Long-term urodynamic findings following colo-, gastro- and ileocystoplasty.

PURPOSE: To evaluate the urodynamic changes in patients who have undergone colocystoplasty (CCP), gastrocystoplasty (GCP) and ileocystoplasty (ICP) in a retrospective study. Changes in urinary continence, incidence of pathologic contractions before and after augmentation, alterations of urodynamic parameters were also examined. METHODS: Eighty-four patients were included in the study who underwent bladder augmentation between 1987 and 2017. Group I: 35 patients with CCP. Group II: 18 patients with GCP. Group III: 31 patients with ICP. Cystometry was performed at 3, 6, and every 12 months, then biannually after augmentation. Pre- and postoperative urodynamic changes were analysed statistically. RESULTS: In Group I, two patients and in Group III, one patient remained incontinent after CCP and ICP. Bladder capacity increased significantly, maximal intra-vesical pressure decreased and compliance improved in all groups (p < 0.001). Postoperative studies showed pathologic contractions in the augmented bladder in half of the patients with GCP, in 43% of patients after CCP and 26% of patients with ICP. CONCLUSION: From the urodynamic point of view, ileum is the most adequate option in the long term. Contractions after augmentation might be caused by the remaining peristalsis of the detubularised segment. Further investigations are needed to evaluate pathologic contractions that remained after detubularisation.

Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Detrusor Hyperactivity with Impaired Contractility via Transient Potential Vanilloid Channels: A Rat Model for Ovarian Hormone Deficiency.

This study explores low-intensity extracorporeal shock wave therapy (LiESWT)'s efficacy in alleviating detrusor hyperactivity with impaired contractility (DHIC) induced by ovarian hormone deficiency (OHD) in ovariectomized rats. The rats were categorized into the following four groups: sham group; OVX group, subjected to bilateral ovariectomy (OVX) for 12 months to induce OHD; OVX + SW4 group, underwent OHD for 12 months followed by 4 weeks of weekly LiESWT; and OVX + SW8 group, underwent OHD for 12 months followed by 8 weeks of weekly LiESWT. Cystometrogram studies and voiding behavior tracing were used to identify the symptoms of DHIC. Muscle strip contractility was evaluated through electrical-field, carbachol, ATP, and KCl stimulations. Western blot and immunofluorescence analyses were performed to assess the expressions of various markers related to bladder dysfunction. The OVX rats exhibited significant bladder deterioration and overactivity, alleviated by LiESWT. LiESWT modified transient receptor potential vanilloid (TRPV) channel expression, regulating calcium concentration and enhancing bladder capacity. It also elevated endoplasmic reticulum (ER) stress proteins, influencing ER-related Ca2+ channels and receptors to modulate detrusor muscle contractility. OHD after 12 months led to neuronal degeneration and reduced TRPV1 and TRPV4 channel activation. LiESWT demonstrated potential in enhancing angiogenic remodeling, neurogenesis, and receptor response, ameliorating DHIC via TRPV channels and cellular signaling in the OHD-induced DHIC rat model.

Time-dependent progress of lower urinary tract dysfunction in streptozotocin-induced diabetic rats with or without low-dose insulin treatment.

Objectives: To examine time-dependent functional and structural changes of the lower urinary tract in streptozotocin-induced diabetic rats with or without low-dose insulin treatment and explore the pathophysiological characteristics of insulin therapy on lower urinary tract dysfunction (LUTD) caused by diabetes mellitus (DM). Methods: Female Sprague-Dawley rats were divided into five groups: normal control (NC) group, 4 weeks insulin-treated DM (4-DI) group, 4 weeks DM (4-DM) group, 8 weeks insulin-treated DM (8-DI) group and 8 weeks DM (8-DM) group. DM was initially induced by i.p. injection of streptozotocin (65 mg/kg), and then the DI groups received subcutaneous implantation of insulin pellets under the mid dorsal skin. Voiding behavior was evaluated in metabolic cages. The function of bladder and urethra in vivo were evaluated by simultaneous recordings of the cystometrogram and urethral perfusion pressure (UPP) under urethane anesthesia. The function of bladder and urethra in vitro were tested by organ bath techniques. The morphologic changes of the bladder and urethra were investigated using Hematoxylin-Eosin and Masson's staining. Results: Both 4-and 8-weeks diabetic rats have altered micturition patterns, including increased 12-h urine volume, urinary frequency/12 hours and voided volume. In-vivo urodynamics showed the EUS bursting activity duration is longer in 4-DM group and shorter in 8-DM group compared to NC group. UPP change in 8-DM were significantly lower than NC group. While none of these changes were found between DI and NC groups. Organ bath showed the response to Carbachol and EFS in bladder smooth muscle per tissue weights was decreased significantly in 4- and 8-weeks DM groups compared with insulin-treated DM or NC groups. In contrast, the contraction of urethral muscle and maximum urethral muscle contraction per gram of the tissue to EFS stimulation were significantly increased in 4- and 8-weeks DM groups. The thickness of bladder smooth muscle was time-dependently increased, but the thickness of the urethral muscle had no difference. Conclusions: DM-induced LUTD is characterized by time-dependent functional and structural remodeling in the bladder and urethra, which shows the hypertrophy of the bladder smooth muscle, reduced urethral smooth muscle relaxation and EUS dysfunction. Low-dose insulin can protect against diuresis-induced bladder over-distention, preserve urethral relaxation and protect EUS bursting activity, which would be helpful to study the slow-onset, time-dependent progress of DM-induced LUTD.

Bladder height to width ratio as a surrogate marker for non-physiological storage pressures in children with spinal dysraphism.

INTRODUCTION: Spinal dysraphism is the most frequent cause of neurogenic bladder. Urodynamic study (UDS) is an important component of the follow-up of a child with neurogenic bladder. However, it suffers from a lack of widespread availability and is further hampered by technical difficulties and difficulty in its interpretation in children. A neurogenic bladder often appears vertically elongated; only limited and sparse literature is available regarding objectively defining the bladder shape and the urodynamic parameters in the cohort. OBJECTIVES: This study aimed to investigate the usefulness of the bladder's height-to-width ratio (HWR) on cystogram as a screening tool for identifying "non-physiological" bladder pressures in children with spinal dysraphism. A prospective study was undertaken to evaluate children operated for spinal dysraphism. Cystogram, ultrasonography and UDS evaluation were performed. HWR was calculated by the ratio of the maximum height to the maximum bladder width at maximum cystometric capacity (MCC), where MCC was calculated using standard Koff's formula, given by (age in years + 2) *30 ml in children more than one year and weight *7 ml for infants. The children were categorised into groups based on maximum detrusor pressure (MDP) into two groups (MDP ≥ 30 cmH2O and MDP < 30 cmH2O). A receiver-operative characteristic curve was constructed to analyse the sensitivity and specificity of HWR in predicting the MDP. RESULTS: A total of 53 children, operated for spinal dysraphism, met the study criteria during the study period, from March 2021 to September 2022. The median age of children was 4 years (IQR-3-5.5 years). The HWR ratio was compared between the two groups and was significantly higher for the non-physiological pressure bladders than for physiological pressure bladders (mean of 1.55 vs 1.26, p = 0.001). On evaluating the sensitivity and specificity of HWR for discerning children with non-physiological bladder pressures were 87.5% and 48.28%, respectively. The area under the curve (AUC) was 0.781, with a cut-off value of 1.3. DISCUSSION: We attempted to evaluate the HWR based on bladder shape objectively. We demonstrated a moderate correlation between the bladder shape and the bladder pressures. An HWR of 1.3 or higher could be significant for identifying a non-physiological bladder storage pressure. CONCLUSION: The height to width ratio of the bladder on cystogram is a useful tool as a surrogate marker for non-physiological storage pressures in bladders of children with spinal dysraphism.

Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model.

Several neurologic diseases including spinal cord injury, Parkinson's disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

Female Type 1 Diabetic Akita Mice Demonstrate Increased Bladder Contractility via FP Receptor Activation due to NLRP3-Mediated Inflammation.

BACKGROUND: Diabetic bladder dysfunction (DBD) is driven in part by inflammation which dysregulates prostaglandin release in the bladder. Precise inflammatory mechanisms responsible for such dysregulation have been elusive. Since prostaglandins impact bladder contractility, elucidating these mechanisms may yield potential therapeutic targets for DBD. In female Type 1 diabetic Akita mice, inflammation mediated by the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is responsible for DBD. Here, we utilized female Akita mice crossbred with NLRP3 knock-out mice to determine how NLRP3-driven inflammation impacts prostaglandin release within the bladder and prostaglandin-mediated bladder contractions. METHODS: Akita mice were crossbred with NLRP3-⁣/- mice to yield four groups of non-diabetics and diabetics with and without the NLRP3 gene. Females were aged to 30 weeks when Akitas typically exhibit DBD. Urothelia and detrusors were stretched ex vivo to release prostaglandins. Prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) were quantified using enzyme linked immunosorbent assays (ELISA). In separate samples, ex vivo contractile force to PGE2 and PGF2α +/- the prostaglandin F (FP) receptor antagonist, AL8810, was measured. FP receptor protein expression was determined via western blotting. RESULTS: Stretch-induced PGE2 release increases in urothelia but decreases in detrusors of diabetics. However, PGE2-mediated bladder contractions are not impacted. Conversely, diabetics show no changes in PGF2α release, but PGF2α-mediated contractions increase significantly. This is likely due to signaling through the FP receptors as FP receptor antagonism prevents this increase and diabetics demonstrate a four-fold increase in FP receptor proteins. Without NLRP3-mediated inflammation, changes in prostaglandin release, contractility, and receptor expression do not occur. CONCLUSION: NLRP3-dependent inflammation dysregulates prostaglandin release and prostaglandin-mediated bladder contractions in diabetic female Akita mice via FP receptor upregulation.

Predictive value of risk factors for bladder dysfunction in Chinese patients with type 2 diabetes mellitus: A case-control study.

OBJECTIVE: To analyze risk factors associated with bladder dysfunction in patients with type 2 diabetes mellitus (T2DM) and to construct a prediction model for early prediction of diabetic bladder dysfunction (DBD). METHODS: We included hospitalized patients with T2DM from the endocrinology department of Shenzhen Hospital, Southern Medical University, Shenzhen, China, from January 2019 to 2022. Factors associated with DBD in bivariate analysis with a p < 0.05 were included in a multivariate logistic regression analysis. Multivariate logistic regression analysis was used to determine independent risk factors and to construct a prediction model. The prediction model was presented as the model formula. The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the above risk factors and the prediction model for DBD. The model was internally verified by Boostrap resampling 1000 times. RESULTS: Two hundred and eleven patients were included in this study, and they were divided into the DBD group (n = 101) and the non-DBD group (n = 110). Eight variables showed significant significance in the bivariate analysis, including age, diabetic peripheral neuropathy (DPN), glycated hemoglobin (HbA1c), urinary microalbumin (mALB), red blood cell count (RBC), white blood cell count (WBC), absolute neutrophil count (ANC), percentage of monocyte (Mono%). Furthermore, multivariate logistic regression analysis revealed that age (OR [95% CI]: 1.077 [1.042-1.112]), p < 0.001; DPN (OR [95% CI]: 2.373 [1.013-5.561]), p = 0.047; HbA1c (OR [95% CI]: 1.170 [1.029-1.330]), p = 0.017 and ANC (OR [95% CI]: 1.234 [1.059-1.438]), p = 0.007 were independent risk factors for the DBD. The prediction model formula was Logit (p) = -6.611 + 0.074 age + 0.864 DPN + 0.157 HbA 1 c + 0.078 ANC. The area under the ROC curve (AUC) for the four risk factors were 0.676, 0.582, 0.618, and 0.674, respectively. The prediction model predicted DBD with higher accuracy than the individual risk factors, AUC = 0.817 (95% CI: 0.757-0.877), and the sensitivity and specificity were 88.1% and 50.0%, respectively. The model internal validation results showed that the AUC = 0.804 (95% CI: 0.707-0.901), and the calibration curve is close to the ideal diagonal line. CONCLUSIONS: Age, DPN, HbA1c, and ANC were risk factors for DBD. The prediction model constructed based on the four risk factors had a good predictive value for predicting the occurrence of DBD.

Perineal ultrasound to assess the urethral spatial movement in stress urinary incontinence in women.

BACKGROUND: Perineal ultrasound as a non-invasive method for the diagnosis of female stress urinary incontinence has attracted more and more attention. However, the criteria for stress urinary incontinence in women using perineal ultrasound have not been fully established. Our study aimed to evaluate characteristics of the urethral spatial movement with perineal ultrasonography. METHODS: A total of 136 female patients with stress urinary incontinence and 44 controls were enrolled. Stress urinary incontinence was diagnosed using the International Consultation on Incontinence Questionnaire Short Form, medical history and physical examination, and severity was assessed using a 1 h pad test. We described the mobility of four equidistant points (A-D) located along the urethra length. The retrovesical and urethral rotation angles were measured using perineal ultrasonography at rest and during the maximal Valsalva maneuver. RESULTS: Patients with stress urinary incontinence showed a more significant vertical movement at Points A, B and C than controls. The mean variations in the retrovesical angle were significantly larger in patients with stress urinary incontinence at rest and during the Valsalva maneuver than in controls (21.0 ± 16.5° vs. 14.7 ± 20.1°, respectively). The cut-off value for the retrovesical angle variation was 10.7° with 72% sensitivity and 54% specificity. There was a receiver-operating characteristic curve area of 0.73 and 0.72 for Points A and B, respectively. A cut-off of 10.8 mm, and 9.4 mm provided 71% sensitivity and 68% specificity and 67% sensitivity and 75% specificity, respectively. CONCLUSIONS: The spatial movement of the bladder neck and proximal urethra, and variations in the retrovesical angle may be correlated with clinical symptoms and facilitate to the assessment of SUI.

Numerical investigation of urethra flow characteristics in benign prostatic hyperplasia.

BACKGROUND AND OBJECTIVE: Conventional practice includes a limited depiction of urethral pressure and flows based on fragmented gross clinical observations. However, with technological advancements in simulations, computational fluid dynamics (CFD) can provide an alternative approach to predict the bladder pressure with a concordant quantitative flow field in the urethra. Thus, this study aims to comprehensively analyze the urine flow characteristics in various urethra models using simulations. METHODS: Three-dimensional urethra models were constructed for seven specific subjects based on clinical radiographs. Simulations with Reynolds averaged Navier-Stokes model were performed to quantitatively investigate the urine flow under various volume flow rate of voided urine. RESULTS: Under benign prostatic hyperplasia, the spindle shape of the prostatic urethra (PRU) generates wake flow. The wake flow was also observed in several regions downstream of the PRU, depending on the urethra shape. This wake flow resulted in total pressure loss and urinary tract dysfunction. When comparing pre- and post-operative urethra models, the bladder pressure decreased by 14.98% in P04 and 4.67% in P06. Thus, we identified variability between surgical results of patients. The bladder pressure according to the volume flow rate of voided urine was investigated using simulations and the theoretical consideration based on hydrodynamics. In theoretical consideration, the bladder pressure was expressed as a second-order polynomial for volume flow rate. These results concur with the simulation results. CONCLUSION: Numerical simulation can describe the urine flow field in the urethra, providing the possibility to predict the bladder pressure without requiring painful, invasive interventions, such as cystoscopy. Furthermore, effective treatments to improve urination function can be formulated to be patient-specific, by detecting causes and problem regions based on quantitative analysis and predicting post-surgical outcomes.

Treatment with the soluble guanylate cyclase activator BAY 60-2770 normalizes bladder function in an in vivo rat model of chronic prostatitis.

BACKGROUND AND PURPOSE: Chronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60-2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. EXPERIMENTAL APPROACH: Forty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8-20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60-2770 or a combination of celecoxib and BAY 60-2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. KEY RESULTS: Induction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60-2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60-2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. CONCLUSION AND IMPLICATIONS: Induction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60-2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.

Integrated Ultrasound With Urodynamics Illustrates Effect of Bladder Volume on Upper Tract Dilation: Should we Trust Surveillance Ultrasounds?

OBJECTIVE: To evaluate if ultrasound during urodynamics (uUS) will show that traditional ultrasound (tUS) routinely underestimates the potential magnitude of upper tract dilation (UTD). METHODS: Prospective pilot study of 10 consecutive patients ≥ 5 years of age undergoing same day uUS and tUS. Using randomized images, the study pediatric radiologist determined anterior-posterior renal pelvic diameter (APD), bladder volume, vesicoureteral reflux (VUR) and UTD grades. A single pediatric urologist determined urodynamic bladder capacity and assigned either hostile, intermediate, abnormal but safe, or normal national spina bifida patient registry classification (NSBPR). RESULTS: Bladder volume on tUS was significantly smaller than final bladder volume on uUS (180 vs 363 ml: P<.001). On average, patient reported maximum catheterized/voided volumes were also 82 ml greater than final bladder capacity on uUS. UTD was upgraded in 25% of kidneys and APD increased by 0.6 cm on uUS over that seen on tUS (P=.001). Units with VUR had greater increases in APD (1.2 P=.007 vs. 0.3 cm P=0.06). Changes in APD stratified by NSBPR revealed average increases of up to 1.3 cm. CONCLUSION: Despite instructions to the contrary, patients come for tUS with a relatively empty bladder as compared to either their urodynamic or patient-reported capacity. This translates to a significant underestimation of UTD with tUS, most notably in those with VUR. Alternatives to traditional protocols include insisting patients wait until their bladder is truly full for tUS, retrograde filling their bladder, or performing uUS. Accurate assessment of UTD severity may help guide long term management.

Effect of Metabolic Syndrome on Anatomy and Function of the Lower Urinary Tract Assessed on MRI.

OBJECTIVE: To investigate the relationship between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) with functional and anatomic changes of the lower urinary tract with MRI. MATERIALS AND METHODS: The bladder and prostate of 95 subjects (56M, 39F) were segmented on T2-weighted pelvic MRI using Materialize Mimics 3D software. Bladder wall volume (BWV), post-void residual (PVR) and prostate volume (PV) were quantified from the 3D renderings. LUTS were quantified using validated questionnaires administered at the time of MRI. Wilcoxin rank sum, win ratio and chi-square tests were used to correlate symptom scores, BWV, PVR and PV in patients 1) without vs with MetS, 2) with mild (IPSS or UDI-6: 0-7) vs moderate-severe (IPSS: 8-35 or UDI-6: ≥8) and 3) normal vs enlarged prostates (>40cm3). Multivariate linear regression was used to determine predictors for BWV, PVR and PV. RESULTS: Men with MetS had increased BWV (66.8 vs 51.1cm3, P = .003), higher PVR (69.1 vs 50.5cc, P= .05) and increased PV (67.2 vs 40.1cm3, P= .01). Women without and with MetS had similar BWV, PVR and LUTS (P= .3-.78). There was no difference in prevalence of MetS, BWV, PVR or PV in men or women with mild vs moderate-severe LUTS (P = .26-.97). Men with enlarged prostates were more likely to have MetS (P = .003). There was no difference in BWV, PVR and LUTS for men with normal vs enlarged prostates (P= .44-.94). In men, BWV was highly correlated with MetS (P = .005) on regression analysis. CONCLUSION: MetS leads to detrusor hypertrophy and may contribute to impaired bladder function, likely related to the effect on the prostate.

Time-Related Changes in Patient Reported Bladder Symptoms and Satisfaction after Spinal Cord Injury.

PURPOSE: Increased time after spinal cord injury (SCI) is associated with a migration to bladder managements with higher morbidity such as indwelling catheter (IDC). Still, it is unclear how this affects bladder-related quality of life (QoL). We hypothesized that time from injury (TFI) would be associated with changes in bladder management, symptoms and satisfaction. MATERIALS AND METHODS: Cross-sectional analysis of time-related changes in patient-reported bladder management, symptoms and satisfaction using the Neurogenic Bladder Research Group SCI Registry. Outcomes included Neurogenic Bladder Symptom Score (NBSS) and bladder-related satisfaction (NBSS-satisfaction). Multivariable regression was performed to assess associations between TFI and outcomes, adjusting for participant characteristics, injury specifics, and psychosocial aspects of health-related QoL. Participants with TFI <1 year were excluded and TFI was categorized 1-5 (reference), 6-10, 11-15, 16-20 and >20 years. RESULTS: Of 1,420 participants mean age at injury was 29.7 years (SD 13.4) and mean TFI was 15.2 years (SD 11.6). Participants grouped by TFI included 298 (21%) 1-5, 340 (24%) 6-10, 198 (14%) 11-15, 149 (10%) 16-20 and 435 (31%) >20 years. As TFI increased, clean intermittent catheterization (CIC) declined (55% 1-5 vs 45% >20 years, p <0.001) and IDC increased (16% 1-5 vs 21% >20 years, p <0.001). On multivariable analysis, increased TFI was associated with fewer bladder symptoms at >20 years from injury (-3.21 [CI -1.29, -5.14, p <0.001]) and better satisfaction (6-10 years -0.20 [CI -0.41, 0.01, p=0.070], 11-15 years -0.36 [CI -0.60, -0.11, p=0.002], 16-20 years -0.59 [CI -0.86, -0.32, p <0.001], >20 years -0.85 [CI -1.07, -0.63, <0.001]). CONCLUSIONS: After SCI, CIC decreases and IDC increases over time; however, increasing TFI is associated with reduced urinary symptoms and improved bladder-related satisfaction.

The inhibitory effect of trimetazidine on detrusor contractility - a potential repositioning of trimetazidine for the treatment of overactive bladder.

OBJECTIVES: This study aimed to identify the effect of trimetazidine (TMZ), an antianginal drug, on detrusor smooth muscle (DSM) contractility and its possible mechanisms of action. METHODS: We performed in-vitro contractility studies on isolated mouse DSM strips and investigated the effect of TMZ on Ca2+ levels in fura-2-loaded A7r5 cells. KEY FINDINGS: TMZ (300 or 1000 µM) inhibited carbachol (CCh)- and KCl-induced contractions and produced a concentration-dependent (10-1000 µM) relaxation in KCl-precontracted DSM strips. TMZ-induced relaxation was markedly decreased by BaCl2, an inward-rectifying K+ channel blocker, but was not altered by preincubation with tetraethylammonium, glibenclamide, 4-aminopyridine, propranolol, L-NAME or methylene blue. TMZ (300 or 1000 µM) reduced both the CaCl2-induced contraction of depolarized DSM strips under Ca2+-free conditions and the CCh-induced contraction of DSM strips preincubated with nifedipine in Ca2+-containing Krebs solution. Furthermore, TMZ (1000 µM) significantly decreased the Ca2+ levels in fura-2-loaded A7r5 cells. CONCLUSIONS: TMZ decreased DSM contractility and caused a concentration-dependent relaxation of the tissue possibly through its actions on Ca2+ transients and K+ channels. Our results provide preclinical evidence that TMZ would be a potential candidate to treat disorders related to the overactivity of the bladder.

Spinal neurochemical mechanisms of acute stress-induced visceral hypersensitivity in healthy rats.

Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 µg) and IT phentolamine hydrochloride (10 µg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 µg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 µg), ondansetron (10 µg), mecamylamine (50 µg), antalarmin (24 µg), aSVG30 (12 µg), and SSR149415 (50 µg).

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection.

Neurogenic lower urinary tract dysfunction typically develops after spinal cord injury. We investigated the time course and the anatomical changes in the spinal cord that may be causing lower urinary tract symptoms following injury. Rats were implanted with a bladder catheter and external urethral sphincter electromyography electrodes. Animals underwent a large, incomplete spinal transection at the T8/9 spinal level. At 1, 2-3, and 4 weeks after injury, the animals underwent urodynamic investigations. Urodynamic investigations showed detrusor overactivity and detrusor-sphincter-dyssynergia appearing over time at 3-4 weeks after injury. Lower urinary tract dysfunction was accompanied by an increase in density of C-fiber afferents in the lumbosacral dorsal horn. CRF-positive Barrington's and 5-HT-positive bulbospinal projections drastically decreased after injury, with partial compensation for the CRF fibers at 3-4 weeks. Interestingly, a decrease over time was observed in the number of GABAergic neurons in the lumbosacral dorsal horn and lamina X, and a decrease of glutamatergic cells in the dorsal horn. Detrusor overactivity and detrusor-sphincter-dyssynergia might therefore arise from a discrepancy in inhibitory/excitatory interneuron activity in the lumbosacral cord as well as input changes which develop over time after injury. The processes point to spinal plastic changes leading to malfunction of the important physiological pathway of lower urinary tract control.

Tadalafil treatment improves cardiac, renal and lower urinary tract dysfunctions in rats with heart failure.

Tadalafil, a phosphodiesterase-5 (PDE5) inhibitor, shown to exert a protection to heart failure (HF) associated damage or lower urinary tract symptoms (LUTS). Thus, we investigated the contribution of tadalafil chronic treatment in the alterations of LUTS in HF rats. Male rats were subjected to aortocaval fistula model for HF induction. Echocardiography, cystometric, renal function and redox cell balance, as well as concentration-response curves to carbachol, KCl, ATP and frequency-response curves to electrical field stimulation (EFS) were evaluated in Sham, HF, Tadalafil and HF-Tadalafil (12 weeks endpoint) groups. HF group to present increased in left-ventricle (LV) mass and in LV end-diastolic- and LV end-systolic volume, with a decreased ejection fraction. Tadalafil treatment was able to decrease in hypertrophy and improve the LV function restoring cardiac function. For micturition function (in vivo), HF animals shown an increase in basal pressure, threshold pressure, no-voiding contractions and decreased bladder capacity, being that the tadalafil treatment restored the cystometric parameters. Contractile mechanism response (in vitro) to carbachol, KCl, ATP and EFS in the detrusor muscles (DM) were increased in the HF group, when compared to Sham group. However, tadalafil treatment restored the DM hypercontractility in the HF animals. Moreover, renal function as well as the oxidative mechanism was impaired in the HF animals, and the tadalafil treatment improved all renal and oxidative parameters in HF group. Our data shown that tadalafil has potential as multi-therapeutic drug and may be used as a pharmacological strategy for the treatment of cardiovascular, renal and urinary dysfunctions associated with HF.

Bladder-colon chronic cross-sensitization involves neuro-glial pathways in male mice.

BACKGROUND: Irritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory pathways, it is likely that those syndromes involve a cross-sensitization of the bladder and the colon. The precise pathophysiology remains poorly understood. AIM: To develop a model of chronic bladder-colon cross-sensitization and to investigate the mech-anisms involved. METHODS: Chronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia. Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions. Myeloperoxidase, used as a marker of colorectal inflammation, was measured in the colon, and colorectal permeability was measured using chambers. c-Fos protein expression, used as a marker of neuronal activation, was assessed in the spinal cord (L6-S1 level) using immunohistochemistry. Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord. The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot. RESULTS: Visceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline (P < 0.0001). This effect started 1 h post-injection and lasted up to 7 d post-injection. No increased permeability or inflammation was shown in the bladder or colon 7 d post-injection. Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord (P < 0.0001). In green fluorescent protein on the fractalkine receptor-positive mice, intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord (P < 0.0001). NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection (P = 0.007 and 0.023 respectively). Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline, a microglia inhibitor, by intracerebroventricular injection of CP-99994 dihydrochloride, a NK1 antagonist, and by intracerebroventricular injection of SB203580, a MAPK-p38 inhibitor. CONCLUSION: We describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice. Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension, mediated by neuroglial interactions, MAPK-p38 phosphorylation and the NK1 receptor.

Improved bladder contractility after transplantation of human mesenchymal stem cells overexpressing hepatocyte growth factor into underactive bladder from bladder outlet obstruction models of rats.

INTRODUCTION: An underactive bladder can lead to difficulty in voiding that causes incomplete emptying of the bladder, suggesting the need for a new strategy to increase bladder contractility in such patients. This study was performed to investigate whether human mesenchymal stem cells (hMSCs) were capable of restoring bladder contractility in rats with underactive bladder due to bladder outlet obstruction (BOO) and enhancing their effects by overexpressing hepatocyte growth factor (HGF) in hMSCs. MATERIALS AND METHODS: The hMSCs were transplanted into the bladder wall of rats. Fifty female Sprague-Dawley rats at six weeks of age were divided into five groups: group 1: control; group 2: sham intervention; group 3: eight-week BOO; group 4: BOO rats transplanted with hMSCs; and group 5: BOO rats transplanted with hMSCs overexpressing HGF. Two weeks after the onset of BOO in groups 4 and 5, hMSCs were injected into the bladder wall. Cystometry evaluation was followed by Masson's trichrome staining of bladder tissues. Realtime PCR and immunohistochemical staining were performed to determine for hypoxia, apoptosis, and angiogenesis. RESULTS: Collagen deposition of bladder increased in BOO but decreased after transplantation of hMSCs. The increased inter-contraction interval and residual urine volume after BOO was reversed after hMSCs transplantation. The decreased maximal voiding pressure after BOO was restored by hMSCs treatment. The mRNA expression of bladder collagen1 and TGF-ß1 increased in BOO but decreased after hMSCs transplantation. The decrease in vWF-positive cells in the bladder following BOO was increased after hMSCs transplantation. Caspase 3 and TUNEL-positive apoptosis of bladder cells increased in BOO but decreased after transplantation of hMSCs. These effects were enhanced by overexpressing HGF in hMSCs. CONCLUSION: Transplantation of hMSCs into bladder wall increased the number of micro-vessels, decreased collagen deposition and apoptosis of detrusor muscle, and improved bladder underactivity. The effects were enhanced by overexpressing HGF in hMSCs. Our findings suggest that the restoration of underactive bladder using hMSCs may be used to rectify micturition disorders in patients following resolution of BOO. Further studies are needed before hMSCs can be used in clinical applications.

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.