than those with DO or control rats. Among rats with DO at 2 wk, linear regression analysis revealed positive correlations between in vivo pressures and protein and mRNA expression of several regulatory molecules. At 6 wk, in the presence of overt signs of bladder decompensation, no clear or consistent alterations in expression of these same targets were observed at the protein level. These data extend prior work to suggest that molecular profiling of key regulatory molecules during the progression of PUO-mediated bladder dysfunction may shed new light on potential biomarkers and/or therapeutic targets.

Aims To investigate the relationship between urinary bladder mucosal expression of β3-adrenoceptor (AR) mRNA and urodynamic findings in patients with lower urinary tract symptoms and benign prostatic obstruction (BPO). Methods During surgical prostate resection of 32 BPO patients, mucosal biopsies were collected and analyzed by reverse transcriptase polymerase chain reaction to determine the expression level of β3-AR mRNA. First desire to void (FDV) and strong desire to void (SDV), detrusor overactivity (DO), and bladder outlet obstruction (BOO) were measured pre-operatively. Patients with FDVs 201 ml and SDVs > 301 ml were assigned to the large capacity group (n = 13). The same patients with positive DO were also assigned to the DO+ group (n = 11), and those with negative DO were assigned to the DO− group (n = 21). Finally, patients whose position on the Schafer nomogram was greater than degree V were assigned to the severe BOO group (n = 17), while those with less than degree IV were assigned to the mild BOO group (n = 15). Results The expression level of β3-AR mRNA was similar in both bladder capacity groups and both DO groups. However, the expression level in the severe BOO group was significantly less than in the mild BOO group (P = 0.043). Conclusions The expression of bladder mucosal β3-AR mRNA was significantly decreased in patients with severe BOO, suggesting that β3-ARs might be affected by the degree of BOO. Neurourol. Urodynam. 32: 88–91, 2013. © 2012 Wiley Periodicals, Inc.

Normal functioning of the urinary bladder and the distal gut is an essential part of daily physiological activity coordinated by the peripheral and central nervous systems. Pathological changes in one of these organs may induce the development of cross-organ sensitization in the pelvis and underlie clinical co-morbidity of genitourinary and GI dysfunctions. Experimental human and animal data suggest that the bladder and distal colon interact under both normal and pathological conditions, however, the directions of these interactions can change dramatically depending on the nature and duration of the applied stimuli. This review article aimed to summarize the clinical data on colon-bladder cross-reflexes in healthy individuals, as well as in patients with co-morbid disorders. It also discusses currently used animal models, experimental approaches, and suggested mechanisms of colon-bladder cross-talk. Additionally, it provides an overview of the potential pharmacological targets to develop treatment options for patients with co-morbid disorders. Presented work resulted from the discussion of colon/bladder interactions during “Think Tank 9” presentations at the International Consultation on Incontinence Research Society meeting held in Bristol, UK, 2011.

Background 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. Methods Spinal cord transected female mice were used as a model for neurogenic bladder overactivity. In vivo methods utilized decerebrate mouse cystometry. In vitro approaches included optical mapping of Ca2+ transient, single unit afferent nerve recordings and tension measurements from bladder sheets and wall cross-sections. Immunohistochemistry was used to measure the expression of β3-adrenergic receptors on dorsal root ganglion (DRG) neurons. Results Our unique approaches revealed the direct effects of BoNT/A in inhibiting neuropeptide release and firing rates in afferents following bladder injections. β3-adrenergic receptor agonists are demonstrated to directly inhibit afferent nerve firing independent of the relaxing effects on bladder smooth muscle. Moreover, data suggest the expression of these receptors on DRG neurons that send projections to the bladder. The mechanism of action of PDE5 inhibitors on bladder overactivity is discussed. Discussion The questions raised during the plenary session of the 2011 International Consultation on Incontinence-Research Society meeting regarding the benefits of BoNT/A, β3-adrenergic receptor agonist and PDE5 inhibitor treatments of overactive bladder are addressed. Conclusion Our findings suggest that the abovementioned agents, in low enough concentrations, can directly inhibit afferent excitability without decreasing detrusor contractility. Accordingly, they have considerable potential for treating the sensory component of lower urinary tract dysfunctions. Neurourol. Urodynam. 31:300–308, 2012. © 2012 Wiley Periodicals, Inc.