Bladder Outlet Obstruction Group Research Articles

Decreased Angiopoietin Expression in Underactive Bladder Induced by Long-term Bladder Outlet Obstruction.

Ischemia of the bladder can occur if neovascular formation cannot keep pace with hypoxia induced by chronic bladder outlet obstruction (BOO). The aim of this study was to examine changes in angiogenesis growth factor expression generated by chronic BOO in a rat model of underactive bladder. Twenty female Sprague-Dawley rats aged 6 weeks were assigned to 4 groups (5 rats per group). Group 1 was the control. Group 2 underwent sham surgery. The rats in groups 3 and 4 underwent BOO and were followed up for 1 week and 8 weeks. Cystometry was carried out together with bladder tissue analysis at 1 week and 8 weeks postoperatively. Real-time polymerase chain reaction (PCR) assays were conducted to determine the expression level of angiogenesis-related growth factors. A hypoxia signaling pathway PCR array was additionally carried out. The group that underwent BOO for 8 weeks showed abnormal bladder function, with a diminished intercontraction interval, decreased maximal voiding pressure, and higher volume of residual urine (P<0.05). Hypoxia-inducible factor-1 alpha expression was elevated in this group. The expression levels of vascular endothelial growth factor (VEGF) and VEGF receptor messenger RNA (mRNA) in the BOO group were comparable to those in the control group. However, angiotensin/tie receptor mRNA expression levels increased at 1 week after BOO, but decreased at 8 weeks after BOO. In animals that underwent BOO, fewer blood vessels exhibited positive immunofluorescent staining for von Willebrand factor. Alterations were also seen in the hypoxia signaling pathway PCR array. In a rat model of underactive bladder caused by surgical BOO, reduced angiopoietin expression was demonstrated. This observation might underlie visceral ischemia and fibrosis associated with the procedure. The findings of this study might offer an improved understanding of the disease processes underlying BOO and facilitate selection of the appropriate time to repair the organ in this condition.

Evaluation of a noninvasive uroflowmetry parameter (Delta Q value) in detrusor underactivity and bladder outlet obstruction

Purpose To determine the significance of the Delta Q value in discrimination between detrusor underactivity (DU) and bladder outlet obstruction (BOO) in adult male patients. Methods A total of 238 patients in this cohort study underwent pressure-flow study. Patients were divided into two groups based on UDS outcomes: DU (n = 121) and BOO (n = 117). From uroflowmetry, 5 variables including maximal flow rate (Qmax), average flow rate (Qave), voiding volume (VV), postvoid residual urine (PVR), and the difference between (Qmax) and (Qave) known as (Delta Q) were obtained. Diagnostic prediction of these variables was evaluated with DU and BOO. Results Delta Q was less in the DU group compared with the BOO group 2.9 ml/s and 6.2 ml/s, respectively. Delta Q showed a promising diagnostic value in the discrimination between DU and BOO. A cut-off value of 6.1 ml/s was found to be discriminatory between the two groups with a sensitivity of 96.58% and specificity of 92.79%. Conclusion Delta Q value has proven to be a useful noninvasive screening and diagnostic tool in differentiating between DU and BOO in men with obstructive lower urinary tract symptoms.

Changes of proapoptotic and antiapoptotic genes affect sensitivity to apoptotic stimuli in impaired contractility due to long term bladder outlet obstruction.

The normal biological process that necessitates cell removal greatly depends on apoptosis. Long term bladder outlet obstruction (BOO) causes damaged smooth muscle cells to undergo apoptosis. However, smooth muscle cell apoptosis that BOO causes is not well known in impaired bladder contractility. Therefore, we designed this study to investigate whether long-term BOO could induce apoptosis activities and to obtain an expression profile of apoptosis related genes. We used 10 Sprague-Dawley six-week-old female rats. We separated them equally into two groups: a sham intervention group (group 1) and an eight-week BOO group (group 2). We conducted cystometric evaluation eight weeks following BOO onset, with processing of bladder tissue for PCR array. Every array comprised 84 genes, which were established to contribute to an apoptosis response, cell differentiation and metabolism, and 12 sequences were established for the regulation of loading and the quality of cDNA. We performed real-time PCR. Changes in gene expression presented as a fold increase/decrease. Alterations of more than two-fold constituted the cut-off determining expression. Group 2 had a greater bladder weight and Impaired bladder contractility. Immunofluorescent staining with CAS3, TUNEL showed increased in the BOO group. In comparison to group 1, group 2 exhibited an at least two-fold upregulation in five genes, the Bcl-2 (15.1), Birc5 (5.8), Cd40lg (7.5), Il10 (16.2), and Naip2 (13.2). They also demonstrated at least a two-fold downregulation in the PRLR (-18.1) gene. Genes Bcl2ald, Circ5, Cd40lg, Il10, Naip2, and PRLR were among the genes with activity against apoptosis. TNF, STAT3 and TP53 mediated the effect that genes had on one another. This study demonstrated that the relative ratios of pro- and antiapoptotic genes determine bladder cell sensitivity cells to apoptotic stimuli in impaired contractility caused by long term BOO. Although we cannot confirm whether this finding is the result of the decompensated phase of the bladder or the process, the gene expression profiles could explain molecular mechanisms of apoptosis in impaired bladder contractility caused by long-term BOO with further studies.

Survivin knockdown alleviates pathological hydrostatic pressure-induced bladder smooth muscle cell dysfunction and BOO-induced bladder remodeling via autophagy.

Aim: Bladder outlet obstruction (BOO) leads to bladder wall remodeling accompanying the progression from inflammation to fibrosis where pathological hydrostatic pressure (HP)-induced alteration of bladder smooth muscle cells (BSMCs) hypertrophic and excessive extracellular matrix (ECM) deposition play a pivotal role. Recently, we have predicted survivin (BIRC5) as a potential hub gene that might be critical during bladder fibrosis by bioinformatics analyses from rat BOO bladder, but its function during BOO progression remains unknown. Here, we investigated the role of survivin protein on bladder dysfunction of BOO both in vitro and in vivo. Methods: Sprague-Dawley female rats were divided into three groups: control group, BOO group, and BOO followed by the treatment with YM155 group. Bladder morphology and function were evaluated by Masson staining and urodynamic testing. To elucidate the underlying mechanism, hBSMCs were subjected to pathological HP of 200cm H2O and co-cultured with the presence or absence of survivin siRNA and/or autophagy inhibitor 3-MA. Autophagy was evaluated by the detection of Beclin1 and LC3B-II expression, proliferation was conducted by the EdU analysis and PCNA expression, and fibrosis was assessed by the examination of Col 1 and Fn expression. Results: BOO led to a gradual alteration of hypertrophy and fibrosis of the bladder, and subsequently induced bladder dysfunction accompanied by increased survivin expression, while these histological and function changes were attenuated by the treatment with YM155. HP significantly increased survivin expression, upregulated Col1 and Fn expression, enhanced proliferation, and downregulated autophagy markers, but these changes were partially abolished by survivin siRNA treatment, which was consistent with the results of the BOO rat experiment. In addition, the anti-fibrotic and anti-proliferative effects of the survivin siRNA treatment on hBSMCs were diminished after the inhibition of autophagy by the treatment with 3-MA. Conclusion: In summary, the upregulation of survivin increased cell proliferation and fibrotic protein expression of hBSMC and drove the onset of bladder remodeling through autophagy during BOO. Targeting survivin in pathological hBSMCs could be a promising way to anti-fibrotic therapeutic approach in bladder remodeling secondary to BOO.

Bladder wall thickness measured by CT can predict bladder outlet obstruction in men: a retrospective cohort study.

To evaluate whether bladder wall thickness (BWT) measured by CT can be used to predict bladder outlet obstruction in men with low urinary tract symptoms (LUTS). From 2015 to 2018, a total of 120 men with lower urinary tract symptoms who underwent both urodynamic studies and CT tests of the lower abdomen or pelvis were involved. Bladder wall thickness values were measured by CT scanning. Based on the urodynamic studies, 120 men were categorized into two groups, including 70/120 men (58.3%) in the bladder outlet obstruction (BOO) group and 50/120 men (41.7%) in the non-BOO group. The mean BWT was thicker in the BOO group than in the non-BOO group (3.87 vs. 2.75mm, p < 0.001). The mean maximum bladder capacity (MBC) was lower in the BOO group than in the non-BOO group (263.42 vs. 308.96ml, p < 0.001). The mean detrusor pressure at maximum urinary flow rate (PdetQmax) was higher in the patients in the BOO group than in those in the non-BOO group (102.28 vs. 49.25 cmH2O, p < 0.001). The ROC curve showed that BWT was a good predictor with an AUC of 0.855 (95% CI 0.785-0.924, p < 0.001). At the cutoff value of 3.20mm, the predictive sensitivity of BWT for BOO was 72.9%, and the specificity was 90%. Increased bladder wall thickness was correlated with bladder outlet obstruction in men with LUTS. Bladder wall thickness measured by CT scans may be a noninvasive parameter to predict bladder outlet obstruction in men with LUTS.

Non-invasive diagnosis of under active bladder: A pilot study.

We assessed the efficacy of voiding efficiency (VE) to distinguish between underactive bladder (UB) and bladder outlet obstruction (BO) without using pressure flow studies (PFS). in male patients, uroflowmetry and post-void residual (PVR) urine data and subsequent pressure flow studies (PFS) data were examined retrospectively. Bladder outlet obstruction index (BOI) and bladder contractility index (BCI) were calculated from patients' PFS values. Patients with BCI < 100 and BOI < 40 were grouped as UB group and patients with BCI > 100 and BOI > 40 were grouped as BOO group. VE was computed as a percentage of volume voided compared to the pre-void bladder volume. In total we examined 93 patients, 44 in UB and 49 in BO group. There was no statistically significant difference between the two groups in relation to Qmax value (p = 0.38). However, total voiding time, time to reach the maximum urinary flow rate and voided volume showed statistically significant difference between the two groups (p < 0.001). Average VE was 63.6 + 2.43% and 46.2 + 2.63%) for UB and BO groups respectively and the difference was statistically significant (p < 0.001). UB can be diagnosed with at least 95% sensitivity and 88% specificity in men over age 80. Non-invasive uroflowmetry and VE measurements were able to differentiate between UB and BOO patients, presenting with identical clinic features, but different findings of PFS.

Clinical features of detrusor underactivity in elderly men without neurological disorders.

To investigate the clinical features of detrusor underactivity (DU) in elderly men without neurological disorders. A total of 336 men aged ≥50 years without neurogenic disorders who underwent pressure flow studies and who had DU or bladder outlet obstruction (BOO) were reviewed retrospectively. According to the bladder contractility index (BCI) and the BOO index (BOOI), the subjects were classified into the following three groups: (a) pure DU group, BCI < 100 and BOOI < 40; (b) DU + BOO group, BCI < 100 and BOOI ≥ 40; and (c) pure BOO group, BCI ≥ 100 and BOOI ≥ 40. Subjective and objective parameters were compared among the three groups, and the predictors for pure DU were evaluated by multivariate analysis. Of the 336 patients, 205 who met the study criteria were included in the analysis: 63 (30.7%) with pure DU, 48 (23.4%) with DU + BOO, and 94 (45.9%) with pure BOO. The proportion of the pure DU group increased with increasing age. Prostate volume was the lowest in the pure DU group. Frequency, urgency on the International Prostate Symptom Score (IPSS), and the IPSS storage subscore were the lowest in the pure DU group. Multivariate analysis showed that age (odds ratio [OR] 1.114 [95% CI, 1.032-1.203], P=.005), prostate volume (OR 0.968 [95% CI, 0.949-0.987], P=.001), and urgency (OR 0.623 [95% CI, 0.431-0.900], P=.012) were predictors of pure DU. Older age, smaller prostate volume, and less urgency may be clinical features of pure DU.

Enhanced Hypoxia-Associated Genes in Impaired Contractility From Bladder Outlet Obstruction.

BackgroundHypoxia damages the bladder wall and contributes to the initiation of bladder dysfunction. The change of hypoxia is not well known in impaired bladder contractility caused by long-term bladder outlet obstruction (BOO). We aimed to find out whether hypoxia of bladder tissue is present and what signaling mechanisms are involved in the decompensated bladder in BOO.MethodsTwenty 6-week-old female Sprague-Dawley rats were divided into 2 groups, 10 rats each: group 1, sham operation; group 2, BOO for 8 weeks. Eight weeks after the onset of BOO, we did cystometric evaluation and processed polymerase chain reaction (PCR) array for hypoxia pathway using bladder tissues. The PCR array consists of 84 genes known to be involved in the hypoxic response, cell differentiation, and metabolism. We did quantitative PCR (qPCR) and immunohistochemical staining of bladder tissue for hypoxia.ResultsEight genes were at least 2-fold upregulated and 3 genes were at least 2-fold downregulated in BOO group, compared with the sham operation group. The up-regulated genes (fold change) belonging to the hypoxia-inducible factor (HIF) 1 interactor included Cdkn2a (11.0), and the down-regulated genes belonging to HIF and co-transcription factors included Hif3a (−39.6) and Per1 (−5.1) by BOO. Genes influenced each other by means of TGFβ1, TNF, and TP53.ConclusionHypoxia genes were increased in impaired contractility because of long-term BOO. The gene expression profiles could explain the molecular mechanisms of hypoxia in impaired contractility because of long-term BOO.

Identifying occult bladder outlet obstruction in women with detrusor-underactivity-like urodynamic profiles

Voiding dysfunction can result from detrusor underactivity (DU), bladder outlet obstruction (BOO), or both. Conceptually, women with high-pressure low-flow urodynamic profiles are diagnosed with BOO without DU. However, the possibility of BOO is often neglected in women with DU-like (low-pressure low-flow) urodynamic (UDS) profiles. By reviewing the videourodynamic studies (VUDS) of 1678 women, our study identified the key factors suggesting urodynamic BOO (determined by radiographic evidence of obstruction) in women with DU-like UDS profiles (Pdet.Qmax < 20 cmH2O and Qmax < 15 mL/s). In 355 women with DU-like UDS profiles, there were 70 (19.7%) with BOO and 285 (80.3%) without BOO. The BOO group had predominantly obstructive symptoms. The BOO group showed significantly decreased bladder sensation, lower detrusor pressure (Pdet.Qmax), lower flow rate (Qmax), smaller voided volume, and larger post-voiding residual (PVR) compared to the non-BOO group. In multivariate analysis, volume at first sensation, Qmax, PVR, and detrusor overactivity (DO) remained independent factors for BOO. The receiver operating characteristic (ROC) areas for the parameters were largest for PVR (area = 0.786) and Qmax (area = 0.742). The best cut-off points were 220 mL for PVR and 4 mL/s for Qmax. Our findings provide simple indicators for BOO in women with DU.

The effect of testosterone replacement therapy on bladder functions, histology, apoptosis, and Rho-kinase expression in bladder outlet obstruction and hypogonadism rat model

Background/aimThe effect of testosterone replacement therapy was investigated on bladder functions, histology, apoptosis as well as Rho-kinase expression in the rat bladder outlet obstruction (BOO) and hypogonadism models. Materials and methods30 mature male rats divided into 4 groups: sham group (n = 8), BOO group (n = 8), BOO + orchiectomy group (n = 7), BOO + orchiectomy + testosterone (T) treatment group (n = 7). Cystometric findings, apoptosis index, Rho-kinase (ROCK-2) expression, and smooth muscle/collagen ratio were compared. Results BOO did not change ROCK-2 expression level, compared to sham group (P > 0.05). However, when compared to BOO group (P < 0.01), BOO + orchiectomy led ROCK-2 increase. The testosterone treatment failed to reverse the up-regulation of ROCK-2 induced by orchiectomy although it tended to lower ROCK-2 level. Compared to sham group (P = 0.002), changes in maximal bladder capacity and leak point pressure were higher (P = 0.026, P = 0.001), and bladder compliance was lower in BOO group. Also, the apoptosis index was different between the two groups (P = 0.380). Smooth muscle/collagen ratio was higher in BOO + orchiectomy + T group than in BOO + orchiectomy group (P = 0.010).ConclusionsThe research draws attention to alternating treatment approaches in case of the presence of hypogonadism and BOO.

Dietary reversal reverts diet-induced alterations in obstructed bladders of Wistar rats

ObjectivesThe aim of this study was to investigate the effects of diet reversal to standard chow on diet-induced changes in structure and function of normal and obstructed bladders in male Wistar rats. MethodsEighty animals were equally divided into sham-surgery and bladder outlet obstruction (BOO) dietary groups and fed standard chow (control), high-carbohydrate, high-fat, and high-protein diets. BOO groups had surgically induced BOO, whereas sham surgery was performed on sham groups at the end of week 8. Animals were continued on the treatment diets for 4 wk after surgery, then the diets were all changed to standard chow for the remainder of the study period. Bladder weight, detrusor contractility, Rho-associated protein kinase (Rho-kinase), and myosin light chain kinase were determined. Polymerase chain reaction was used to assay for transforming growth factor-β, connecting tissue growth factor, hypoxia-inducible factor-1α, and platelet-derived growth factor subunit A levels in the bladder. C-reactive protein, insulin-like growth factor-1, nerve growth factor, and C-X-C motif chemokine ligand 12 concentrations were determined by enzyme-linked immunosorbent assay. The collagen content of the bladder was estimated by liquid chromatography/mass spectrometry. ResultsReversal of diet to standard chow resulted in reversal of diet-induced changes in all variables measured in obstructed bladders. High-fat-diet-induced alterations in normal bladders were also reversed. ConclusionThe results suggested that in obstructed bladders of animals, reversal of the diet could reverse all diet-associated changes that increase inflammation and fibrosis in obstructed bladders. This is especially important in changes related to high consumption of fatty diets and associated lower urinary tract symptoms.

Uroflowmetry pattern in detrusor underactivity and bladder outlet obstruction in male patients with lower urinary tract symptoms.

To investigate if uroflowmetry (UFM) curve patterns could differentiate between detrusor underactivity (DU) and bladder outlet obstruction (BOO). A hundred consecutive data sets of male patients who were evaluated using UFM and invasive urodynamics (pressure flow study) were retrospectively collected. DU and BOO were diagnosed according to the bladder contractility index and BOO index. The UFM curve with two or more notches was defined as sawtooth pattern, and the interrupted pattern was defined if several curves with interruptions reducing to zero were noted. We also compared other UFM parameters including maximum and average flow rates (Qmax and Qave), voiding time, time to Qmax, the slope to first peak flow, the number of notches on the curve (sawtooth pattern), the number of curves (interrupted pattern), and the maximum drop on the sawtooth pattern. Twenty-five and forty-nine patients were categorized in the BOO group and the DU group, respectively. The incidence of sawtooth pattern was significantly higher in the DU group (57%) than in the BOO group (32%), while the incidence of interrupted pattern was not different between the two groups (36% in the BOO group and 49% in the DU group). There were significant differences in age (area under the curve=0.75), prostatic volume (0.67), the slope to first peak flow (0.58), the number of notches on the curve (0.61), and the maximum drop (0.76) between the two groups. The sawtooth UFM pattern is more common in patients with DU than in those with BOO. New parameters on UFM curve patterns could be helpful to evaluate DU and BOO without invasive urodynamics.

Gender-dependent bladder response to one-day bladder outlet obstruction

Development of bladder fibrosis, loss of compliance, and voiding dysfunction are among the severe consequences of various lower urinary conditions, for example, bladder outlet obstruction (BOO), neurogenic bladder, and radiotherapy to the pelvic area. The bladder remodelling results in significant changes in bladder function and architecture, and may ultimately be deleterious for kidney function. The molecular signals underlying pathologic bladder remodelling, as well as the impact of gender, remain poorly understood. To investigate the bladder remodelling after one day BOO, whether the remodelling is different between different bladder sections, and whether genders may affect the remodelling. Thirty male and 30 female C57BL/6NRj mice were randomly divided into Control, Sham and BOO groups with ten mice per group. A 24-h total urethral obstruction was performed at the proximal urethra. Histological changes were observed via H&E, trichrome and immunohistochemistry staining. Harvested bladders were divided into upper and lower sections for analysis. Protein and gene expression were detected by Western blotting and qPCR. No significant changes in bladder wall thickness were observed following BOO, while increased bladder mass after BOO was found in female mice only. We detected FN and ⍺-SMA upregulation in the male upper bladder segment. Female BOO mice bladders showed increased α-SMA expression in both bladder segments, but no difference of FN was observed in either bladder segments. BOO-induced upregulation of TGF-β and Gremlin were detected in both male and female bladders, while downregulation of BMP-7 was detected only in male bladders. Furthermore, phosphorylation of both SMAD2/3 and SMAD1/5/9 were increased in male bladders following BOO, whereas female mice exhibited increased pSMAD2/3 in the upper and increased pSMAD1/5/9 in the lower bladder segment. Our data indicate that some specific proteins and growth factors were detected as early alterations of tissue which may lead to fibrosis. In addition, the males tended to have more pronounced response than females. However, the causes and consequences of the findings need to be further investigated.

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.

USE OF PROSTATE AND BLADDER SONOMORPHOLOGY FOR DIAGNOSIS OF BLADDER OUTLET OBSTRUCTION IN PATIENTS WITH SYMPTOMATIC BENIGN PROSTATIC HYPERPLASIA

Background: Benign prostatic hyperplasia (BPH) is a common urological problem more frequently seen in elderly people causing lower urinary tract symptoms (LUTS). About 28% of patients with BPH have moderate or severe LUTS and a considerable portion of these patients require LUTS treatment, pressure flow studies PFS is the gold standard for diagnosing obstruction, however the test is invasive, unpleasant costly, time consuming and technically difficult with limited availability to the patient. Objective: To evaluate the accuracy of the bladder and prostate sonomorphologic parameters for the diagnosis of bladder outlet obstruction (BOO) in patients with lower urinary tract symptoms (LUTS) with benign prostatic hyperplasia (BPH). Patients and Methods: A prospective clinical trial was carried out during the period from January 2017 to January 2019 at the Urology Departments; Al-Hussein and Sayed Galal, Al-Azhar University Hospitals, and Police Authority Hospital, Cairo, Egypt to 512 patients seeking treatment for LUTS/BPH underwent a series of measurements, including medical history with LUTS assessment using the International Prostate Symptom Score (IPSS), physical examination with digitorectal and focal neurological examinations, routine urinalysis, and serum creatinine and prostate-specific antigen (PSA) measurements. Results: During the study period, 209 patients completed the follow up protocol and included in the study, the mean age of the study population was 64.51 years, the mean total IPSS score was 19.18, the mean duration of symptoms was 6.4 mo., the mean total prostate volume, transitional zone volume, and transitional zone index were 42.5 g, 25.7 g, and 0.6 respectively. The mean bladder parameters studied intravesical prostatic protrusion, bladder wall thickness was 11.3 mm, 4.85 mm, 30.1 g respectively, the mean prostate parameters studied prostate urethral length, prostate urethral angel were 41.8 mm and 34.3˚. Out of 209 patients studied 113 (54.1%) patients were obstructed (BOO group) and 96 (45.9%) were not (non- BOO group). All parameters were comparable between the two groups. Conclusions: Some sonomorphologic parameters of bladder and prostate (IPP, PUA, BWT and Qmax) are useful alternative to PFS for diagnosis of symptomatic BOO/BPH.

The effects of oral administration of the novel muscarinic receptor antagonist DA-8010 on overactive bladder in rat with bladder outlet obstruction

BackgroundDA-8010 is a novel compound developed for the treatment of overactive bladder (OAB) and urinary incontinence. The aims of this study were to investigate the effects of DA-8010 on OAB in a rat model.MethodsStudy animals were divided into the following five groups of seven animals each: a sham-operated control group, a control group with partial bladder outlet obstruction (BOO) (OAB group), and three DA-8010 (doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day, respectively) with partial BOO groups. Oral administration of the drugs was continued for 14 days after 2 weeks of partial BOO. After 4 weeks of partial BOO, cystometrography was performed in all groups. Additionally, pro-inflammatory cytokines, Rho-kinases, and histology of the bladder were analyzed.ResultsThere was a significant increase in the contraction interval and a decrease in contraction pressure in the 3 mg/kg/day DA-8010 group versus those in the OAB group. Rho kinase was also significantly decreased in the DA-8010 3 mg/kg/day dosage treatment group. The increased ratio of collagen to smooth muscle after partial BOO was significantly attenuated in the DA-8010 3 mg/kg/day dosage group.ConclusionsOral administration of DA-8010 at 3 mg/kg/day improved findings in an OAB rat model induced by partial BOO. Our results suggest that the novel muscarinic receptor antagonist DA-8010 may be a promising drug for treating patients with OAB.

The Effects of Bladder Diverticulum on the Pathophysiology of Bladder Outlet Obstruction: An Experimental Study in Guinea Pigs.

Objectives:This study is the first to urodynamically and histopathologically evaluates the effects of bladder diverticulum (BD) secondary to bladder outlet obstruction (BOO).Methods:Guinea pigs (n=32) weighing 900–1,000 g were divided randomly into four groups: Sham, BD, BOO, and BD combined with BOO. All guinea pigs in the four groups underwent urodynamic evaluation preoperatively and at 1 month postoperatively. The bladders were removed and examined histopathologically.Results:The post-operative filling detrusor pressure was lower in the Sham group (7.1±1.6 cm H2O) than in the BD (21.4±5.6 cm H2O) and BD with BOO groups (23.6±9.3 cm H2O) (p<0.05). There was no difference between the Sham and BOO (9.5±4.0) groups. Post-operative bladder compliance was better in the Sham group (2.3±0.8 ml/cm H2O) than in the BD (0.9±0.22 ml/cm H2O) and BD with BOO groups (0.6±0.3 ml/cm H2O) (p<0.05). Involuntary detrusor contraction was not observed in the Sham or BOO groups, but was observed in 37.5% of subjects in the BD and BD with BOO groups. On histological examination, the bladder wall was thicker (3.75±0.68 mm) (p=0.601), and the connective tissue volume was significant increased (p=0.046), in the bladder muscularis mucosa in the BD groups compared to the BOO group.Conclusion:Physiological and histopathological changes in the bladder with BD combined with BOO are more evident than with BOO alone.

The effect of mirabegron on bladder blood flow in a rat model of bladder outlet obstruction.

To evaluate the effects of mirabegron on bladder blood flow in a rat model of bladder outlet obstruction (BOO). Adult female Sprague-Dawley rats were divided into three groups based on whether they underwent a sham operation (sham group) or an operation to establish partial BOO (BOO and BOO + mirabegron groups). The BOO + mirabegron group was treated with mirabegron (0.3mg/kg/h, subcutaneously) for 14days. Subsequently, we performed continuous cystometry, bladder blood flow measurements with a 2D laser blood flow imager, hematoxylin-eosin staining of the bladder tissue, and malondialdehyde (MDA) measurements in the bladder tissue. Cystometry revealed significantly higher peak pressure, more residual urine volume, and lower voiding efficiency in the BOO and BOO + mirabegron groups than in the sham group. The BOO + mirabegron group had significantly fewer non-voiding contractions (NVCs) than the BOO group, while the latter had more frequent NVCs than the sham group. The BOO and BOO + mirabegron groups had significantly decreased bladder blood flow than the sham group, whereas the BOO + mirabegron group showed significantly increased bladder blood flow than the BOO group. The bladder tissue in the BOO group contained more hypertrophic detrusor muscle compared to the sham group, while mirabegron treatment suppressed detrusor hypertrophy. The MDA levels were significantly higher in the BOO group than in the BOO + mirabegron and sham groups. Mirabegron treatment significantly improved BOO-induced bladder dysfunction through the amelioration of bladder blood flow.

Clinical characteristics and useful signs to differentiate detrusor underactivity from bladder outlet obstruction in men with non-neurogenic lower urinary tract symptoms.

To investigate the clinical characteristics and useful signs to differentiate detrusor underactivity from bladder outlet obstruction in men with non-neurogenic lower urinary tract symptoms. A total of 638 treatment-naive men with non-neurogenic lower urinary tract symptoms who underwent subjective and objective evaluations were reviewed retrospectively. We divided the patients into detrusor underactivity and bladder outlet obstruction groups based on urodynamic findings, and compared parameters obtained from questionnaires and non-invasive tests. Detrusor underactivity was defined as bladder contractility index≤100 and bladder outlet obstruction index≤40, whereas bladder outlet obstruction was defined as bladder contractility index>100 and bladder outlet obstruction index>40. Of 638 patients, 145 (22.7%) had detrusor underactivity and 273 (42.8%) had bladder outlet obstruction. Total international prostate symptom score and international prostate symptom score-voiding subscore were significantly higher in the detrusor underactivity group. There were significant differences in prostate volume, intravesical prostatic protrusion, and all uroflowmetry parameters between the two groups. In multivariate logistic regression analysis, lower intravesical prostatic protrusion (cut-off value 8.2mm), lower bladder voiding efficiency (cut-off value 70%), and the presence of sawtooth and interrupted waveform on uroflowmetry were significant predictive factors for detrusor underactivity. In particular, the incidence of sawtooth and interrupted waveform was significantly higher in the detrusor underactivity group (80%) than in the bladder outlet obstruction group (12.8%), which showed both high sensitivity (80%) and specificity (87.2%) in differentiating detrusor underactivity from bladder outlet obstruction. Sawtooth and interrupted waveform on uroflowmetry can be a useful predictive factor for detrusor underactivity. In addition, lower intravesical prostatic protrusion and bladder voiding efficiency can be of supplementary use.

α1 -Blocker inhibits non-voiding contractions and decreases the level of intravesical prostaglandinE2 in rats with partial bladder outlet obstruction.

To elucidate the mechanism of action of the α1 -blocker, naftopidil, in partial bladder outlet obstruction animals, by studying non-voiding contractions, and the levels of mediators were measured with resiniferatoxin treatment. A total of 35 female Wistar rats were randomly divided into a sham or bladder outlet obstruction group, and rats in each group were given vehicle or resiniferatoxin. Incomplete urethral ligation was applied to the bladder outlet obstruction group. After cystometry, the intravesical level of prostaglandinE2 and adenosine 5'-triphosphate was measured in the instilled perfusate collected. Naftopidil was given at the time of cystometry. In bladder outlet obstruction rats, non-voiding contractions, bladder capacity, and the intravesical levels of prostaglandinE2 and adenosine 5'-triphosphate were markedly increased compared with sham rats. Naftopidil decreased non-voiding contractions, enlarged the bladder capacity, and decreased the intravesical levels of prostaglandinE2 and adenosine 5'-triphosphate. Resiniferatoxin enhanced non-voiding contractions. The effects of naftopidil on non-voiding contractions and the intravesical level of prostaglandin E2 , but not adenosine 5'-triphosphate, were tolerant to resiniferatoxin. In bladder outlet obstruction rats, one cause of generation of non-voiding contractions might be bladder wall distension, but not transient receptor potential cation channelV1. The increase in intravesical prostaglandinE2 might also be associated with the generation of non-voiding contractions. Naftopidil inhibits the increase in non-voiding contractions and decreases the intravesical level of prostaglandinE2 , which are independent of transient receptor potential cation channelV1.