Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Benign prostatic hyperplasia nodules in patients treated with celecoxib and/or finasteride have reduced levels of NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, a mitochondrial protein essential for efficient function of the electron transport chain.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.

Changes in the treatment landscape of metastatic hormone-sensitive prostate cancer following approval of upfront androgen receptor signaling inhibitors: A multicenter study.

BACKGROUND: A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone-sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). METHODS: We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan-Meier method was used to assess oncological outcomes, including time to castration-resistant prostate cancer (CRPC), progression-free survival 2 (PFS2, duration from initial treatment to tumor progression during second-line treatment), cancer-specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. RESULTS: In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Kaplan-Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grades 3-4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. CONCLUSIONS: Initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first-line treatment option given its superior oncological outcomes.

Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.

BACKGROUND: The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). RESULTS: Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. CONCLUSIONS: These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.

Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump.

Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome c oxidase subunit 2, transforming growth factor-ß1, interleukin-1ß, hypoxia-inducible factor-1α, α1A-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca2+ channel subunit-α1D, neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-ß1, interleukin-1ß, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.

Angiogenesis in bladder tissues is strongly correlated with urinary frequency and bladder pain in patients with interstitial cystitis/bladder pain syndrome.

OBJECTIVES: To examine the correlation among bladder inflammation, angiogenesis, fibrosis and urothelial denudation in biopsied bladder specimens, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores in interstitial cystitis/bladder pain syndrome patients with or without Hunner lesions (Hunner type interstitial cystitis or non-Hunner type interstitial cystitis). METHODS: Bladder biopsied tissues were collected from 12 Hunner type interstitial cystitis female patients, 12 non-Hunner type interstitial cystitis female patients and 12 age-matched non-interstitial cystitis female patients (controls). Immunohistochemical stainings of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-ß, SLUG associated with epithelial mesenchymal transition and E-cadherin as well as Masson trichrome staining were evaluated. The significant correlation between the expression of tissue necrotic factor-α, mast cell tryptase, vascular endothelial growth factor, CD31, transforming growth factor-ß, collagen, SLUG or E-cadherin, and O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes or visual analog scale pain scores was then examined. RESULTS: The expression of tissue necrotic factor-α, vascular endothelial growth factor, CD31, transforming growth factor-ß and SLUG was significantly increased in non-Hunner type interstitial cystitis and Hunner type interstitial cystitis patients compared with controls whereas the significant increases in the expression of mast cell tryptase and collagen were observed in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. On the other hand, the expression of E-cadherin was significantly decreased in Hunner type interstitial cystitis patients compared with controls and non-Hunner type interstitial cystitis patients. In addition, the increased expression of CD31 in bladder tissues was strongly correlated with O'Leary-Sant symptom indexes, O'Leary-Sant problem indexes and visual analog scale pain scores. CONCLUSIONS: These results suggest that bladder angiogenesis evident as the increased expression of CD31 is strongly correlated with urinary frequency and bladder pain in patients with non-Hunner type interstitial cystitis and Hunner type interstitial cystitis.

Bladder wall injection of mesenchymal stem cells ameliorates bladder inflammation, overactivity, and nociception in a chemically induced interstitial cystitis-like rat model.

INTRODUCTION AND HYPOTHESIS: We investigated the effects of bladder wall injection of mesenchymal stem cells (MSCs) on bladder tissues, function, and nociceptive behavior in a chemically induced interstitial cystitis-like rat model. METHODS: Chemical cystitis of female rats was induced by intravesical instillation of 0.1 N hydrochloride (HCl) once a week for 2 weeks. Bladders were harvested 1, 2, 3, and 4 weeks after the second application for histological examination. Adipose-derived MSCs (HCl + MSCs) or phosphate-buffered saline (HCl + PBS) was injected into the bladder wall at the time of the second application of HCl. Histological examination, nociceptive behavior, and cystometrograms were evaluated 2 weeks after the injection compared with controls, which received instillation and injection of PBS into the bladder (sham + PBS). RESULTS: The number of mast cells and expression of tumor necrosis factor-α (TNF-α) and transforming growth factor-ß (TGF-ß) were significantly increased at 1 and 2 weeks, and expression of collagen fibers was significantly increased from 2-4 weeks after the second application of HCl. Significantly increased nociceptive behavior, number of mast cells, expression of TNF-α, TGF-ß, and collagen fibers were observed in HCl + PBS compared with sham + PBS, whereas these changes were significantly decreased in HCl + MSCs compared with HCl + PBS. In addition, bladder capacity and voiding threshold pressures were significantly decreased in HCl + PBS but not in HCl + MSCs compared with sham + PBS. CONCLUSIONS: The results suggest that bladder injection of MSCs ameliorates inflammation and fibrosis in bladder tissues, bladder overactivity, and nociception in a rat model of chemically induced cystitis.

[Clinical Evaluation of Primary Aldosteronism with Subclinical Cushing's Syndrome].

Primary aldosteronism characterized by the overproduction of aldosterone by the adrenal glands, is sometimes accompanied by autonomous cortisol secretion. In this study, we retrospectively analyzed 8 cases of primary aldosteronism (PA) with subclinical Cushing's syndrome (SCS). A total of 71 patients with PA underwent surgery at Jikei University Hospital from 2004 to 2013, and 8 of them were diagnosed with coexistent SCS. Four patients were male and four were female. The mean patient age was 56.9 years. One of the patients also had pheochromocytoma in the adrenal gland on the ipsilateral side. All patients had hypertension, 6 had hypokalemia, 5 had diabetes mellitus, and 3 had hyperlipidemia. All patients had autonomous cortisol secretion as shown in 1 mg- or 8 mg-dexamethasone suppression tests even though baseline cortisol levels were normal. Adrenal venous blood sampling with adrenocorticotropic hormone (ACTH) stimulation was performed on 5 patients, but the localization of PA could not be detected in 1 patient. Adrenocortical scintigraphy revealed suppression of the contra-lateral adrenal uptake in all 7 patients. Six patients including one patient who showed complete suppression of the contra-lateral adrenal uptake in adrenocortical scintigraphy, and 2 patients, whose ACTH levels were less than the detection limit, received postoperative steroid hormone replacement. In the literature, SCS co-existed in approximately 8. 6% of the patients with PA. In our study, SCS co-existed in approximately 11.3%. The degree of the autonomous secretion of cortisol varied with the patient, and some cases are accompanied by Cushing's syndrome. Therefore, it is important to analyze the autonomous cortisol secretion even in patients with PA.

Two cases of pelvic hematoma after prostatic urethral lift surgery.

Introduction: There are few reports of pelvic hematoma after prostatic urethral lift. Here, we report two cases of pelvic hematoma in Japan. Case presentation: The first case was a 71-year-old man with benign prostatic hyperplasia who underwent prostatic urethral lift. Although the procedure was uneventful, he experienced lower abdominal pain the day after the operation. CT revealed a hematoma in the right pelvis; however, it was manageable with conservative treatment. The second case was a 68-year-old man. The procedure was uneventful; however, 6 days after the operation, a subcutaneous hematoma appeared in the lower abdomen. CT revealed a hematoma in the left pelvis. We then performed pelvic hematoma removal surgery. Conclusions: Pelvic hematomas after PUL may requires attention, particularly in men with the narrow pelvises. Appropriate compression of the prostate and a high lithotomy position procedure could effectively avoid the occurrence of pelvic hematomas.

Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate.

Importance: The association between the use of bone-modifying agents (BMAs) and the outcomes among patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with abiraterone acetate plus prednisone (AAP) remains unclear. Objective: To investigate the association between BMA use and the outcomes of patients with mCSPC receiving AAP. Design, Setting, and Participants: In this cohort study, a post hoc analysis of individual participant data from the LATITUDE trial was performed. The LATITUDE trial, a phase 3 randomized clinical trial, aimed to assess the efficacy of AAP and androgen deprivation therapy (ADT) vs dual-placebo and ADT in patients with high-risk mCSPC (data cutoff, August 15, 2018). Eligible patients had newly diagnosed prostate cancer with metastases and at least 2 of 3 high-risk factors (Gleason score ≥8, presence of ≥3 lesions on bone scan, or presence of measurable visceral metastasis). The trial was conducted at 235 sites in 34 countries. Data for the present study were evaluated from July 18 to September 23, 2023. Exposures: Use of BMAs was defined as the administration of bisphosphonates and denosumab within 90 days before and after randomization. Main Outcomes and Measures: The primary outcomes were time to skeletal-related events (SREs) and overall survival (OS). An SRE was defined as a clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery involving bone. Differences in these outcomes were examined using the restricted mean survival time from inverse probability of treatment weighting-adjusted Kaplan-Meier curves, estimated until the last event was observed (longest time observed, 63.9 months). Treatment × covariate interactions were analyzed using weighted Cox proportional hazards regression models for the total cohort. Results: In the total cohort of 1199 patients (956 [79.7%] younger than 75 years), 597 (49.8%) received AAP and ADT, including 474 (79.4%) younger than 75 years and 384 (64.3%) with more than 10 bone metastases (AAP cohort); 602 (50.2%) were treated with dual placebo and ADT, including 482 (80.1%) younger than 75 years and 377 (62.6%) with more than 10 bone metastases (ADT cohort). In the AAP cohort, 132 patients (22.1%) received BMAs, while in the ADT cohort, 131 (21.8%) did. Zoledronic acid was the most frequently administered BMA in both the AAP (93 [70.5%]) and the ADT (88 [67.2%]) cohorts. During the median follow-up of 51.8 (IQR, 47.2-57.0) months in the AAP cohort, BMA use was associated with a longer time to SRE (difference, 7.8 [95% CI, 4.2-11.3] months) but not with OS (difference, 1.6 [95% CI, -2.5 to 5.8] months). In the ADT cohort, BMA use was associated with both time to SRE (difference, 9.3 [95% CI, 5.2-13.3] months) and OS (difference, 5.5 [95% CI, 3.2-9.8] months). No evidence was found that the outcomes of BMA varied by AAP or ADT (hazard ratio for time to SRE, 0.99 [95% CI, 0.48-2.08]; P = .99 for interaction; hazard ratio for OS, 1.31 [95% CI, 0.88-1.96]; P = .18 for interaction). Conclusions and Relevance: The findings of this cohort study suggest that use of BMAs was associated with a longer time to SRE in patients with high-risk mCSPC treated with ADT, with or without AAP, suggesting that BMA use might provide benefits to this population.

Does age impact clinical outcomes of radical nephroureterectomy in the elderly?-results from a multicenter retrospective study.

Background: Few studies have addressed the efficacy of nephroureterectomy for managing upper tract urothelial carcinoma (UTUC) in very elderly patients (those aged 85 years and older). We aimed to elucidate the association between age and clinical outcomes in patients with UTUC who underwent radical nephroureterectomy. Methods: We retrospectively analyzed data from 847 patients who underwent nephroureterectomy for UTUC. These patients were classified into four age brackets: young (≤64 years, n=177), intermediate (65-74 years, n=300), elderly (75-84 years, n=312), and very elderly (≥85 years, n=58). We applied logistic regression models to ascertain predictors of postoperative complications. Cox's proportional hazards models were used to evaluate key prognostic factors affecting non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Results: In all, 56 patients reported postoperative complications. An Eastern Cooperative Oncology Group performance status ≥2 was identified as a significant predictor for postoperative complications whereas age did not show a noteworthy correlation. Kaplan-Meier survival analyses indicated that very elderly patients had notably poorer OS than younger groups. Nevertheless, the differences in NUTRFS and CSS across the age brackets were not statistically significant. In multivariable analyses, very elderly age was a substantial independent determinant of OS but not NUTRFS or CSS. Conclusions: The therapeutic benefits of surgical procedures are relatively consistent across age groups. This underscores the potential of considering surgical treatment for UTUC in patients aged 85 and above, provided they are deemed fit to withstand the surgical rigors and associated invasiveness.

Perioperative renal function change and oncological outcomes of radical nephroureterectomy in patients with upper tract urothelial carcinoma: A multicenter retrospective study.

BACKGROUND: The effect of radical nephroureterectomy (RNUx) on postoperative renal function in patients diagnosed with upper tract urothelial carcinoma (UTUC) has not been thoroughly explored. METHODS: We conducted a retrospective analysis including 785 patients who underwent RNUx for UTUC. We assessed the preoperative and postoperative estimated glomerular filtration rates (eGFRs) and factors related to the decline in eGFR. Additionally, we examined the effect of comorbidities (diabetes or hypertension) on the postoperative eGFR at 1 year. Cox proportional hazard models were employed to investigate the clinical effect of RNUx on oncological outcomes, including non-urothelial tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median preoperative and postoperative eGFR levels were 54.7 and 40.6 ml/min/1.73 m2 respectively. The proportions of patients with preoperative and postoperative eGFR ≥60 mL/min/1.73 m2 were 35.9% and 5.1%, respectively. The median decline in the eGFR after surgery was 26.8%. Patients with preoperative eGFR <60 ml/min/1.73 m2 demonstrated significantly lower odds of a postoperative decline in eGFR of 25% or more. The effect of comorbidities on postoperative eGFR at 1 year was significant (P = 0.048). The 3-year NUTRFS, CSS, and OS rates were 72.9%, 85.2%, and 81.5%, respectively. Preoperative chronic kidney disease was an independent factor associated with inferior NUTRFS, CSS, and OS. CONCLUSION: Different degrees of impairment of renal function occur among UTUC patients. Only 5.1% of patients retain a postoperative eGFR ≥60 ml/min/1.73 m2. Preoperative renal impairment was linked to reduced odds of postoperative eGFR decrease and associated with survival. In addition, the presence of comorbidities had a significant effect on the decline in eGFR. These findings emphasize the importance of developing evidence-based perioperative treatment strategies for UTUC patients with impaired renal function.

Reduction of Bladder Capacity Under Anesthesia Following Multiple Recurrences and Repeated Surgeries of Hunner Lesions in Patients With Interstitial Cystitis.

PURPOSE: To investigate the influence of multiple recurrences and repeated surgeries of Hunner lesions on bladder capacity under general anesthesia in patients with interstitial cystitis (IC). METHODS: We retrospectively reviewed the clinical records of Hunner-type IC (HIC) patients who underwent transurethral fulguration or resection of Hunner lesions combined with hydrodistension by a single surgeon between 2011 and 2020. Recurrence was defined as reappearance of uncontrolled urinary symptoms in association with new Hunner lesions identified by cystoscopy. Recurrent Hunner lesions were then treated by transurethral surgeries. The recurrence-free rate, potential predictive factors of recurrence, and changes in bladder capacity under anesthesia were examined at each surgical procedure. RESULTS: A total of 92 surgeries were performed in 47 HIC patients, 23 (49%) of whom required multiple procedures (range, 1-5 times). The mean recurrence-free time after the first surgery was 21.7 months. The recurrence-free rate was 53% at 24 months, and decreased to 32% at 48 months. There were no significant differences in age, sex, bladder capacity under anesthesia at the first surgery, duration from symptom onset to the first surgery, O'Leary-Sant questionnaire including symptom and problem indexes, visual analogue scale pain score, and the number of comorbidities between the cases with or without recurrence. Bladder capacity under anesthesia was gradually decreased as the number of surgeries was increased, and bladder capacity at the fourth procedure was significantly decreased to 80% of the capacity at the first surgery. CONCLUSION: These results suggest that multiple recurrences and repeated surgeries of Hunner lesions result in a reduction of bladder capacity under anesthesia in HIC patients although no predictive factors for recurrence of Hunner lesions were detected.

E-cadherin deficiency promotes prostate macrophage inflammation and bladder overactivity in aged male mice.

Decreased E-cadherin immunostaining is frequently observed in benign prostatic hyperplasia (BPH) and was recently correlated with increased inflammation in aging prostate. Homozygous E-cadherin deletion in the murine prostate results in prostate inflammation and bladder overactivity at 6 months of age. However, this model is limited in that while E-cadherin is significantly reduced in BPH, it is not completely lost; BPH is also strongly associated with advanced age and is infrequent in young men. Here, we examined the functional consequences of aging in male mice with prostate luminal epithelial cell-specific E-cadherin heterozygosity. In control mice, aging alone resulted in an increase in prostate inflammation and changes in bladder voiding function indicative of bladder underactivity. At 24 months of age, mice with prostate-specific Cre-mediated heterozygous deletion of E-cadherin induced at 7 weeks of age developed additional prostatic defects, particularly increased macrophage inflammation and stromal proliferation, and bladder overactivity compared to age-matched control mice, which are similar to BPH/LUTS in that the phenotype is slow-progressing and age-dependent. These findings suggest that decreased E-cadherin may promote macrophage inflammation and fibrosis in the prostate and subsequent bladder overactivity in aging men, promoting the development and progression of BPH/LUTS.

Prostate-Specific Deletion of Cdh1 Induces Murine Prostatic Inflammation and Bladder Overactivity.

Benign prostatic hyperplasia (BPH) is an age-related debilitating prostatic disease that is frequently associated with prostatic inflammation and bothersome lower urinary tract symptoms (LUTS). Animal models have shown that formalin- and bacterial-induced prostatic inflammation can induce bladder dysfunction; however, the underlying mechanisms contributing to prostatic inflammation in BPH and bladder dysfunction are not clear. We previously reported that E-cadherin expression in BPH is downregulated in hyperplastic nodules compared with expression in adjacent normal tissues. Here, we explored the potential consequences of prostatic E-cadherin downregulation on the prostate and bladder in vivo using an inducible murine model of prostate luminal epithelial-specific deletion of Cdh1. The prostate-specific antigen (PSA)-CreERT2 transgenic mouse strain expressing tamoxifen-inducible CreERT2 recombinase driven by a 6-kb human PSA promoter/enhancer was crossed with the B6.129-Cdh1tm2Kem/J mouse to generate bigenic PSA-CreERT2/Cdh1-/- mice. Deletion of E-cadherin was induced by transient administration of tamoxifen when mice reached sexual maturity (7 weeks of age). At 21 to 23 weeks of age, the prostate, bladder, and prostatic urethra were examined histologically, and bladder function was assessed using void spot assays and cystometry. Mice with Cdh1 deletion had increased prostatic inflammation, prostatic epithelial hyperplasia, and stromal changes at 21 to 23 weeks of age, as well as changes in bladder voiding function compared with age-matched controls. Thus, loss of E-cadherin in the murine prostate could result in prostatic defects that are characteristic of BPH and LUTS, suggesting that E-cadherin downregulation could be a driving force in human BPH development and progression.

Additive effects of intravenous and intravesical application of vibegron, a ß3-adrenoceptor agonist, on bladder function in rats with bladder overactivity.

To examine the effects of intravenous and intravesical application of vibegron, a new ß3-adrenoceptor (ß3-AR) agonist, on bladder function in rats with oxotremorine methiodide (oxo-M: a nonselective muscarinic receptor agonist)-induced bladder overactivity. Cystometry was performed in conscious female rats with intravesical instillation of oxo-M (200 µM). In oxo-M-treated rats, vehicle or vibegron (1 and 10 mg/kg) was cumulatively applied intravenously at 30-min intervals. In other groups of rats, oxo-M + vehicle or oxo-M + vibegron (10, 100 µM, and 1 mM) was cumulatively instilled intravesically at 60-min intervals followed by intravenous application of vibegron (10 mg/kg). Expression of ß3-ARs in the bladder was also evaluated using immunohistochemical staining. Intravenous application of vibegron (10 mg/kg) significantly increased bladder capacity (1.3 times) and decreased baseline, threshold, and maximal voiding pressure compared with vehicle. Next, intravesical application of vibegron (1 mM) significantly increased threshold pressure and bladder capacity (1.2 times) compared with vehicle. Combined treatments of intravesical (1 mM) and intravenous (10 mg/kg) application of vibegron induced a significantly larger degree of increases in bladder capacity (1.4 times) compared with vehicle. In addition, ß3-ARs were expressed throughout the rat bladder, mainly in the urothelium. These results suggest that vibegron excreted in urine as an unchanged compound can induce the additive inhibitory effects on bladder overactivity possibly through urothelial ß3-AR activation, which inhibits the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressure and bladder capacity without affecting bladder contractile function after intravesical vibegron application.

Effects of combined treatment of tadalafil and tamsulosin on bladder dysfunction via the inhibition of afferent nerve activities in a rat model of bladder outlet obstruction.

PURPOSE: To investigate the effects of combined treatment of tadalafil (a phosphodiesterase-5 inhibitor) and tamsulosin (an α1-adrenoceptor antagonist) on bladder dysfunction in a rat model of bladder outlet obstruction (BOO). METHODS: Cystometry was performed in conscious female BOO rats 6 weeks after partially ligation of the urethra. Either tadalafil (0.03, 0.1 and 0.3 mg/kg) or tamsulosin (0.001, 0.003 and 0.01 mg/kg) was cumulatively applied intravenously at 30-min intervals to examine changes in cystometric parameters and blood pressures. Changes in cystometric parameters and blood pressures were also checked when tadalafil (0.3 mg/kg), tamsulosin (0.003 mg/kg) or both were intravenously applied. RESULTS: In BOO rats, application of either tadalafil (0.3 mg/kg) or tamsulosin (0.003, 0.01 mg/kg) alone significantly increased threshold pressures and intercontraction intervals whereas there were no significant changes in other cystometric parameters. In addition, because a significant reduction in blood pressures was detected after the administration of tamsulosin (0.01 mg/kg), tamsulosin at a lower dose (0.003 mg/kg) was used for the combined treatment. The combination therapy of tadalafil and tamsulosin induced a significantly larger rate of increase in intercontraction intervals (1.7 times) compared with monotherapy of either drug (1.3 times each) although the combined therapy did not affect blood pressures. CONCLUSIONS: These results suggest that the combination therapy of tadalafil and tamsulosin can induce the additive inhibitory effects on urinary frequency compared with monotherapy, more likely via inhibition of the afferent limb of micturition reflex rather than the efferent function as evidenced by the increases in threshold pressures and intercontraction intervals without affecting bladder contractile function.