Psychological stress induced bladder overactivity in female mice is associated with enhanced afferent nerve activity.

Psychological stress has been linked to the development and exacerbation of overactive bladder symptoms, as well as afferent sensitisation in other organ systems. Therefore, we aimed to investigate the effects of water avoidance stress on bladder afferent nerve activity in response to bladder filling and pharmaceutical stimulation with carbachol and ATP in mice. Adult female C57BL/6J mice were exposed to either water avoidance stress (WAS) for 1 h/day for 10 days or normal housing conditions. Voiding behaviour was measured before starting and 24-h after final stress exposure and then animals were euthanised to measure afferent nerve activity in association with bladder compliance, spontaneous phasic activity, contractile responses, as well as release of urothelial mediators. WAS caused increased urinary frequency without affecting urine production. The afferent nerve activity at low bladder pressures (4-7 mmHg), relevant to normal physiological filling, was significantly increased after stress. Both low and high threshold nerves demonstrated enhanced activity at physiological bladder pressures. Urothelial ATP and acetylcholine release and bladder compliance were unaffected by stress as was the detrusor response to ATP (1 mM) and carbachol (1 µM). WAS caused enhanced activity of individual afferent nerve fibres in response bladder distension. The enhanced activity was seen in both low and high threshold nerves suggesting that stressed animals may experience enhanced bladder filling sensations at lower bladder volumes as well as increased pain sensations, both potentially contributing to the increased urinary frequency seen after stress.

Low-Intensity Extracorporeal Shock Wave Therapy Promotes Bladder Regeneration and Improves Overactive Bladder Induced by Ovarian Hormone Deficiency from Rat Animal Model to Human Clinical Trial.

Postmenopausal women with ovary hormone deficiency (OHD) are subject to overactive bladder (OAB) symptoms. The present study attempted to elucidate whether low-intensity extracorporeal shock wave therapy (LiESWT) alters bladder angiogenesis, decreases inflammatory response, and ameliorates bladder hyperactivity to influence bladder function in OHD-induced OAB in human clinical trial and rat model. The ovariectomized (OVX) for 12 months Sprague-Dawley rat model mimicking the physiological condition of menopause was utilized to induce OAB and assess the potential therapeutic mechanism of LiESWT (0.12 mJ/mm2, 300 pulses, and 3 pulses/second). The randomized, single-blinded clinical trial was enrolled 58 participants to investigate the therapeutic efficacy of LiESWT (0.25 mJ/mm2, 3000 pulses, 3 pulses/second) on postmenopausal women with OAB. The results revealed that 8 weeks' LiESWT inhibited interstitial fibrosis, promoted cell proliferation, enhanced angiogenesis protein expression, and elevated the protein phosphorylation of ErK1/2, P38, and Akt, leading to decreased urinary frequency, nocturia, urgency, urgency incontinence, and post-voided residual urine volume, but increased voided urine volume and the maximal flow rate of postmenopausal participants. In conclusion, LiESWT attenuated inflammatory responses, increased angiogenesis, and promoted proliferation and differentiation, thereby improved OAB symptoms, thereafter promoting social activity and the quality of life of postmenopausal participants.

Transcutaneous electrical nerve stimulation and solifenacin succinate versus solifenacin succinate alone for treatment of overactive bladder syndrome: A double-blind randomized controlled study.

OBJECTIVE: We evaluated a combination of transcutaneous electrical nerve stimulation (TENS) and solifenacin succinate versus solifenacin alone in the treatment of overactive bladder (OAB). METHODS: Ninety-seven female outpatients with OAB were screened for this double-blind randomized controlled study. Eighty-six patients who met our inclusion criteria were divided randomly into two groups. In group A (43 patients), patients received oral solifenacin and "fake" TENS on the foot; in group B (43 patients), patients received oral solifenacin and effective TENS on the foot. Improvements in OAB symptoms were assessed by Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire (OAB-q), voiding diaries and urodynamic tests. 70 of 86 patients (36 in group A, 34 in group B) completed the 2 months of treatment and 3 months of follow-up. RESULTS: Statistically, the maximum bladder volume and OAB symptoms of both groups improved significantly after treatment. The improvement in group B was significantly better than that in group A, as indicated by the maximum bladder volume, OAB-q score and voiding diary. Some mild adverse effects were observed, including dry mouth, stomach upset, constipation, muscle pain and local paresthesia. CONCLUSION: The combination of TENS and solifenacin was more effective in improving OAB symptoms than solifenacin alone.

Tadalafil ameliorates bladder overactivity by restoring insulin-activated detrusor relaxation via the bladder mucosal IRS/PI3K/AKT/eNOS pathway in fructose-fed rats.

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration-response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1Ser307 and pIRS2Ser731 and downregulation of PI3K/pPI3KTyr508, AKT/pAKTSer473, and eNOS/peNOSSer1177 in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.

Correlation of severity of pelvic organ prolapse with lower urinary tract symptoms.

OBJECTIVE: Relationships between pelvic organ prolapse (POP) staging and lower urinary tract symptoms (LUTS) are controversial. In this study, we evaluated correlations of POP staging with LUTS in different compartments. MATERIALS AND METHODS: From January 2016 to December 2017, 250 consecutive patients with urogynecologic complaints who were referred to our urodynamic unit were recruited into this study. Different stages of different compartments (anterior, central and posterior) of POPs according to IUGA and ICS terminology were re-grouped into four categories as stage 0, 1, 2, and 3 (including stage 4 because of a limited number of patients in stage 4). Pearson correlation coefficient and general linear regression were used for correlations of POP staging in different compartments and LUTS (stress urinary incontinence, overactive bladder and voiding symptoms) as well as their associated factors. RESULTS: Only OAB had a moderate correlation with different compartments of POP (anterior vaginal wall: -0.3116; cervix: -0.2954 and posterior vaginal wall: -0.3779; all p < 0.05). Stage 1 AVWP significantly increased (39.6%) the occurrence of OAB compared to no prolapse. Posterior compartment (stage 1-3) prolapse reduced the occurrence of OAB. CONCLUSION: Only stage 1 AVWP is associated with an increase in OAB, and posterior compartment prolapse may reduce the occurrence of OAB.

Gabapentin reduces painful bladder hypersensitivity in rats with lipopolysaccharide-induced chronic cystitis.

Although interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pain and urinary symptoms, effective treatments have not been established. The aim of this study was to adapt a chronic cystitis model in rats using lipopolysaccharide (LPS), which reflects IC/BPS pathology, and characterize the model's histological and behavioral effects. Furthermore, we investigated the effect of an α2 δ subunit ligand, gabapentin (GBP), on bladder hypersensitivity of rats with chronic cystitis. Cystitis models were created by repeated intravesical injections of LPS. In the histological examination, the LPS-injected group had greater inflammatory response, fibrosis, and abnormally thick re-epithelialization. In the LPS-injected group, LPS prompted hyperalgesia in both the lower abdomen and hind paw regions after day 1 of the first injection compared with the saline-injected controls, without any recovery for 21 days at least. During cystometry, the LPS-injected group showed bladder hyperactivity at all times. Systemic administration of GBP reduced cystitis-related pain due to chronic inflammation and reduced the increased frequency of voiding in the LPS-injected group. These results suggest that repeated intravesical injections of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats, while GBP is effective in the management of those symptoms in this chronic cystitis model. The current study identifies a relatively simple method to develop an animal model for chronic cystitis and provides evidence that GBP may be an effective treatment option for patients with IC/BPS.

Mechanosensitivity Is a Characteristic Feature of Cultured Suburothelial Interstitial Cells of the Human Bladder.

Bladder dysfunction is characterized by urgency, frequency (pollakisuria, nocturia), and dysuria and may lead to urinary incontinence. Most of these symptoms can be attributed to disturbed bladder sensitivity. There is growing evidence that, besides the urothelium, suburothelial interstitial cells (suICs) are involved in bladder afferent signal processing. The massive expansion of the bladder during the filling phase implicates mechanical stress delivered to the whole bladder wall. Little is known about the reaction of suICs upon mechanical stress. Therefore, we investigated the effects of mechanical stimulation in cultured human suICs. We used fura-2 calcium imaging as a major physiological readout. We found spontaneous intracellular calcium activity in 75 % of the cultured suICs. Defined local pressure application via a glass micropipette led to local increased calcium activity in all stimulated suICs, spreading over the whole cell. A total of 51% of the neighboring cells in a radius of up to 100 µm from the stimulated cell showed an increased activity. Hypotonic ringer and shear stress also induced calcium transients. We found an 18-times increase in syncytial activity compared to unstimulated controls, resulting in an amplification of the primary calcium signal elicited in single cells by 50%. Our results speak in favor of a high sensitivity of suICs for mechanical stress and support the view of a functional syncytium between suICs, which can amplify and distribute local stimuli. Previous studies of connexin expression in the human bladder suggest that this mechanism could also be relevant in normal and pathological function of the bladder in vivo.

Investigating the associations of mucosal P2Y6 receptor expression and urinary ATP and ADP concentrations, with symptoms of overactive bladder.

AIM: To characterize purinergic signaling in overactive bladder (OAB). METHODS: Mucosal biopsies were taken by flexible cystoscopy from patients with storage symptoms referred to Urology Departments of collaborating hospitals. Immunohistochemistry (n = 12) and Western blot analysis (n = 28) were used to establish the qualitative and quantitative expression profile of P2Y6 in human mucosa. Participants from the general population provided a mid-stream urine sample. Bioluminescent assays were used to quantify adenosine triphosphate (ATP; n = 66) and adenosine diphosphate (ADP; n = 60) concentrations, which were normalized to creatinine (Cr) concentration. All participants completed a questionnaire (International Consultation on Incontinence Questionnaire - Overactive Bladder) to score urinary symptoms of OAB. RESULTS: P2Y6 immunoreactivity, more prominent in the urothelium (colocalized with the uroepithelial marker pan-cytokeratin), was more greatly expressed in OAB compared to age- and sex-matched controls (benign prostatic hyperplasia) without OAB symptoms. Mucosal P2Y6 was positively correlated only with incontinence (P = .009). Both urinary ATP and its hydrolysis product, ADP, an agonist to P2Y6, were positively correlated with total OAB symptom score (P = .010 and P = .042, respectively). CONCLUSIONS: The positive correlation of P2Y6 only with incontinence may indicate a different phenotype in OAB wet and warrants further investigation. Positive correlations of ATP and ADP with total OAB symptom score demonstrate upregulation in purinergic signaling in OAB; shown previously only in animal models. Further research is required to validate whether purinoceptors are indeed new therapeutic targets for this highly prevalent symptom complex.

Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats.

Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty-five female Sprague-Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia-inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.

Prevalence and clinical characteristics of overactive bladder in systemic sclerosis.

Objectives: Overactive bladder (OAB) is a clinical diagnosis defined with the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence. Objective was to evaluate the demographic and clinical characteristics of Japanese systemic sclerosis (SSc) patients with OAB.Methods: OAB was diagnosed by OAB symptom score (OABSS) in 104 Japanese SSc patients (93 women and 11 men). Differential diseases of OAB were conducted by urologists.Results: The prevalence of OAB in SSc patients was 27.9% (29/104). SSc patients with OAB were characterized by old age, a long history of morbidity (15.4 vs. 11.2 years, p < .01), high anti-centromere antibody positive rate (75.9 vs. 44%, p < .05), high incidence of gastroesophageal reflux disease (93.1 vs. 73.3%, p < .05), low anti-SS-A antibody positive rate (6.9 vs. 26.8%, p < .05), and low incidence of internal lung disease (17.9 vs. 45.7%, p < .05) compared to SSc patients without OAB.Conclusion: This is the first study that evaluated the prevalence and clinical features of OAB in Japanese SSc patients. Since SSc patients might be prone to develop OAB, it was thought that OAB should be noted as one of the complications of SSc patients.

Attenuated BK channel function promotes overactive bladder in a rat model of obesity.

Overactive bladder (OAB) is mostly observed in obese individuals, and is associated with enhanced excitability and contractility of the detrusor smooth muscle (DSM). Large-conductance voltage- and Ca2+-activated K+ (BK) channels reduce the excitability and contractility of the DSM. We tested whether obesity-induced OAB is associated with altered BK channel expression and activity in the DSM. Seven-week-old female Sprague-Dawley rats (N=80) were fed a normal or high-fat diet (HFD) for 12 weeks. HFD-fed rats exhibited a higher average bodyweight and urodynamically established detrusor overactivity. mRNA levels of the Kcnma1 (BKα subunit) and Kcnmb1 (BKß1 subunit) in whole tissues and cells from the DSM were reduced in HFD-fed rats. A selective BK channel opener, NS1619, was then applied to DSM cells from the two groups of rats. Patch-clamp techniques revealed that spontaneous transient outward currents, NS1619-induced activation of spontaneous transient outward currents, and whole-cell BK currents, as well as NS1619-induced membrane hyperpolarization, were attenuated in DSM cells from HFD-fed rats. The relaxation effect of NS1619 on contractility was reduced in DSM strips from HFD-fed rats. Thus, impaired expression of Kcnma1 and Kcnmb1 in the DSM contributes to obesity-induced OAB, suggesting that BK channels could be a useful treatment targets in OAB.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Assessment of Overactive Bladder after Laparoscopic Lateral Suspension for Pelvic Organ Prolapse.

BACKGROUND: Pelvic organ prolapses (POP) and overactive bladder (OAB) may coexist and both negatively impact quality of life in women. The correlation between POP and OAB remains unclear, but these patients may have the OAB resolution after the surgical treatment of POP. Aim of our study was to assess the anatomical results and the effect on OAB symptoms in women who underwent laparoscopic lateral suspension for POP. MATERIALS AND METHODS: This prospective study included all women with apical POP who underwent surgical repair with laparoscopic uterine lateral suspension from January 2016 to December 2017. The baseline and the 1-year follow-up included post-void residual measurement, urinalysis, vaginal examination, OAB symptoms evaluation, and administration of questionnaires (PFDI-20, UDI 6). RESULTS: 64 women underwent laparoscopic lateral suspension for uterine prolapse and 78.1% had concomitant anterior vaginal wall defect. At 1-year follow-up the anatomic success rates were 84.4% for the apical and 76.2% for the anterior compartment. The comparison between OAB symptoms before and after the surgical procedure showed the resolution of OAB in 76% of the women, while de novo OAB was present in 2.6%. With the questionnaires 95.3% (61/64) of our patients were satisfied after the POP repair. We documented a trend in ameliorating of OAB regardless of the POP-Q stage. However, the Pearson test showed this correlation as statistically significant only in women with anterior vaginal wall defect stage III and apical stage II. No patient had vaginal exposure of the polypropylene mesh. CONCLUSION: Our data show how laparoscopic lateral suspension is an effective procedure for apical and anterior vaginal wall defects. This study provides further evidence for the concept that OAB in women with POP >II stage improves after a successful POP surgery. These women may benefit from a resolution of OAB and POP symptoms with the improvement of patient's quality of life.

Nerve sprouting and neurogenic inflammation characterize the neurogenic detrusor overactive bladder of patients no longer responsive to drug therapies.

Urothelium and Lamina Propria (LP) are considered an integrate sensory system which is able to control the detrusor activity. Complete supra-sacral spinal cord lesions cause Neurogenic Detrusor Overactivity (NDO) whose main symptoms are urgency and incontinence. NDO therapy at first consists in anti-muscarinic drugs; secondly, in intra-vesical injection of botulinum toxin. However, with time, all the patients become insensitive to the drugs and decide for cystoplastic surgery. With the aim to get deeper in both NDO and drug's efficacy lack pathogenesis, we investigated the innervation, muscular and connective changes in NDO bladders after surgery by using morphological and quantitative methodologies. Bladder innervation showed a significant global loss associated with an increase in the nerve endings located in the upper LP where a neurogenic inflammation was also present. Smooth muscle cells (SMC) anomalies and fibrosis were found in the detrusor. The increased innervation in the ULP is suggestive for a sprouting and could condition NDO evolution and drug efficacy length. Denervation might cause the SMC anomalies responsible for the detrusor altered contractile activity and intra-cellular traffic and favour the appearance of fibrosis. Inflammation might accelerate these damages. From the clinical point of view, an early anti-inflammatory treatment could positively influence the disease fate.

Long-lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically-induced prostatic inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the major causes of lower urinary tract symptoms (LUTS), including storage LUTS such as urinary frequency and urgency. Recently, a growing number of clinical studies indicate that prostatic inflammation could be an important pathophysiological mechanism inducing storage LUTS in patients with BPH. Here we aimed to investigate whether nonbacterial prostatic inflammation in a rat model induced by intraprostatic formalin injection can lead to long-lasting bladder overactivity and changes in bladder afferent neuron excitability. METHODS: Male Sprague-Dawley rats were divided into four groups (n = 12 each): normal control group, 1-week prostatic inflammation group, 4-week inflammation group, and 8-week inflammation group. Prostatic inflammation was induced by formalin (10%; 50 µL per lobe) injection into bilateral ventral lobes of the prostate. Voiding behavior was evaluated in metabolic cages for each group. Ventral lobes of the prostate and the bladder were then removed for hematoxylin and eosin (HE) staining to evaluate inflammation levels. Continuous cystometrograms (CMG) were recorded to measure intercontraction intervals (ICI) and voided volume per micturition. Whole-cell patch clamp recordings were performed on dissociated bladder afferent neurons labeled by fluorogold injected into the bladder wall, to examine the electrophysiological properties. RESULTS: Results of metabolic cage measurements showed that formalin-treated rats exhibited significantly (P < 0.05) increases in micturition episodes/12 hours and decrease in voided volume per micturition at every time point post injection. Continuous CMG illustrated the significant ( P < 0.05) higher number of nonvoiding contractions per void and shorter ICI in formalin-treated rats compared with control rats. HE staining showed significant prostatic inflammation, which declined gradually, in prostate tissues of formalin-induced rats. In patch clamp recordings, capsaicin-sensitive bladder afferent neurons from rats with prostatic inflammation had significantly ( P < 0.05) lower thresholds for spike activation and a "multiple" firing pattern compared with control rats at every time point post injection. CONCLUSIONS: Formalin-induced prostatic inflammation can lead to long-lasting bladder overactivity in association with bladder afferent neuron hyperexcitability. This long-lasting model could be a useful tool for the study of inflammation-related aspects of male LUTS pathophysiology.

Bladder overactivity and afferent hyperexcitability induced by prostate-to-bladder cross-sensitization in rats with prostatic inflammation.

KEY POINTS: There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, both dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate-to-bladder cross-sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, could be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation. ABSTRACT: Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non-bacterial prostatic inflammation. We demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, and IL-1α, IL-1ß, and IL-6 levels inside the prostate, but not in the bladder, following intraprostatic formalin injection induced an increase in NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve. A significant proportion (18-19%) of dorsal root ganglion neurons were double labelled by dye tracers injected into either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2X2 increased, and Kv1.4, a potassium channel α-subunit that can form A-type potassium (KA ) channels, decreased at mRNA levels in bladder afferent and double-labelled neurons vs. non-labelled neurons, and slow KA current density decreased in association with hyperexcitability of these neurons. Collectively, non-bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate-to-bladder afferent cross-sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.

Downregulation of TRPC6 expression is a critical molecular event during FK506 treatment for overactive bladder.

PURPOSE: It has been suggested that FK506 could improve some symptoms of OAB in both clinical settings and animal models; however, its mechanism of action is not well-understood. Here, we investigated the effect of FK506 on TRPC6 in bladder smooth muscle, and explored the possible involvement of TRPC6 in OAB. METHODS: FK506 was injected intraperitoneally into rats in which OAB was induced via BOO, and urodynamic indices were recorded. Rats and human bladder smooth muscle tissues with or without OAB were examined for TRPC6 expression by western blot, RT-PCR and IF staining. Cultured BSMCs were treated with PDGF, TRPC6 siRNAs and FK506. Then the TRPC6 expression and cellular proliferation were examined, and the Ca2+ influx and contractility of BSMCs were examined by time-lapse Ca2+ imaging and collagen gel contraction. Finally, IF and Co-IP were performed to test the effects of FK506 on NFAT translocation to the nucleus and the interaction of TRPC6 with FKBP12, respectively. RESULTS: FK506 improved urodynamic indices of OAB rats, and TRPC6 was expressed in rats and human bladder tissues. TRPC6 elevation in OAB rats was inhibited by FK506, and this inhibition coincided with improvements in urodynamic indices. PDGF enhanced TRPC6 expression, cellular proliferation, Ca2+ influx and contractility of BSMCs, and these effects were inhibited by TRPC6 siRNAs and FK506. FK506 inhibited NFAT translocation to the nucleus and disrupted the interaction of TRPC6 with FKBP12. CONCLUSIONS: Our results collectively indicate that FK506 may be used to treat OAB, and that TRPC6 may serve as an attractive target for therapeutic intervention in OAB.

Positive Association of Male Overactive Bladder Symptoms and Androgen Deprivation: A Nationwide Population-based Cohort Study.

BACKGROUND/AIM: The role of androgen in the modulation of voiding function is still uncertain. The aim of this study was to evaluate the association of androgen deprivation therapy (ADT) and overactive bladder (OAB) in men in a population-based cohort. MATERIALS AND METHODS: This study examined the records of newly-diagnosed prostate cancer subjects receiving ADT only in the Taiwan National Health Insurance Research Database in the years between 2001 and 2007. As controls men without cancer were selected and divided into three groups, 1) benign prostate hyperplasia treated with an alpha-blocker (BPH-alpha blocker), 2) BPH treated with a 5-alpha reductase inhibitor (BPH-5ARI) and 3) healthy controls. OAB events were censored by definition of drug prescriptions for more than one month and risk analysis among each group was performed. RESULTS: The healthy control group had decreased risk of OAB compared to the prostate cancer group and the BPH-5ARI group showed a higher risk of OAB than the prostate cancer group. Subgroup analysis showed that independently of age or comorbidities, the prevalence of OAB was significantly lower in the healthy control group. Moreover, the cumulative incidence of OAB showed a time-dependent pattern with a significant increase after ADT for 5 years. CONCLUSION: Androgen deprivation in prostate cancer patients was associated with an increased risk of OAB that was treatment duration-dependent. This result is consistent with an inhibitory role of androgen in the modulation of male voiding function.

Atherosclerosis as a predictor of transient exacerbation of overactive bladder symptoms after robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: To assess whether atherosclerosis is involved in the development of overactive bladder and the function of lower urinary tract after robot-assisted radical prostatectomy. METHODS: The present cohort consisted of 80 consecutive participants. The preoperative cardio-ankle vascular index was used to evaluate the presence of atherosclerosis. The present cohort was split into two groups, the atherosclerotic group, whose cardio-ankle vascular index was ≥9.0, and the control group, whose index was <9.0. The overactive bladder symptom score and lower urinary tract function were compared for 12 months after surgery. RESULTS: The total score of the questionnaire was significantly higher at 6 and 9 months after surgery in the atherosclerosis group (P = 0.04, P = 0.03, respectively). Both the urgency and urgency incontinence subscores of the questionnaire showed a parallel tendency to that of the total score after surgery. At 3 months after surgery, there was a significant increase in the prevalence of de novo overactive bladder in the atherosclerosis group (P = 0.04). At 9 and 12 months after surgery, there was a significant decrease of voided volume in the atherosclerotic group (P < 0.01, P = 0.04, respectively). CONCLUSIONS: Atherosclerosis delays the improvement in both overactive bladder symptoms and storage function postoperatively, and it is involved in the transient increase in the prevalence of de novo overactive bladder. Atherosclerosis might be a predictor of the development of overactive bladder after robot-assisted radical prostatectomy.

Do patient characteristics predict which patients with overactive bladder benefit from a higher fesoterodine dose?

INTRODUCTION AND HYPOTHESIS: We sought to determine whether baseline characteristics predict which overactive bladder (OAB) patients benefit from fesoterodine 8 mg versus 4 mg. METHODS: In double-blind, placebo-controlled, flexible-dose trials, baseline characteristics of OAB patients with ≥ 1 urgency urinary incontinence (UUI) episodes/24 h who escalated from fesoterodine 4 mg to 8 mg were evaluated. Possible dose-escalation predictors (age; sex; previous antimuscarinic use; UUI, micturitions, and urgency episodes/24 h; race; body mass index; time to dose escalation; OAB duration) were compared in escalators versus non-escalators. Patients from fixed-dose trials with dose-escalator characteristics were identified (matched dose-escalator sample) to assess changes from baseline with fesoterodine 4 mg, 8 mg, and placebo. RESULTS: In flexible-dose trials, significant predictors of fesoterodine dose escalation were younger age (≤ 65.8 years), greater number of baseline micturitions (≥ 13.1) and urgency episodes/24 h (≥ 10.9), greater OAB duration (≥ 9.1 years), and more frequent previous antimuscarinic use (58.3%), but not baseline UUI episodes/24 h. In the matched dose-escalator sample (fesoterodine 4 mg: n = 215; 8 mg: n = 198; placebo: n = 217), change from baseline in UUI episodes significantly improved with fesoterodine 8 mg versus 4 mg (P = 0.043) and with both doses versus placebo (P < 0.001). Dry mouth and constipation rates were higher with fesoterodine 8 mg. CONCLUSIONS: Dose-escalator patients had a significantly greater UUI response with fesoterodine 8 mg versus 4 mg. Given the potential for adverse events, fesoterodine 4 mg is recommended to start; however, patients with UUI and identified predictors may benefit from initial treatment with fesoterodine 8 mg or rapid dose escalation.