Partial Bladder Research Articles

Does and duration of exposure time dependent regulation of proteins in the urinary bladder of hamsters exposed to sodium arsenite

Does and duration of exposure time dependent regulation of proteins in the urinary bladder of hamsters exposed to sodium arsenite

Bladder Hyperactivity Induced by Oxidative Stress and Bladder Ischemia: A Review of Treatment Strategies with Antioxidants.

Overactive bladder (OAB) syndrome, including frequency, urgency, nocturia and urgency incontinence, has a significantly negative impact on the quality-of-life scale (QoL) and can cause sufferer withdrawal from social activities. The occurrence of OAB can result from an imbalance between the production of pro-oxidants, such as free radicals and reactive species, and their elimination through protective mechanisms of antioxidant-induced oxidative stress. Several animal models, such as bladder ischemia/reperfusion (I/R), partial bladder outlet obstruction (PBOO) and ovarian hormone deficiency (OHD), have suggested that cyclic I/R during the micturition cycle induces oxidative stress, leading to bladder denervation, bladder afferent pathway sensitization and overexpression of bladder-damaging molecules, and finally resulting in bladder hyperactivity. Based on the results of previous animal experiments, the present review specifically focuses on four issues: (1) oxidative stress and antioxidant defense system; (2) oxidative stress in OAB and biomarkers of OAB; (3) OAB animal model; (4) potential nature/plant antioxidant treatment strategies for urinary dysfunction with OAB. Moreover, we organized the relationships between urinary dysfunction and oxidative stress biomarkers in urine, blood and bladder tissue. Reviewed information also revealed the summary of research findings for the effects of various antioxidants for treatment strategies for OAB.

178 Suspected Cauda Equina Syndrome in a District General Hospital

Abstract Introduction Cauda Equina Syndrome (CES) is rare but when the diagnosis is delayed patient morbidity is significant. Recently, NICE Clinical Knowledge Summaries have updated their red flags on CES to be more explicit enabling earlier referral and diagnosis. A joint project between Orthopaedics and Radiology departments aimed to assess the current pathway of Cauda Equina Investigation at a District General Hospital. Method Data was collected from the local Radiology database for requests between July 2017 and August 2018. This included both direct requests to assess for CES and implied. Raw data revealed a potential of 600 patients, of which we have analysed 332 patients met the eligibility criteria. Results Only 58 patients had a documented complete bladder function assessment, of those 33% had incomplete or partial bladder emptying. Time to MRI scan ranged from 50mins – 23 hours & 52 mins. 47% had negative scans with CES or Cord compromise on MRI scan was demonstrated on 9%. 23 patients were transferred urgently to the receiving tertiary centre. Conclusions We found that nearly 90% of patients were being incompletely assessed and time to scan ranged significantly. We are producing a trust wide suspected CES pathway to improve patient assessment.

Fibroblast Growth Factor 2 Promotes Bladder Hypertrophy Caused by Partial Bladder Outlet Obstruction.

Non-invasive biomarkers to identify patients with bladder outlet obstruction (BOO)-related dysfunction are still needed to guide clinical practice. The current study aims to investigate molecular alterations and biomarkers associated with partial BOO (PBOO) in rats. Sprague–Dawley rats were used to establish the BOO model. Serum samples from 60 patients with benign prostatic hyperplasia (BPH) were used for enzyme-linked immunosorbent assay analysis. RNA sequencing and TMT-labeling proteomic analyses were conducted to identify molecular alterations. Masson’s trichrome, H&E, and immunohistochemical staining and western blotting were conducted by using conventional methods following the manufacturer’s instructions. Rats with PBOO experienced hypertrophy of smooth muscle cells and hyperplasia of interstitial cells during the first 4 weeks after the initiation of obstruction. Four weeks later, rats with PBOO showed activation of the adaptive immune response, cell death and apoptosis. The levels of brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) in the serum gradually increased in the first 4 weeks and gradually decreased after week 4. FGF2 levels slightly correlated with prostate volume (R = 0.156, P = 0.0028) but not with age or BMI in BPH patients. No correlations were found between BDNF levels and prostate volume, age or BMI. BOO induces a change from bladder compensation to decompensation at week 4. FGF2 is involved in the development of hypertrophy in the PBOO bladder and shows a positive correlation with prostate volume in BPH patients.

Metformin ameliorates bladder dysfunction in a rat model of partial bladder outlet obstruction.

Alteration of bladder morphology and function was the most important consequence of bladder outlet obstruction (BOO). Using a rat model of partial BOO (pBOO), we found that rats treated with metformin showed lower baseline pressures with a reduced inflammatory reaction in the early phase (2 wk) after pBOO. The NLR family pyrin domain containing 3 inflammasome pathway was inhibited in pBOO rat bladders with treatment of metformin in the early phase. Metformin reduced the activity of NLR family pyrin domain containing 3 in primary urothelial cells. In the chronic phase (9 wk after pBOO), metformin treatment ameliorated bladder fibrosis and improved the reduced compliance. Treatment with metformin suppressed the activation of Smad3 and compensated the diminished autophagy in 9-wk pBOO rat bladders. Autophagy was inhibited with upregulation of profibrotic proteins in primary fibroblasts from chronic pBOO bladders, which could be restored by administration of metformin. The antifibrotic effects of metformin on fibroblasts were diminished after silencing of AMP-activated protein kinase or light chain 3B. In summary, this study elucidates that oral administration of metformin relieves inflammation in the bladder during the early phase of pBOO. Long-term oral administration of metformin can prevent functional and histological changes in the pBOO rat bladder. The current study suggests that metformin might be used to prevent the development of bladder dysfunction secondary to BOO.NEW & NOTEWORTHY The present study in a rat model showed that oral administration of metformin alleviated inflammation following partial bladder outlet obstruction in the early phase and ameliorated bladder fibrosis as well as bladder dysfunction by long-term treatment. Our study indicated that metformin is a potential drug to inhibit bladder remodeling and alleviate bladder dysfunction. Clinical trials are needed to validate the effect of metformin on the bladder dysfunction and bladder fibrosis in the future.

Are sham-operated mice a valid comparator in studies using a bladder outlet obstruction model? A pitfall reveals a meaningful insight.

To evaluate voiding behavior characteristics in intact and sham mice, and to examine whether intact mice show changes in "normal" micturition with aging. A total of 72 8-week-old mice were divided into two groups - intact and sham - and the latter group was subjected to a sham of partial bladder outlet obstruction surgery. Urination frequency was evaluated (through metabolic cages) at 1, 2, 3, 6 and 12months after the surgery (or at the equivalent time points for the intact mice). To address possible mechanisms for aging and surgical effects on urinary behavior, quantitative real-time polymerase chain reaction assays were carried out. Primary data were evaluated using scatter plots and descriptive statistics. In sham mice, urination frequency showed strong variation at the earlier post-surgical time points (especially at 1month), with variation decreasing with time. Quantitative real-time polymerase chain reaction showed that the serotonin2C receptor-encoding mRNA accumulated to >28-fold higher levels at 24months compared with 3months in intact mice. A major limitation of the quantitative real-time polymerase chain reaction experiments was that we did not separate whole bladder into muscle and mucosa. Although a sham operation is typically used in partial bladder outlet obstruction experiments to provide control animals, the sham group might itself show increased variation in micturition frequency at early times after surgery, compared with intact animals.

Urethral reconstruction in aphallia using transpubic exposure and colonic monti neo-urethra – An addition to the De Castro reconstruction

Fashioning a functioning neo urethra in a boy with aphallia is one of the unsolved problems in this condition. We present our technique and outcome of operative exposure and neo urethral construction in four aphallic boys. Retrospective study of the records of four aphallic boys operated in the period 2015-2019 was undertaken. The demographics, presentation, operative procedure, current follow up and voiding outcome was noted. The neo phallus was constructed by the De Castro technique in four aphallic boys aged 1-8 years. Pre operative assessment revealed bladder outflow obstruction in two and urinary incontinence in one boy. The operative exposure afforded after reflection of the De Castro flap was utilized in doing a limited pubic symphysiectomy. This exposed the bladder neck, urethra and the urethral termination into the ano rectum. The healthy native urethra was isolated by disconnecting it from its ano rectal termination and a neo urethra constructed from a segment of proximal sigmoid colon by its reconfiguration into a Monti type tube. The neo urethra was then anastomosed to the native urethra and laid within the bed of the De Castro flap so as to reach the neo phallic termination. The De Castro flap was then tabularized over the neo urethra to form the new phallus. Appendicular or ileal Monti Mitrofanoff was also added to the reconstruction. Three boys are voiding well. One boy had a partial bladder outflow obstruction resulting from operative correction of incontinence and is dry on intermittent catheterization. Follow up was for 1-4 years and upper tracts are stable or improved. We describe the transpubic approach to the construction of a reliable neo urethra in the form of a Monti tube from the sigmoid colon in four boys with aphallia. We believe this to be a useful addition to the De Castro procedure for neo phallic construction.

IgG4 Related Disease Presenting As a Solid Ovarian Mass with Ureteric and Bladder Involvement: A Case Report

Study Objective IgG4-related disease (IgG4-RD), a systemic immune-mediated condition, presenting as a solid ovarian mass concerning for malignancy resected using a minimally invasive approach. Design A case report of a 43-year-old G3P3 with a history of total abdominal hysterectomy for fibroids presenting with pelvic pain and a newly diagnosed pelvic mass on imaging. Medical history was significant for diabetes. Setting N/A Patients or Participants N/A Interventions The procedure performed included laparoscopic resection of the right ovarian mass, enbloc resection of the lower right ureteral, partial radical cystectomy, uretoneocystotomy and bladder reconstruction. Measurements and Main Results CT abdomen and pelvis demonstrated prominent retroperitoneal lymph nodes and moderate right-sided hydronephroureterosis secondary to compression by the pelvic mass. Pelvic MRI demonstrated heterogeneous enhancement of the mass with possible bladder invasion. Tumor markers, CA -125 and CEA, were within normal limits. Intraoperative findings included a solid, complex right adnexal mass adherent to the right pelvic side wall incasing the right ureter with no clear ability to delineate tissue planes. In addition, the mass was found to be infiltrating the bladder around the ureteral orifice mimicking tumor invasion. Pathology report demonstrated extensive sclerosing fibrosis with ureteral obliteration, lymphocytic infiltrates and obliterative phlebitis highly suggestive of IgG4-RD. The pelvic washings were negative for malignant cells. On follow up, patient with resolved pelvic pain and no evidence of recurrence on imaging. Adjuvant corticosteroid treatment was initiated by Rheumatology to reduce recurrence risk. Conclusion IgG4-RD is a rare diagnosis that has yet to be described as an adnexal mass. Due to the close resemblance to malignancy, recognizing this disease clinically becomes very important. Given the evidence that there is response to early glucocorticoid therapy, it is important for gynecologists to be aware of this disease to facilitate an expedited diagnosis to prevent potential unnecessary invasive procedures.

Changes in the expression and function of the PDE5 pathway in the obstructed urinary bladder.

Our study aims to explore changes in bladder contractility and the phosphodiesterase type 5 (PDE5) signalling pathway in response to partial bladder outlet obstruction (PBOO). A surgically induced male rat PBOO model and human obstructed bladder tissues were used. Histological changes were examined by H&E and Masson's trichrome staining. Bladder strip contractility was measured via organ bath. The expressions of nitric oxide synthase (NOS) isoforms, PDE5, muscarinic cholinergic receptor (CHRM) isoforms and PDE4 isoforms in bladder were detected by RT‐PCR and Western blotting. The immunolocalization of the PDE5 protein and its functional activity were also determined. PBOO bladder tissue exhibited significant SM hypertrophy and elevated responsiveness to KCl depolarization and the muscarinic receptor agonist carbachol. NOS isoforms, PDE5, CHRM2, CHRM3 and PDE4A were up‐regulated in obstructed bladder tissue, whereas no change in PDE4B and PDE4D isoform expression was observed. With regard to PDE5, it was expressed in the SM bundles of bladder. Interestingly, obstructed bladder exhibited less relaxation responsiveness to sodium nitroprusside (SNP), but an exaggerated PDE5 inhibition effect. The up‐regulation of PDE5 could contribute to the lack of effect on Qmax for benign prostatic hyperplasia/lower urinary tract symptom (BPH/LUTS) patients treated with PDE5 inhibitors. Moreover, PDE5 (with presence of NO) and PDE4 may serve as new therapeutic targets for bladder diseases such as BPH‐induced LUTS and overactive bladder (OAB).

Long-term administration of alpha-1 blocker can reverse the micturition pattern in a bladder outlet obstruction murine model.

To investigate the effect of chronic administration of an alpha-1 blocker on micturition patterns in long-term partial bladder outlet obstruction. Mice were divided into three groups: a normal group, in which animals were fed a standard diet; a partial bladder outlet obstruction group, in which the proximal urethra was tied and animals were fed a standard diet; and a partial bladder outlet obstruction+naftopidil group, in which the proximal urethra was tied and animals were fed a standard diet containing naftopidil. Micturition behavior was evaluated in all groups for 6months after partial bladder outlet obstruction surgery. The parameters evaluated included voided volume, time per void, urination frequency and total urine volume. Quantitative assessment of gene expression was also carried out. Total urine volume, as well as total and average voided volume during night, was significantly decreased in partial bladder outlet obstruction+naftopidil mice compared with partial bladder outlet obstruction animals. The levels of transcripts encoding 5-hydroxytryptamine2A and tissue inhibitor of metalloproteinase2 were significantly decreased in the partial bladder outlet obstruction+naftopidil group compared with the partial bladder outlet obstruction group. Long-term administration of an alpha-1 blocker seems to reverse the disturbance of the micturition pattern caused by partial bladder outlet obstruction. Mechanistically, this effect might be mediated by changes in the expression of a serotonin receptor and/or in the activity of the fibrogenesis pathway.

β-Adrenoceptor regulates contraction and inflammatory cytokineexpression of human bladder smooth muscle cells via autophagy under pathological hydrostatic pressure.

Abnormal intravesical pressure created by partial bladder outlet obstruction (PBOO) triggered the progression from chronic inflammation to fibrosis, initiating structural and functional alterations of bladder. To elucidate the underlying mechanisms of contraction and inflammatory response, we investigated the isolated human bladder smooth muscle cells (hBSMC) under pathological hydrostatic pressure (HP) mimicking the in vivo PBOO condition. hBSMCs were subjected to HP of 200 cm H2 O to explore the contraction and inflammatory cytokineexpression of hBSMC treated with β-adrenoceptors (ADRBs) and/or autophagy signaling pathway agonists and/or antagonists. We showed that pathological HP induced the release of the proinflammatory cytokines, including monocyte chemotactic protein-1, regulated upon activation normal T cell expressed and secreted factor, and interleukin-6. HP downregulated ADRB2 and ADRB3 expression, which was consistent with the results of the PBOO rat model. ADRB2 or autophagy activation repressed pathological HP-induced proinflammatory cytokineproduction. ADRB2, ADRB3 or autophagy activation ameliorated the HP-enhanced contraction. The increased contraction and autophagy activity by ADRB2 agonist under HP conditions were reversed by pretreatment with antagonists of adenosine monophosphate-activated protein kinase (AMPK). The present study provides evidence that the ADRB3 agonist suppresses hBSMC contraction under pathological HP conditions. Moreover, the ADRB2 agonist negatively regulates the contraction and inflammatory response of hBSMCs through AMPK/mTOR-mediated autophagy under pathological HP. These findings provide a theoretical basis for potential therapeutic strategies for patients with PBOO.

Expression of NGF, MCP-1, uroplakin III, and NOS in bladder urothelium after partial urethral obstruction in rats

Although several cytokines, chemokines, and growth factors have been suggested to play a role in the development of bladder fibrosis and functional changes, the mechanisms that are effective in the pathogenesis of partial bladder outlet obstruction (pBOO)-induced bladder fibrosis are not well understood. We investigated the expressions of nerve growth factor (NGF), monocyte chemoattractant protein-1 (MCP-1), uroplakin III (URPIII), inducible nitric oxide synthase (iNOS), and endothelial NOS (eNOS) that may be involved in fibrosis in rats with partial urethral obstruction for 1, 2 and 3 weeks, and the changes in the associated ischemic and inflammatory processes. After 1, 2, and 3 weeks of pBOO, blood samples were collected for assessment of renal function from the rats under anesthesia. The bladders were dissected for the tissue antioxidant enzyme activities and lipid peroxidation, including malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant status (TAS) and total oxidant status (TOS). The immunohistochemical studies were performed. Histopathologically, the number of urothelial layers was calculated and the thickness of the detrusor smooth muscle and lamina propria were quantitatively measured. Additionally, the edema and congestion in the submucosa were evaluated. Twenty-eight male Sprague-Dawley rats were used in this study. Three separate experimental groups of pBOO (1 week [n=7], 2 weeks [n=7], and 3 weeks [n=7]) were created, with an additional sham-operated control group (n=7). The MDA levels increased in pBOO groups. The SOD values were decreased in the pBOO group for 1 week, and higher in the 3-week pBOO group. The TAS levels were increased in the 3 week pBOO group. The TOS levels increased in the pBOO groups. The number of urothelial layers was decreased in pBOO groups. The lamina propria, the smooth muscle thickness, edema and congestion were increase in the 1 and 2 week pBOO groups. The NGF and MCP-1 expression was increased in the 1-week and 2-week pBOO groups. The expression of URPIII in the epithelium gradually increased in the pBOO groups. In the pBOO groups, iNOS expression in the epithelium cells was significantly elevated. However, the eNOS expression was also significantly increased in the 2 week pBOO group. Our study shows that overexpression of immunohistochemical parameters together with the negative effects of ischemic and inflammatory processes that subjected to pBOO for 1, 2 and 3 weeks may play a potential role in detrusor fibrosis in the rat bladders induced by pBOO. However, understanding of the immunohistochemical parameters investigated in this experimental study is limited, and further studies targeting their relationship to pBOO could help us develop new strategies.

Mesenchymal stem cells ameliorate partial bladder outlet obstruction-induced epithelial-mesenchymal transition type II independent of mast cell recruitment and degranulation.

Partial bladder outlet obstruction (pBOO) results in increased urinary storage pressure and significant morbidity. Increased pressure results in a sequence of programmed events: an initial inflammatory phase, smooth muscle hypertrophy, and fibrosis. Although epithelial-mesenchymal transition (EMT) and mast cell accumulation play intermediary roles in some fibrotic conditions, their role in pBOO has not yet been elucidated. Mesenchymal stem cell (MSC) therapy is emerging as a promising treatment for several conditions. It potently inhibits bladder deterioration after pBOO; however, its mechanism of action is insufficiently understood. Thus, we hypothesize that EMT type II pathway plays a significant role in pBOO, aided by the recruitment and activation of mast cells, and these are potently inhibited by MSCs. pBOO was surgically induced in female Sprague-Dawley rats and simultaneously treated with MSCs. Treatment effect was determined after two or four weeks and compared to untreated controls. Immunohistochemistry was used to measure markers characteristic of EMT (vimentin, collagenase, and collagen). Whole and degranulated mast cell counts were also performed. pBOO resulted in an increased expression of collagenase, vimentin, and collagen. Mast cell recruitment increased proportionately to the length of bladder obstruction. MSC treatment significantly mitigated the EMT type II response, but mast cell recruitment and degranulation were unaffected. Our results demonstrate the involvement of EMT type II in the pathophysiology of pBOO and confirm its mitigation with MSC treatment independent of mast cells response. The observations provide insight into the mechanism of action and have therapeutic ramifications.

Bladder outlet obstruction disrupts circadian bladder function in mice

The circadian clock programs daily rhythms and coordinates multiple behavioural processes, including micturition. Partial bladder outlet obstruction (pBOO) in mice produces hyperactive voiding. However, long-term effects of pBOO on bladder function have not been clarified. In this study, we investigated micturition under conditions of impaired circadian bladder function by inducing long-term pBOO by tying the proximal urethra. Micturition behavior was evaluated at 1, 3, 6 and 12 months after surgery. We used automated voided stain on paper method for a precise micturition recording for mice. And quantitative assessment of gene expression was performed at 24 months after pBOO surgery using qRT-PCR procedure. The micturition frequencies in the pBOO group were significantly decreased at 3, 6, and 12 months compared to those at 1 month after operation in the same group (p < 0.05). Body weight of pBOO mice was significantly increased compared to sham operated mice at 12 months. The expression level of mRNA was exhibited a 3.4-fold nominal increased for a 5-HT2B receptor in the pBOO group compared to the sham group. The current study found that long-term pBOO led to disruption of the circadian bladder function (the day/night cycle) in mice, similar to those observed in human as nocturia. This disruption is possible involvement of the gain of body weight and/or serotonergic alteration after pBOO.

644 - Pathological analysis focused on inflammatory changes in bladder dysfunction following partial bladder outlet obstruction

644 - Pathological analysis focused on inflammatory changes in bladder dysfunction following partial bladder outlet obstruction

643 - Oral administration of tadalafil can suppress both bladder dysfunction and detrusor fibrosis in male rats with partial bladder outlet obstruction (BOO)

643 - Oral administration of tadalafil can suppress both bladder dysfunction and detrusor fibrosis in male rats with partial bladder outlet obstruction (BOO)

Effects of Visceral Interoception on Topological Properties of the Brain - A Graph Theory Analysis of Resting state fMRI.

Recent neuroimaging studies have employed graph theory as a data-driven approach to describe topological organization of the brain under different neurological disorders or task conditions and across life span. In this exploratory study, we tested whether subtle differences in interoception related to intravesical fullness can alter brain topological architecture in healthy participants. 17 right-handed women underwent a series of resting state fMRI scans that included catheterization and partial bladder filling. Using a whole brain regions of interest (ROIs), we computed several graph theory metrics to assess the efficiency of brain-wide information exchange. Results showed that brain network's topological properties significantly changed in many brain regions when we binary compared different interoceptive resting state conditions. Notably, we observed changes in global efficiency in the salience network, the central executive network, anterior dorsal attention network and the posterior default-mode network (DMN) as bladder became full and interoceptive signals intensified. Moreover, degree (the number of connections for each node), and betweenness centrality (how connected a particular region is to other regions) differed between the empty bladder, the catheterized empty bladder, and the catheterized and partially filled bladder. Comparing resting state data before and after an interoceptive task (repeated intravesical infusion and drainage) further showed increased average path length for the salience networks and decreased clustering coefficient of the DMN. These results suggest visceral interoception influences brain topological properties of resting state networks.

Robotic Low Anterior Resection and Partial Bladder Resection for Management of Locoregional Endometrial Cancer Recurrence

To demonstrate a robotic tumor debulking for management of locoregional endometrial cancer recurrence. Case report. Tertiary referral center in New Haven, CT. A 70-year-old patient with a history of stage IB endometrioid endometrial cancer presented with rectal bleeding 3 years after the completion of treatment. A mass involving the distal sigmoid colon/upper rectum and bilateral distal periureteral masses were visualized on imaging. There was no distant metastatic disease. Colonoscopic biopsies were consistent with endometrial cancer recurrence. Because the patient was symptomatic with rectal bleeding and had no distant metastasis, it was recommended that she undergo surgical resection for management of this locoregional recurrence. The patient was placed in reverse Trendelenburg position with a rightward tilt to mobilize the splenic flexure. Once the cephalad aspect of the descending colon mobilization was completed, the patient was placed in Trendelenburg lithotomy position to expose the pelvis. A robot was docked at this point and the pelvic avascular spaces were delineated. A medial-to-lateral approach was used in mobilization of the sigmoid colon mesentery. The left ureter was identified and the sigmoid branches of inferior mesenteric artery were sealed. The descending/sigmoid colon junction was stapled. After complete mobilization of the sigmoid colon, the tumor-free upper rectum was delineated and stapled. Attention was then turned to the distal peri-ureteral masses. The 2-cm mass on the right, which was densely adherent to the distal right ureter, was completely resected after extensive ureterolysis. The resection of the 4-cm mass on the left which involved both the distal left ureter and the bladder dome required an intentional cystotomy and a partial cystectomy to attain negative margins (Supplemental Figure 1). The procedure was continued with the bowel anastomosis. The anvil was introduced through the vagina and was placed into the proximal limb through an antimesenteric incision. An end-to-end tension-free anastomosis was performed and adequate vascularization was confirmed with intravenous indocyanine green. Robotic low anterior resection and partial bladder resection were performed without any complications with negative margins. Robotic tumor debulking should be considered in appropriate patients when managing locoregional recurrence of endometrial cancer [1,2].

Long-term tadalafil administration can prevent functional and structural changes of the urinary bladder in male rats with partial bladder outlet obstruction.

There have been few reports on whether long-term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes. Eight-week-old male Sprague-Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks. In BOO rats, a significant increase in the number of non-voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats. Long-term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non-obstructed rats.

β-Adrenoceptors regulate matrix metalloproteinase expression in human urothelial cells under hydrostatic pressure.

The bladder wall is constantly subjected to intravesical pressure during the filling and voiding cycles. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) under elevated intravesical pressure contributes to pathological changes in the bladder. To investigate the changes in human urothelial cells (HUCs) under elevated intravesical pressure, this study analyzed the effect of β-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs exposed to pathological hydrostatic pressure (HP) (70 cm H2 O) for 6 hours. Quantitative polymerase chain reaction, Western blot analysis, and cell fluorescence staining were used to explore the effect of β-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs after agonist and/or antagonist treatment. The expression levels of β2 - and β3 -adrenoceptor, MMP1, and MMP2 were greatly downregulated, while the expression of TIMP1 was greatly upregulated. Formoterol and BRL 37344, which are agonists of β2 - and β3 -adrenoceptor, respectively, significantly increased MMP1 and MMP2 expression under 70 cm H2 O. As a classic downstream pathway of β2 - and β3 -adrenoceptor, protein kinase A (PKA) signaling inhibited MMP1 and MMP2 expression by regulating cAMP response element binding protein (CREB) activity. MMP1 and MMP2 expression in HUCs under 70 cm H2 O was modified by β2 - and β3 -adrenoceptor via the PKA/CREB pathway. This outcome suggests that MMPs likely participate in the pathological effects of elevated intravesical pressure. The underlying mechanism of β2 - and β3 -adrenoceptor in elevated intravesical pressure was also revealed; this mechanism constitutes a new potential therapeutic target for partial bladder outlet obstruction.