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This study investigates whether hAFSCs can improve bladder function in partial bladder outlet obstruction (pBOO) rats by targeting specific cellular pathways. Thirty-six female rats were divided into sham and pBOO groups with and without hAFSCs single injection into the bladder wall. Cystometry, inflammation/hypoxia, collagen/fibrosis/gap junction proteins, and smooth muscle myosin/muscarinic receptors were examined at 2 and 6 weeks after pBOO or sham operation. In pBOO bladders, significant increases in peak voiding pressure and residual volume stimulated a significant upregulation of inflammatory and hypoxic factors, TGF-β1 and Smad2/3. Collagen deposition proteins, collagen 1 and 3, were significantly increased, but bladder fibrosis markers, caveolin 1 and 3, were significantly decreased. Gap junction intercellular communication protein, connexin 43, was significantly increased, but the number of caveolae was significantly decreased. Markers for the smooth muscle phenotype, myosin heavy chain 11 and guanylate-dependent protein kinase, as well as M2 muscarinic receptors, were significantly increased in cultured detrusor cells. However, hAFSCs treatment could significantly ameliorate bladder dysfunction by inactivating the TGFβ-Smad signaling pathway, reducing collagen deposition, disrupting gap junctional intercellular communication, and modifying the expressions of smooth muscle myosin and caveolae/caveolin proteins. The results support the potential value of hAFSCs-based treatment of bladder dysfunction in BOO patients. [ABSTRACT FROM AUTHOR]

A role of Yes1-associated transcriptional regulator (YAP) and WW domain-containing transcription regulator 1 (TAZ) in vascular and gastrointestinal contractility due to control of myocardin (Myocd) expression, which in turn activates contractile genes, has been demonstrated. Whether this transcriptional hierarchy applies to the urinary bladder is unclear. We found that YAP/TAZ are expressed in human detrusor myocytes and therefore exploited the Itga8-CreERT2 model for the deletion of YAP/TAZ. Recombination occurred in detrusor, and YAP/TAZ transcripts were reduced by >75%. Bladder weights were increased (by ≈22%), but histology demonstrated minimal changes in the detrusor, while arteries in the mucosa were inflamed. Real-time quantitative reverse transcription PCR (RT-qPCR) using the detrusor demonstrated reductions of Myocd (-79 ± 18%) and serum response factor (Srf) along with contractile genes. In addition, the cholinergic receptor muscarinic 2 (Chrm2) and Chrm3 were suppressed (-80 ± 23% and -80 ± 10%), whereas minute increases of Il1b and Il6 were seen. Unlike YAP/TAZ-deficient arteries, SRY (sex-determining region Y)-box 9 (Sox9) did not increase, and no chondrogenic differentiation was apparent. Reductions of smooth muscle myosin heavy chain 11 (Myh11), myosin light-chain kinase gene (Mylk), and Chrm3 were seen at the protein level. Beyond restraining the smooth muscle cell (SMC) program of gene expression, YAP/TAZ depletion silenced SMC-specific splicing, including exon 2a of Myocd. Reduced contractile differentiation was associated with weaker contraction in response to myosin phosphatase inhibition (-36%) and muscarinic activation (reduced by 53% at 0.3 µM carbachol). Finally, short-term overexpression of constitutively active YAP in human embryonic kidney 293 (HEK293) cells increased myocardin (greater than eightfold) along with archetypal target genes, but contractile genes were unaffected or reduced. YAP and TAZ thus regulate myocardin expression in the detrusor, and this is important for SMC differentiation and splicing as well as for contractility. [ABSTRACT FROM AUTHOR]

This study investigates whether hAFSCs can improve bladder function in partial bladder outlet obstruction (pBOO) rats by targeting specific cellular pathways. Thirty-six female rats were divided into sham and pBOO groups with and without hAFSCs single injection into the bladder wall. Cystometry, inflammation/hypoxia, collagen/fibrosis/gap junction proteins, and smooth muscle myosin/muscarinic receptors were examined at 2 and 6 weeks after pBOO or sham operation. In pBOO bladders, significant increases in peak voiding pressure and residual volume stimulated a significant upregulation of inflammatory and hypoxic factors, TGF-β1 and Smad2/3. Collagen deposition proteins, collagen 1 and 3, were significantly increased, but bladder fibrosis markers, caveolin 1 and 3, were significantly decreased. Gap junction intercellular communication protein, connexin 43, was significantly increased, but the number of caveolae was significantly decreased. Markers for the smooth muscle phenotype, myosin heavy chain 11 and guanylate-dependent protein kinase, as well as M2 muscarinic receptors, were significantly increased in cultured detrusor cells. However, hAFSCs treatment could significantly ameliorate bladder dysfunction by inactivating the TGFβ-Smad signaling pathway, reducing collagen deposition, disrupting gap junctional intercellular communication, and modifying the expressions of smooth muscle myosin and caveolae/caveolin proteins. The results support the potential value of hAFSCs-based treatment of bladder dysfunction in BOO patients.

Objectives: Antimuscarinic medications are the first‐line treatments for overactive bladder, the most common form of bladder dysfunction. Their primary action is thought to block detrusor muscarinic receptors. It is unclear, however, if these therapeutics have actions on other tissues within the lower urinary tract. This study assessed whether clinical antimuscarinics have a functional impact on urothelium with lamina propria (U&LP) tissue. Methods: Strips of porcine detrusor and U&LP were mounted in carbogen‐gassed Krebs‐bicarbonate solution at 37°C. The tissues were paired with carbachol‐response curves performed in the absence or presence of each antimuscarinic. pEC50 values for each curve were analyzed and estimated affinities calculated. Results: Both detrusor and U&LP tissues contracted with muscarinic receptor stimulation, which was inhibited by commonly used antimuscarinics. In detrusor samples (p < 0.001 for all), right parallel shifts from the control were observed in response to oxybutynin (1 µM), solifenacin (1 µM), tolterodine (1 µM), darifenacin (100 nM), trospium (100 nM) and fesoterodine (100 nM). This shift was consistent in U&LP samples, with no significant differences between the two layers. Conclusions: The data suggests that clinical antimuscarinics are as effective at inhibiting tonic contractions of the U&LP as they are on detrusor, presenting the U&LP as an alternate target of these medications in the treatment of lower urinary tract symptoms. [ABSTRACT FROM AUTHOR]

Introduction: It has been hypothesized that the urinary microbiome might play an important role in OAB. Studies have been conducted on the association between OAB symptoms and the microbiome, although a possible causality still has to be determined. Material and Methods: In this study, 12 female patients, ≥18 years of age, with 'OAB DO+' and 9 female patients with 'OAB DO-' were included. Patients were excluded if they met one of the following exclusion criteria: bladder tumors and previous bladder operations; sacral neuromodulation; injection of Botox in the bladder; and TOT or TVT operations. Urine samples were collected and stored with patient informed consent and with the approval of the Hospital Ethical Review Board (Arnhem–Nijmegen). All OAB patients underwent urodynamics before collecting urine samples, and the diagnosis of detrusor overactivity was confirmed by two individual urologists. In addition, samples from 12 healthy controls who did not undergo urodynamic evaluation were analyzed. The 16S rRNA V1–V2 region amplification and gel electrophoresis were used to determine the microbiota. Results: 12 of the OAB patients had DO shown on their urodynamic studies; the remaining 9 patients had a normoactive detrusor on their urodynamic measurements. Overall, there were no substantial differences among the demographic characteristics of the subjects. The samples were classified as the following: 180 phyla, 180 classes, 179 orders, 178 families, 175 genera, and 138 species. The least commonly observed phyla were Proteobacteria, with an average presence of 10%, followed by Bacteroidetes with 15%, Actinobacteria with 16%, and Firmicutes with 41%. Most of the sequences could be classified according to the genus level for each sample. Discussion: Significant differences were observed in the urinary microbiome of patients with overactive bladder syndrome who have detrusor overactivity on urodynamics compared to OAB patients without detrusor overactivity and matched controls. OAB patients with detrusor overactivity have a significantly less diverse microbiome and show a higher proportion of Lactobacillus, particularly Lactobacillus iners. The results imply that the urinary microbiome could be involved in the pathogenesis of a specific phenotype of OAB. The urinary microbiome could be a new starting point to study the causes and treatments of OAB. [ABSTRACT FROM AUTHOR]

BackgroundThere is a lack of understanding of the clinical significance of detrusor contraction duration (DCD) measured on urodynamic studies (UDS). We aimed to identify patient characteristics, presenting symptoms and urodynamic parameters associated with DCD in women.MethodsUsing a single-institution database of UDS (2015-2019), 405 female patients with measurable detrusor contractions were identified. Baseline characteristics, presenting symptoms and UDS parameters were analyzed. Bladder outlet obstruction (BOO) was characterized using the Blaivas-Groutz nomogram. Wilcox Rank Sum Tests were used for descriptive statistics, and a univariable generalized linear model conforming to a gamma distribution was used.ResultsMedian age was 65 years (IQR 52-75), BMI was 27.5 kg/m2 (IQR 23.9-31.1) and DCD was 90 seconds (IQR 57-124). On univariable analysis, degenerative disc disease (β = -17.9, p = 0.02), pelvic radiation (β = -31.91, p = 0.04), and stress incontinence (β = -14.11, p = 0.03) were associated with reduced DCD. Black race was associated with longer DCD (β = 22.92, p = 0.01). Analysis of UDS parameters revealed a significant increase in DCD per unit increase of bladder capacity (β = 0.08, p

Purpose: A prospective case–control study was conducted to evaluate glycogen deposition within the detrusor and its correlation with the urodynamic findings in patients with bladder outlet obstruction (BOO) due to benign prostate hyperplasia (BPH). Material and methods: Data from 50 patients with BPH (Study Group) and 20 controls (Control Group) were analyzed. BOO was confirmed by pressure-flow studies. The main outcome was glycogen deposition within the bladder wall. Bladder tissue biopsies were obtained from all patients, and histological assessment of the detrusor glycogen content was performed using Periodate Acid Schiff's (PAS) stain. The obtained glycogen score ranged from 0 (no staining of glycogen granules) to 3 (staining of glycogen granules within the detrusor adjacent to the urothelium). Results: Fifty patients and 20 controls were included. Increased glycogen deposition was observed in 37 (74%) and 2 (10%) patients in the Study and Control Group, respectively (p < 0.01, OR 25.6, 95% CI 5.2–125.8). In the subgroup analysis, no statistically significant difference was found between glycogen deposition score and IPSS, maximum detrusor pressure at maximum flow (PdetQmax) and duration of LUTS. In multivariate logistic regression, history of retention was the only variable which could predict high glycogen deposition (p = 0.019). Conclusions: Our results demonstrate increased detrusor glycogen deposition in patients with BOO due to BPH, but the amount of deposition did not seem to correlate with symptom severity and duration or urodynamic findings. [ABSTRACT FROM AUTHOR]

To investigate a possible central mechanism of action of Botulinum toxin A (BoNT/A) following injection in the bladder, complementary to the acknowledged peripheral bladder effect, we studied changes in the expression of neuropeptides and receptors involved in lower urinary tract function in the spinal cord (SC) and dorsal root ganglia (DRG) of normal rats following BoNT/A bladder injection. Thirty-six Sprague-Dawley rats, divided into three groups of n = 12, received bladder injections of 2U or 5U OnabotulinumtoxinA (BOTOX®), or saline. Six animals from each group were sacrificed on days 7 and 14. Expression of Tachykinin 1 (Tac1), capsaicin receptor (TRPV1), neuropeptide Y (NPY), proenkephalin (PENK) and muscarinic receptors M1, M2, M3, was evaluated in the bladder, L6-S1 DRG, and SC segments using real-time PCR and Western blotting. Real-time PCR revealed increased expression of NPY in all tissues except for SC, and increased TRPV1 and PENK expression in DRG and SC, whereas expression of Tac1, M1 and M2 was decreased. Less significant changes were noted in protein levels. These findings suggest that bladder injections of OnabotulinumtoxinA may be followed by changes in the expression of sensory, sympathetic and cholinergic bladder function regulators at the DRG/SC level. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: Cilnidipine is a fourth-generation calcium channel blocker that is clinically used to treat hypertension. It is a dihydropyridine that blocks L- and N-type calcium channels. The inhibitory effect of cilnidipine on isolated detrusor muscle contractility has not been studied. This study investigated the inhibitory effect of cilnidipine on isolated caprine (goat) detrusor muscle contractility and the reversal of the inhibition by calcium channel openers. Methods: Fourteen caprine detrusor strips were made to contract using 80 mM potassium chloride before and after addition of three concentrations (20, 40, and 60 µM) of cilnidipine. Two reversal agents, the L-type calcium channel opener FPL64716, and the N-type calcium channel opener GV-58, were investigated for their ability to reverse the inhibitory effect of 40 µΜ cilnidipine on potassium chloride-induced detrusor contractility. Results: Cilnidipine caused a dose-dependent and statistically significant inhibition of detrusor contractility at all concentrations of cilnidipine used (20, 40, and 60 µΜ). The inhibitory effect of 40 µM cilnidipine on detrusor contractility was significantly reversed by the addition of FPL64716 and GV-58. Conclusions: Cilnidipine inhibits the contractility of the isolated detrusor by blocking L- and N-type calcium channels. Cilnidipine could be evaluated for treating clinical conditions requiring relaxation of the detrusor such as overactive bladder.

For descriptive purposes, the urinary tract is divided into upper and lower parts. The kidneys and ureters make up the upper urinary tract with the urinary bladder and urethra forming the lower urinary tract. In this article, a detailed description of the surgical and functional anatomy of the urinary bladder is followed by a description of the clinical anatomy of the female and male urethra. There then follows a brief description of the relevant anatomy of the prostate and seminal vesicles. While not strictly involved in the conduction of urine from the bladder to the exterior, the prostate and seminal vesicles are so intimately related (both topographically and functionally) to the urethra and bladder that no account of the lower urinary tract in the male would be complete without them. It is conventional therefore to regard the prostate and seminal vesicles as part of the lower urinary tract. [ABSTRACT FROM AUTHOR]

Background Multiparametric magnetic resonance imaging (mp-MRI) of urinary bladder (UB) is a novel imaging to predict detrusor muscle invasion in Bladder cancer (BC). The Vesical Imaging–Reporting and Data System (VI-RADS) was introduced in 2018 to standardize the reporting of BC with mp-MRI and to diagnose muscle invasion. This study was performed to evaluate the role of mp-MRI using VI-RADS to predict muscle invasive BC. Methods This prospective study was carried from June 2020 to May 2021 in a tertiary care institute. Thirty-six patients with untreated BC underwent mp-MRI followed by transuretheral resection of the tumor (TURBT). Mp-MRI findings were evaluated by two radiologists and BC was categorized according to VI-RADS scoring system. Resected tumors along with separate biopsy from the base were reported by two pathologists. Histopathological findings were compared with VI-RADS score and the performance of VI-RADS for determining detrusor muscle invasion was analyzed. Results VI-RADS scores of 4 and 5 were assigned to 9 (25%) and 15 (41.7%) cases, respectively, while 4 (13.3%) cases had VI-RADS score 3 on mp-MRI. VI-RADS 1 and 2 lesions were observed in six (16.7%) and two (5.5%) cases, respectively. On histopathology, 23 cases (63.9%) had muscle-invasive cancer and 13 cases (36.1%) had non–muscle-invasive cancer. The sensitivity and diagnostic accuracy of mp-MRI in predicting muscle invasive BC was 95.6 and 80.6%, respectively. Conclusion Mp-MRI has high sensitivity and diagnostic accuracy in predicting muscle invasive BC and should be advocated for evaluation of BC prior to surgery.

Introduction: It has been hypothesized that the urinary microbiome might play an important role in OAB. Studies have been conducted on the association between OAB symptoms and the microbiome, although a possible causality still has to be determined. Material and Methods: In this study, 12 female patients, ≥18 years of age, with ‘OAB DO+’ and 9 female patients with ‘OAB DO-’ were included. Patients were excluded if they met one of the following exclusion criteria: bladder tumors and previous bladder operations; sacral neuromodulation; injection of Botox in the bladder; and TOT or TVT operations. Urine samples were collected and stored with patient informed consent and with the approval of the Hospital Ethical Review Board (Arnhem–Nijmegen). All OAB patients underwent urodynamics before collecting urine samples, and the diagnosis of detrusor overactivity was confirmed by two individual urologists. In addition, samples from 12 healthy controls who did not undergo urodynamic evaluation were analyzed. The 16S rRNA V1–V2 region amplification and gel electrophoresis were used to determine the microbiota. Results: 12 of the OAB patients had DO shown on their urodynamic studies; the remaining 9 patients had a normoactive detrusor on their urodynamic measurements. Overall, there were no substantial differences among the demographic characteristics of the subjects. The samples were classified as the following: 180 phyla, 180 classes, 179 orders, 178 families, 175 genera, and 138 species. The least commonly observed phyla were Proteobacteria, with an average presence of 10%, followed by Bacteroidetes with 15%, Actinobacteria with 16%, and Firmicutes with 41%. Most of the sequences could be classified according to the genus level for each sample. Discussion: Significant differences were observed in the urinary microbiome of patients with overactive bladder syndrome who have detrusor overactivity on urodynamics compared to OAB patients without detrusor overactivity and matched controls. OAB patients with detrusor overactivity have a significantly less diverse microbiome and show a higher proportion of Lactobacillus, particularly Lactobacillus iners. The results imply that the urinary microbiome could be involved in the pathogenesis of a specific phenotype of OAB. The urinary microbiome could be a new starting point to study the causes and treatments of OAB.

Background: Urinary incontinence is a major problem both in man and animals particularly dogs. L-arginine, the precursor of NO, relaxes coronary artery smooth muscle by opening of KATP channels. L-arginine has beneficial circulatory effects in patients with essential and secondary hypertension. However, not much is known about the role of L-arginine on bladder physiology. In view of this, the present work investigated the functional role of L-arginine on detrusor smooth muscle of goat. Methods: Detrusor strips of goat, collected from local abattoir were mounted in a thermostatically controlled (37±0.5C) organ bath (20 ml capacity) containing physiological solution. After 1 hr of equilibrium, carbachol (CCh) (10-5 M) was used to induce sub-maximal contraction. L-arginine (10-3 M) was added at the plateau of contraction to see any observable effect in absence and presence of modulators of NO and ion channels. Result: L-arginine (10-3 M) reversed the contractions induced by CCh (10-5 M) on detrusor tissues. Methylene blue (MB) (10-5 M), the non-specific guanylyl cyclase inhibitor, failed to attenuate the relaxant response of L-arginine but, the NO synthase inhibitor L-NAME (310-6 M) inhibited the relaxant response of L-arginine. The KATP channel blocker glibenclamide (10-6 M) failed to inhibit the relaxation induced by L-arginine while KCa channel blocker tetraethylammonium (TEA) (10-3 M) inhibited the relaxant response of L-arginine. The results of the present study suggest that L-arginine produces relaxation of goat detrusor muscle and the L-arginine-elicited relaxation is NO-dependent but guanylyl cyclase independent which activates KCa channels. [ABSTRACT FROM AUTHOR]

Aim: We previously reported that some urodynamic parameters change with repetitive filling in children with neurogenic lower urinary tract dysfunction (LUTD). In this study, we aimed to search if three‐times repeated filling cystometries (FC) and pressure‐flow studies (PFS) would change the urodynamics parameters in children with non‐neurogenic LUTD. Materials and Methods: All children with three repeated FC and PFS between June 2017 and December 2018 were included in the study. Urodynamic reports and charts were evaluated retrospectively. The first sensation of bladder filling (FSBF), maximum cystometric capacity (MCC), detrusor pressure at the FSBF (Pdet.first.sens), maximum detrusor pressure during filling (Pdet.fill.max), presence of detrusor over activity, compliance, maximum urine flow (Qmax), detrusor pressure at the maximum urine flow (PdetQmax), residual urine and presence of detrusor sphincter dyssynergy (DSD) were compared among three‐times repeated urodynamic studies. Results: Forty children were included in the study. 27 (67.5%) were girls and 13 (32.5%) were boys. Median age was 9 (3.4–17) years. Indications were LUTD with low grade vesicoureteral reflux in 19 (47.5%), LUTD refractory to conservative management in 13 (32.5%), urinary tract infection with LUTD in 6 (15%) and secondary enuresis in 2 (5%). Pdet.first.sens, presence of DO, MCC, Qmax, PdetQmax, residual urine, flow pattern, and presence of DSD were comparable in all three repeated tests. The third FC may show decreased filling detrusor pressures and increased compliance with no change on capacity. Conclusion: In children with non‐neurogenic LUTD, three‐times repeated FC and PFS present comparable results except FSBF, Pdet.fill.max, and compliance at the third test. [ABSTRACT FROM AUTHOR]

Purpose: Treatment of voiding dysfunction due to detrusor underactivity (DU) remains challenging. This study sought to determine the characteristics of video urodynamic study (VUDS) in female DU and outcomes after active treatment. Methods: A total of 409 female patients with VUDS-proven DU were recruited. All patients received conservative bladder management, with others receiving active treatment, such as oral medication, transurethral incision of bladder neck (TUI-BN), surgery for prolapse, and urethral botulinum toxin A (BoNT-A) injection, according to their VUDS characteristics. Treatment outcomes were then analyzed by different VUDS characteristics. Results: Satisfactory treatment outcomes were noted in 123 patients (30.0%), among whom 35 and 88 had a VE of > 90% and > 66.7%, respectively. A total of 165 patients (40.3%) had voiding efficiency (VE) of 33.3–66.7%, whereas 121 (29.6%) remained unable to void (12.5%) or had a VE of < 33.3% (17.1%). Conservative treatment had the worst outcome. Patients with normal or slightly reduced bladder sensation (49.3%) and those with a post-void residual (PVR) of < 250 mL (59.4%) displayed better satisfactory outcome after treatment; while TUI-BN and urethral BoNT-A injection promoted better treatment results. Patients with detrusor acontractility and a PVR of ≥ 500 mL still achieved high VE rates (> 66.7%) after TUI-BN. A 56.3% satisfactory outcome was achieved after TUI-BN, whereas 58.1% satisfactory outcome was noted in those with a tight external sphincter after medical treatment. Conclusion: Female patients with DU exhibited VE improvement after active treatment. Patients with very low detrusor contractility and absent bladder sensation generally exhibited poor treatment outcomes. [ABSTRACT FROM AUTHOR]

World studies have shown that the mean prevalence of overactive bladder (OAB) ranges today from 11 to 16% of the global population and is common in both men and women. In addition, OAB is a diagnosis by exclusion. The article discusses two large groups of the causes of pathology: neurological and non-neurological. The former includes various diseases and conditions that lead to a complex abnormality in the urinary mechanism, namely, involuntary detrusor contractions and increased intravesical pressure. Spinal trauma, brain strokes and spinal strokes, multiple sclerosis, Parkinson’s disease, etc. are the most common of them. Unidentified factors constitute the second group of causes resulting in urgent frequent urination, and what is meant here is idiopathic detrusor hyperactivity (IDH). In this case, a patient may have these symptoms amidst full health without any neurological history. According to the available current guidelines, the treatment of OAB includes a three-step algorithm and suggests lifestyle changes, drug therapy and, finally, minimally invasive methods of treatment. Historically, M-anticholinergics are the main drugs for the treatment of OAD symptoms. However, administration of drugs from this group may often be impossible due to prominent side effects, which are more commonly reported among elderly patients. Unlike M-anticholinergics, Mirabegron is the only β3-adrenergic receptor agonist today that has shown a high efficacy and safety profile based on the results of large-scale placebo-controlled clinical trials.

Objective: The management of psychiatric patients is often complicated by medical comorbidities, complex pharmacological regimens, and side effects secondary to these regimens. In the current study, it was aimed to investigate the effects and mechanism of action of trazodone on rat bladder smooth muscle contractility in vitro. Method: Sixteen adult male Wistar albino rats were euthanized by the cervical dislocation method following ether anesthesia. Two muscle strips of 2x10 mm in size were prepared vertically from the bladder by opening a longitudinal incision from the neck of the bladder in the direction of the apex. The strips were tied properly and hung in the organ bath. All contraction amplitudes and frequencies were recorded. After a 45-min adaptation period, contractions were induced by applying 10-5 M acetylcholine (ACh) to all spontaneously contracting bladder strips. After 20 min, doses of trazodone (10-9 M vs 10-3 M) were given cumulatively. The resulting effects were recorded. Results: The groups were compared within themselves: a significant difference was found between the initial tensions in the group with ACh-induced contractions and the tensions after the administration of trazodone at 10-9, 10-8, 10-7, 10-6, 10-5, 10-4, and 10-3 M doses (p<0.0001). In the group with spontaneous contractions, a significant difference was found between the initial tensions and the tensions after the administration of trazodone at 10-9, 10-8, 10-5, and 10-4 M doses (p<0.0001). Conclusion: Results showed that trazodone had a significant inhibitory effect on bladder smooth muscle contractions in vitro, especially at concentrations of 10-4 and 10-3 M. [ABSTRACT FROM AUTHOR]

Patients with neurogenic lower urinary tract dysfunction (NLUTD) experience urinary incontinence with or without difficult urination, which might promote recurrent urinary tract infection (UTI) and exacerbate upper urinary tract function. Nonetheless, appropriate bladder management has been shown to reduce urological complications and improve quality of life. In addition to pharmacological therapy and surgical intervention, botulinum toxin A (BoNT-A) has been widely utilized in NLUTD. The therapeutic efficacy of detrusor BoNT-A injections for neurogenic detrusor overactivity due to spinal cord injury (SCI), multiple sclerosis, or other central nervous system lesions, such as cerebrovascular accident, Parkinson disease, early dementia, and pediatric NLUTD due to myelomeningocele, has been well established, with repeated BoNT-A injections every 6 to 9 months being necessary to maintain its therapeutic effects. Urethral BoNT-A injection can decrease urethral sphincter resistance and facilitate efficient voiding in patients with NLUTD who wish to preserve self-voiding. Detrusor BoNT-A injection can also decrease the occurrence of autonomic dysreflexia in patients with SCI, even after failed augmentation enterocystoplasty, with additional benefits including reduced UTI episodes and preserved renal function with repeated injections. However, this treatment does have some side effects. Complete informed consent for BoNT-A injection therapy with full disclosure of its potential complications should therefore be obtained before this procedure is undertaken.

Objective: To investigate the effects of concomitant injections of botulinum toxin-A (BoNT-A) into the detrusor and external urethral sphincter muscles in suprasacral spinal cord injured patients with detrusor overactivity and detrusor sphincter dyssynergia. Design: An open treatment trial with pre- and posttreatment evaluations. Subjects: Male suprasacral spinal cord injury patients (n = 20) with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who emptied their bladder by reflex voiding and were unwilling to increase the frequency of intermittent catheterization. Methods: Cystoscopic guidance of 200 U BoNT-A injections into the detrusor muscle and 100 U into external urethral sphincter muscles were applied. The urodynamic parameters, voiding diaries and quality of life scores using Urinary Distress Inventory, Short Form (UDI-6) and Incontinence Impact Questionnaire, Short Form (IIQ-7) were compared. Results: All participants experienced a significant mean reduction in maximal detrusor pressure and maximal urethral pressure profile, and a mean significant increase in maximal cystometric bladder capacity 12 weeks after concomitant injections. Bladder diaries demonstrated persistently increased spontaneous voided volume, but no increase in post-void residual ratio, daily clean intermittent catheterization (CIC) frequency and diaper pad use from baseline to 24 weeks. UDI-6 scores were significantly improved at 4 and 12 weeks and IIQ-7 scores improved only at 12 weeks. Conclusion: Concomitant detrusor and external urethral sphincter BoNT-A injections may decrease detrusor and urethral pressure without increasing postvoid residual ratio and diaper pad use. For spinal cord injury patients with neurogenic detrusor overactivity and detrusor sphincter dyssynergia who are unwilling, or for whom it is inconvenient, to increase CIC frequency and who want to preserve spontaneous voiding, this treatment may provide an optional alternative. LAY ABSTRACT Detrusor botulinum toxin type A (BoNT-A) injection has become the standard of care for bladder overactivity associated with neurological pathology in recent years. However, increased post-void residual and even acute urinary retention make it difficult for patients to accept this treatment. Our study demonstrates that a combination of detrusor and urethra sphincter BoNT-A injections may relieve detrusor and urethral pressures without increasing intermittent catheterization (IC) frequency. Life quality associated with voiding is also improved after combined injections. Physicians should take into account the patient’s expectation and ability to manage his bladder when planning BoNT-A injection in treatment of neurogenic lower urinary tract dysfunction (NLUTD) in spinal cord injury (SCI) patients. For male SCI patients with NLUTD who are unwilling or inconvenient to increase IC frequency and want to preserve spontaneous voiding, this treatment may provide optional alternative.

The human bladder maintains a cycle of filling, storing, and micturating throughout an individual's lifespan. The cycle relies on the ability of the bladder to expand without increasing the intravesical pressure, which is only possible with the controlled relaxation of well-complaint muscles and the congruously organized construction of the bladder wall. A competent bladder outlet, which functions in a synchronous fashion with the bladder, is also necessary for this cycle to be completed successfully without deterioration. In this paper, we aimed to review the contemporary physiological findings on bladder physiology and examine the effects of amino acids on clinical conditions affecting the bladder, with special emphasis on the available therapeutic evidence and possible future roles of the amino acids in the treatment of the bladder-related disorders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Inflammation is often associated with several bladder dysfunctions, including overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/PBS). As such, inflammation of the bladder and the actions of inflammatory mediators may contribute to the development of urinary symptoms. This study assessed the actions of PGE2, PGF2, PGD2, TXA2, and PGI2 on urinary bladder urothelium with lamina propria (U&LP), and detrusor smooth muscle. Methods Studies were carried out using isolated tissue baths, where strips of porcine bladder U&LP or detrusor were exposed to varying concentrations of prostaglandin agonists (1 μM and 10 μM). Results All assessed prostaglandin agonists contracted both the U&LP and detrusor smooth muscle, with the rank order of contractile response effectiveness as: PGE2 > PGF2α > TXA2 > PGD2 > PGI2. In U&LP, treatment with PGE2 (10 μM) increased tonic contractions by 1.36 ± 0.09 g (n = 42, p

ABSTRACT: Background: Overactive bladder (OAB) is a common clinical condition for which current drug treatment comprises drugs blocking the cholinergic nerve supply, or augmenting the adrenergic nerve supply, to the detrusor muscle of the urinary bladder. Current treatments have drawbacks, including lack of efficacy and the development of adverse effects in some patients. Hence, new and better drugs for treating OAB will be clinically useful. Objective: This review is meant to provide information on drugs currently undergoing preclinical or clinical trials for the treatment of OAB published in journal articles or elsewhere. Methods: The cited articles were retrieved from PubMed and Google Scholar from January 1, 1990, to December 31, 2021. The search terms used were contraction or contractility, detrusor, inhibition, isolated or in vitro, in vivo, overactive bladder, and relaxant effect or relaxation. Results: There are 4 classes of new drugs under various stages of development for the treatment of OAB. These are drugs acting on the autonomic nerve supply to the detrusor muscle of the urinary bladder that include the anticholinergics tarafenacin and afacifenacin and the β3 adrenoceptor agonists solabegron and ritobegron; drugs acting on ion channels in the detrusor muscle (eg, potassium channel openers and calcium channel blockers), drugs acting on cellular enzymes like phosphodiesterase-5 inhibitors and Rho kinase inhibitors, and drugs acting on miscellaneous targets (eg, pregabalin and trimetazidine). Conclusions: Drugs currently used to treat OAB target only the cholinergic and adrenergic cellular signalling pathways. There are many other drugs under trial targeting other cellular pathways that may be useful for treating OAB. Their approval for clinical use might improve the treatment of patients with OAB. (Curr Ther Res Clin Exp. 2022; 83:XXX–XXX)

To investigate a possible central mechanism of action of Botulinum toxin A (BoNT/A) following injection in the bladder, complementary to the acknowledged peripheral bladder effect, we studied changes in the expression of neuropeptides and receptors involved in lower urinary tract function in the spinal cord (SC) and dorsal root ganglia (DRG) of normal rats following BoNT/A bladder injection. Thirty-six Sprague-Dawley rats, divided into three groups of n = 12, received bladder injections of 2U or 5U OnabotulinumtoxinA (BOTOX®), or saline. Six animals from each group were sacrificed on days 7 and 14. Expression of Tachykinin 1 (Tac1), capsaicin receptor (TRPV1), neuropeptide Y (NPY), proenkephalin (PENK) and muscarinic receptors M1, M2, M3, was evaluated in the bladder, L6-S1 DRG, and SC segments using real-time PCR and Western blotting. Real-time PCR revealed increased expression of NPY in all tissues except for SC, and increased TRPV1 and PENK expression in DRG and SC, whereas expression of Tac1, M1 and M2 was decreased. Less significant changes were noted in protein levels. These findings suggest that bladder injections of OnabotulinumtoxinA may be followed by changes in the expression of sensory, sympathetic and cholinergic bladder function regulators at the DRG/SC level.

A geroscience-informed approach to the increasing prevalence of bladder control problems in older adults requires understanding the impact of aging on dynamic mechanisms that ensure resilience in response to stressors challenging asymptomatic voluntary control over urine storage and voiding. Bladder control is predicated on sensory neural information about bladder volume. Modulation of volume-induced bladder wall tensions by autonomic and mucosal factors controls neural sensitivity to bladder volume. We hypothesized that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels integrate these factors and thereby mediate adrenergic detrusor tension control. Furthermore, loss of HCN expression compromises that integration and could result in loss of precision of detrusor control. Using a life-span mouse model, reverse transcription quantitative real-time PCR and pharmacologic studies in pretensioned intact and mucosa-denuded bladder strips were made. The dominant hcn1 expression declines with maturation and aging; however, aging is also associated with increased variance around mean values. In strips from Mature animals, isoproterenol had less effect in denuded muscle strips than in intact strips, and HCN blockade diminished isoproterenol responsiveness. With aging, variances about mean response values significantly increased, paralleling hcn1 expression. Our findings support a role for HCN in providing neuroendocrine/paracrine integration and suggest an association of increased heterogeneity of HCN expression in aging with reductions in response precision to neuroendocrine control. The functional implication is an increased risk of dysfunction of brainstem/bladder regulation of neuronal sensitivity to bladder volume. This supports the clinical model of the aging bladder phenotype as an expression of loss of resilience, and not as emerging bladder pathology with aging. [ABSTRACT FROM AUTHOR]

Study Design Observational study. Purpose This study aims to assess the clinical and urodynamic parameters in patients with spinal tuberculosis (TB) exhibiting lower urinary tract symptoms (LUTS) at the time of presentation and after spinal surgical intervention. Overview of Literature Variable urodynamic findings in patients with spinal TB. Methods We prospectively evaluated 10 patients with spinal TB exhibiting LUTS. Urinary symptoms were assessed by the American Urological Association (AUA) symptom score. We performed a urodynamic study (UDS), including electromyography, in all patients before and 3 months after spinal surgery. Results The mean age of patients was 29.7 years (range, 15–52 years), and the mean AUA symptom score was 12.5 and 11.8 before and after spinal surgery, respectively. Overall, five patients exhibited improvement in the AUA symptom score, and three showed no change, while two patients’ condition worsened. We observed detrusor overactivity (DO) in two patients, and detrusor sphincter dyssynergia (DSD) in four patients. In addition, high-pressure voiding (HPV) was noted in two patients. On follow-up after spinal surgery, DO and DSD exhibited no improvement. Although HPV resolved, two patients developed new-onset poor compliance with worsening DO and DSD. Furthermore, two patients had bilateral hydronephrosis before surgery, which resolved on follow-up. Conclusions Patients with spinal TB exhibiting LUTS can display a spectrum of clinical presentations and variable UDS findings. As two patients exhibited new onset poor compliance with bilateral hydronephrosis in one of them, this study concludes that a close follow-up for upper tracts in these patients is required despite successful spinal surgery.

Background: Urinary bladder detrusor smooth muscle cells exhibit spontaneous electrical activities comprising various signal types. Aims and Objectives: This article introduces and analyzes a rare category of signals observed in such activity, named spontaneous depolarization-linked hyperpolarization (sDLH). Materials and Methods: A mouse model was used in the study, where all the occurrences of sDLHs were pooled together from multiple intracellular recording sessions. Four features – (i) resting membrane potential (RMP) (R, in mV), (ii) depolarization amplitude (D, in mV), (iii) hyperpolarization amplitude (H, in mV), and (iv) time course of the hyperpolarization (T, in ms) – were evaluated from all sDLHs. Results: The analysis of results indicated that (a) the signals appear more frequently in cells with higher RMP, (b) the depolarization amplitudes seem to be distributed randomly and have no correlation with other features, (c) hyperpolarization amplitudes show two distinct clusters and exhibit strong correlation with the RMP, and (d) time course of hyperpolarization phase shows no distinct groups and is distributed in a window larger than that of any other signals seen in the intracellular recordings. With the help of the results obtained from the analysis, a hypothesis for the biophysical origin of these signals is proposed. Conclusions: This needs to be tested experimentally, and if proved right, would help extend the boundaries of our current understanding of the detrusor smooth muscle system.

Abstract During development, maturation, or aging, the expression and function of urinary bladder smooth muscle (UBSM) ion channels can change, thus affecting micturition. Increasing evidence supports a novel role of transient receptor potential melastatin‐4 (TRPM4) channels in UBSM physiology. However, it remains unknown whether the functional expression of these key regulatory channels fluctuates in UBSM over different life stages. Here, we examined TRPM4 channel protein expression (Western blot) and the effects of TRPM4 channel inhibitors, 9‐phenanthrol and glibenclamide, on phasic contractions of UBSM isolated strips obtained from juvenile (UBSM‐J, 5–9 weeks old) and adult (UBSM‐A, 6–18 months old) male guinea pigs. Compared to UBSM‐J, UBSM‐A displayed a 50–70% reduction in total TRPM4 protein expression, while the surface‐to‐intracellular expression ratio (channel trafficking) remained the same in both age groups. Consistent with the reduced total TRPM4 protein expression in UBSM‐A, 9‐phenanthrol showed lower potencies and/or maximum efficacies in UBSM‐A than UBSM‐J for inhibiting amplitude and muscle force of spontaneous and 20 mM KCl‐induced phasic contractions. Compared to 9‐phenanthrol, glibenclamide also attenuated both spontaneous and KCl‐induced contractions, but with less pronounced differential effects in UBSM‐A and UBSM‐J. In both age groups, regardless of the overall reduced total TRPM4 protein expression in UBSM‐A, cell surface TRPM4 protein expression (~80%) predominated over its intracellular fraction (~20%), revealing preserved channel trafficking mechanisms toward the cell membrane. Collectively, this study reports novel findings illuminating a fundamental physiological role for TRPM4 channels in UBSM function that fluctuates with age.

During development, maturation, or aging, the expression and function of urinary bladder smooth muscle (UBSM) ion channels can change, thus affecting micturition. Increasing evidence supports a novel role of transient receptor potential melastatin‐4 (TRPM4) channels in UBSM physiology. However, it remains unknown whether the functional expression of these key regulatory channels fluctuates in UBSM over different life stages. Here, we examined TRPM4 channel protein expression (Western blot) and the effects of TRPM4 channel inhibitors, 9‐phenanthrol and glibenclamide, on phasic contractions of UBSM isolated strips obtained from juvenile (UBSM‐J, 5–9 weeks old) and adult (UBSM‐A, 6–18 months old) male guinea pigs. Compared to UBSM‐J, UBSM‐A displayed a 50–70% reduction in total TRPM4 protein expression, while the surface‐to‐intracellular expression ratio (channel trafficking) remained the same in both age groups. Consistent with the reduced total TRPM4 protein expression in UBSM‐A, 9‐phenanthrol showed lower potencies and/or maximum efficacies in UBSM‐A than UBSM‐J for inhibiting amplitude and muscle force of spontaneous and 20 mM KCl‐induced phasic contractions. Compared to 9‐phenanthrol, glibenclamide also attenuated both spontaneous and KCl‐induced contractions, but with less pronounced differential effects in UBSM‐A and UBSM‐J. In both age groups, regardless of the overall reduced total TRPM4 protein expression in UBSM‐A, cell surface TRPM4 protein expression (~80%) predominated over its intracellular fraction (~20%), revealing preserved channel trafficking mechanisms toward the cell membrane. Collectively, this study reports novel findings illuminating a fundamental physiological role for TRPM4 channels in UBSM function that fluctuates with age. [ABSTRACT FROM AUTHOR]

Abstract Hyperglycemic memory is associated with several complications of diabetes. Although there is some physiological evidence that this phenomenon occurs with diabetic bladder dysfunction (DBD), there have been no studies in bladder that provide evidence of hyperglycemic memory at the molecular/biochemical level. In the present studies, we determined the effects of long‐term diabetes on the metabolome of bladder detrusor in a rat model of streptozotocin‐induced type‐1‐diabetes and the ability of insulin treatment to normalize metabolic changes. These studies demonstrated that although insulin reversed a majority of the metabolic changes caused by diabetes, with long‐term diabetes there was a persistent decrease in the methylation index (indicated by a reduced ratio of S‐adenosylmethionine to S‐adenosyl homocysteine) after insulin treatment. We confirmed a “hypomethylated environment” develops in diabetic detrusor by demonstrating an overall reduction in methylated detrusor DNA that is only partially reversed with glycemic control. Furthermore, we confirmed that this hypomethylated environment is associated with epigenetic changes in the detrusor genome, which are again mostly, but not completely, reversed with glycemic control. Overall our studies provide strong molecular evidence for a mechanism by which diabetes alters methylation status and gene expression in the detrusor genome, and that these epigenetic modifications contribute to hyperglycemic memory. Our work suggests novel treatment strategies for diabetic patients who have attained glycemic control but continue to experience DBD. For example, epigenomic data can be used to identify “actionable gene targets” for its treatment and would also support a rationale for approaches that target the hypomethylation index.

To explore contractile actions of angiotensin II (ATII) on the muscularis mucosae (MM) of the bladder, ATII‐induced contractions were compared between MM and the detrusor smooth muscle (DSM) of the pig bladder by isometric tension recordings. Effects of ATII on spontaneous Ca2+ transients in MM were visualized using Cal‐520 fluorescence. ATII receptor type 1 (ATR1) expression in MM and DSM was also examined by immunohistochemistry. ATII (1 nM–1 μM) caused phasic contractions of MM in a concentration‐dependent manner, while ATII (10 nM–10 μM) had no or marginal effects on DSM contractility. ATII (100 nM)‐induced MM contractions had an amplitude of approximately 70% of carbachol (1 μM)‐induced or 90% of U46619 (100 nM)‐induced contractions. Candesartan (10 nM), an ATR1 blocker, prevented the contractile effects of ATII (1 nM) in MM, while ATR1 immunofluorescence was greater in MM than DSM. ATII (10–100 pM) increased the frequency but not the amplitude of spontaneous Ca2+ transients in MM. Both urothelium‐intact and ‐denuded MM strips developed comparable spontaneous phasic contractions, but ATII, carbachol and U46619‐induced contractions were significantly larger in urothelium‐denuded than urothelium‐intact MM strips. In conclusion, the MM appears to have a much greater sensitivity to ATII compared with DSM that could well sense circulating ATII, suggesting that MM may be the predominant target of contractile actions induced by ATII in the bladder while the urothelium appears to inhibit MM contractility. [ABSTRACT FROM AUTHOR]

Hyperglycemic memory is associated with several complications of diabetes. Although there is some physiological evidence that this phenomenon occurs with diabetic bladder dysfunction (DBD), there have been no studies in bladder that provide evidence of hyperglycemic memory at the molecular/biochemical level. In the present studies, we determined the effects of long‐term diabetes on the metabolome of bladder detrusor in a rat model of streptozotocin‐induced type‐1‐diabetes and the ability of insulin treatment to normalize metabolic changes. These studies demonstrated that although insulin reversed a majority of the metabolic changes caused by diabetes, with long‐term diabetes there was a persistent decrease in the methylation index (indicated by a reduced ratio of S‐adenosylmethionine to S‐adenosyl homocysteine) after insulin treatment. We confirmed a "hypomethylated environment" develops in diabetic detrusor by demonstrating an overall reduction in methylated detrusor DNA that is only partially reversed with glycemic control. Furthermore, we confirmed that this hypomethylated environment is associated with epigenetic changes in the detrusor genome, which are again mostly, but not completely, reversed with glycemic control. Overall our studies provide strong molecular evidence for a mechanism by which diabetes alters methylation status and gene expression in the detrusor genome, and that these epigenetic modifications contribute to hyperglycemic memory. Our work suggests novel treatment strategies for diabetic patients who have attained glycemic control but continue to experience DBD. For example, epigenomic data can be used to identify "actionable gene targets" for its treatment and would also support a rationale for approaches that target the hypomethylation index. [ABSTRACT FROM AUTHOR]

Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K+ channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K+ (KV) channel superfamily, KV type 7 (KV7) channels — KV7.1–KV7.5 members encoded by KCNQ1–KCNQ5 genes — have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM KV7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe KV7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of KV7 channel selective modulators on DSM excitability, contractility, and intracellular Ca2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM KV7 channels that are now actively ongoing in our laboratory.

Impairments of the lower urinary tract function including urine storage and voiding are widely spread among patients with spinal cord injuries. The management of such patients includes bladder catheterization, surgical and pharmacological approaches, which reduce the morbidity from urinary tract-related complications. However, to date, there is no effective treatment of neurogenic bladder and restoration of urinary function. In the present study, we examined neuromodulation of detrusor (Detr) and external urethral sphincter by epidural electrical stimulation (EES) of lumbar and sacral regions of the spinal cord in chronic rats. To our knowledge, it is the first chronic study where detrusor and external urethral sphincter signals were recorded simultaneously to monitor their neuromodulation by site-specific spinal cord stimulation (SCS). The data obtained demonstrate that activation of detrusor muscle mainly occurs during the stimulation of the upper lumbar (L1) and lower lumbar (L5-L6) spinal segments whereas external urethral sphincter was activated predominantly by sacral stimulation. These findings can be used for the development of neurorehabilitation strategies based on spinal cord epidural stimulation for autonomic function recovery after severe spinal cord injury (SCI).

Relaxation and contraction of the urinary bladder smooth muscle, also known as the detrusor smooth muscle (DSM), facilitate the micturition cycle. DSM contractility depends on cell excitability, which is established by the synchronized activity of multiple diverse ion channels. K+ channels, the largest family of channels, control DSM excitability by maintaining the resting membrane potential and shaping the action potentials that cause the phasic contractions. Among the members of the voltage-gated K+ (KV) channel superfamily, KV type 7 (KV7) channels — KV7.1–KV7.5 members encoded by KCNQ1–KCNQ5 genes — have been recently identified as functional regulators in various cell types including vascular, cardiac, and neuronal cells. Their regulatory roles in DSM, however, are just now emerging and remain to be elucidated. To address this gap, our research group has initiated the systematic investigation of human DSM KV7 channels in collaboration with clinical urologists. In this comprehensive review, we summarize the current understanding of DSM Kv7 channels and highlight recent discoveries in the field. We describe KV7 channel expression profiles at the mRNA and protein levels, and further elaborate on functional effects of KV7 channel selective modulators on DSM excitability, contractility, and intracellular Ca2+ dynamics in animal species along with in vivo studies and the limited data on human DSM. Within each topic, we highlight the main observations, current gaps in knowledge, and most pressing questions and concepts in need of resolution. We emphasize the lack of systematic studies on human DSM KV7 channels that are now actively ongoing in our laboratory. [ABSTRACT FROM AUTHOR]

Impairments of the lower urinary tract function including urine storage and voiding are widely spread among patients with spinal cord injuries. The management of such patients includes bladder catheterization, surgical and pharmacological approaches, which reduce the morbidity from urinary tract-related complications. However, to date, there is no effective treatment of neurogenic bladder and restoration of urinary function. In the present study, we examined neuromodulation of detrusor (Detr) and external urethral sphincter by epidural electrical stimulation (EES) of lumbar and sacral regions of the spinal cord in chronic rats. To our knowledge, it is the first chronic study where detrusor and external urethral sphincter signals were recorded simultaneously to monitor their neuromodulation by site-specific spinal cord stimulation (SCS). The data obtained demonstrate that activation of detrusor muscle mainly occurs during the stimulation of the upper lumbar (L1) and lower lumbar (L5-L6) spinal segments whereas external urethral sphincter was activated predominantly by sacral stimulation. These findings can be used for the development of neurorehabilitation strategies based on spinal cord epidural stimulation for autonomic function recovery after severe spinal cord injury (SCI). [ABSTRACT FROM AUTHOR]

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Background: Inflammation is often associated with several bladder dysfunctions, including overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/PBS). As such, inflammation of the bladder and the actions of inflammatory mediators may contribute to the development of urinary symptoms. This study assessed the actions of PGE2, PGF2, PGD2, TXA2, and PGI2 on urinary bladder urothelium with lamina propria (U&LP), and detrusor smooth muscle.Methods: Studies were carried out using isolated tissue baths, where strips of porcine bladder U&LP or detrusor were exposed to varying concentrations of prostaglandin agonists (1 μM and 10 μM).Results: All assessed prostaglandin agonists contracted both the U&LP and detrusor smooth muscle, with the rank order of contractile response effectiveness as: PGE2 > PGF2α > TXA2 > PGD2 > PGI2. In U&LP, treatment with PGE2 (10 μM) increased tonic contractions by 1.36 ± 0.09 g (n = 42, p < 0.001) and phasic contractions by 40.4 ± 9.6% (n = 42, p < 0.001). In response to PGF2α (10 μM), U&LP tonic contractions increased by 0.79 ± 0.06 g (n = 14, p < 0.001) and phasic activity by 13.3% ± 5.3% (n = 15, p < 0.05). In detrusor preparations, PGE2 (10 μM) increased tonic contractions by 1.32 ± 0.13 g (n = 38, p < 0.001) and PGF2α (10 μM) by 0.97 ± 0.14 g (n = 12, p < 0.001). Only 34% (n = 48) of all detrusor preparations exhibited spontaneous activity prior to the addition of any agonist at a frequency of 2.03 ± 0.12 cpm. In preparations that did not exhibit initial phasic activity, all of the prostaglandin agonists were capable of commencing phasic activity.Conclusions: The urinary bladder U&LP and detrusor respond to a variety of prostaglandin agonists, with their activation resulting in direct contractions, as well as increases to spontaneous contractile activity. This study presents the prostaglandin receptor system as a potential therapeutic target for lower urinary tract dysfunction. [ABSTRACT FROM AUTHOR]

Cl- channels serve as key regulators of excitability and contractility in vascular, intestinal, and airway smooth muscle cells. We recently reported a Cl- conductance in detrusor smooth muscle (DSM) cells. Here, we used the whole cell patch-clamp technique to further characterize biophysical properties and physiological regulators of the Cl- current in freshly isolated guinea pig DSM cells. The Cl- current demonstrated outward rectification arising from voltage-dependent gating of Cl- channels rather than the Cl- transmembrane gradient. An exposure of DSM cells to hypotonic extracellular solution (Δ 165 mOsm challenge) did not increase the Cl- current providing strong evidence that volume-regulated anion channels do not contribute to the Cl- current in DSM cells. The Cl- current was monotonically dependent on extracellular pH, larger and lower in magnitude at acidic (5.0) and basic pH (8.5) values, respectively. Additionally, intracellularly applied phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] analog [PI(4,5)P2-diC8] increased the average Cl- current density by approximately threefold in a voltage-independent manner. The magnitude of the DSM whole cell Cl- current did not depend on the cell surface area (cell capacitance) regardless of the presence or absence of PI(4,5)P2-diC8, an intriguing finding that underscores the complex nature of Cl- channel expression and function in DSM cells. Removal of both extracellular Ca2+ and Mg2+ did not affect the DSM whole cell Cl- current, whereas Gd3+ (1 mM) potentiated the current. Collectively, our recent and present findings strongly suggest that Cl- channels are critical regulators of DSM excitability and are regulated by extracellular pH, Gd3+, and PI(4,5)P2. [ABSTRACT FROM AUTHOR]

In order to study the construction and application of urinary system model with functional bladder module, bladder model was designed, and appropriate materials was selected to make it, and its performance was studied. The results showed that in the analysis of pressure performance of bladder model, more detrusor instability was found in the model than in the urodynamic test, and there was significant statistical difference (P < 0.01). In the analysis of bladder safety capacity, it was found that the bladder safety capacity in the model was much larger than that measured by urodynamics, and there was significant statistical difference (P < 0.01). In the analysis of detrusor workmanship and contraction rate, it was found that the normal model group was significantly smaller than the obstruction group, and there was significant statistical difference (P < 0.01). Comparing the detrusor contraction rate of the two groups, it was found that the normal group and the obstruction group had significant difference at t3, and there was no statistical difference between the other two groups. Therefore, through this study, it is found that the understanding of urinary system can be enhanced by building bladder model, and the basic operating skills of medical staff can be improved more easily by using bladder model, which achieves the expected results of the experiment. Although some shortcomings have been found in the course of the study, it still provides experimental reference for the clinical study of bladder in the future. [ABSTRACT FROM AUTHOR]

The detrusor, a key component of the urinary bladder wall, is a densely innervated syncytial smooth muscle tissue. Random spontaneous release of neurotransmitter at neuromuscular junctions (NMJs) in the detrusor gives rise to spontaneous excitatory junction potentials (SEJPs). These sub-threshold passive signals not only offer insights into the syncytial nature of the tissue, their spatio-temporal integration is critical to the generation of spontaneous neurogenic action potentials which lead to focal contractions during the filling phase of the bladder. Given the structural complexity and the contractile nature of the tissue, electrophysiological investigations on spatio-temporal integration of SEJPs in the detrusor are technically challenging. Here we report a biophysically constrained computational model of a detrusor syncytium overlaid with spatially distributed innervation, using which we explored salient features of the integration of SEJPs in the tissue and the key factors that contribute to this integration. We validated our model against experimental data, ascertaining that observations were congruent with theoretical predictions. With the help of comparative studies, we propose that the amplitude of the spatio-temporally integrated SEJP is most sensitive to the inter-cellular coupling strength in the detrusor, while frequency of observed events depends more strongly on innervation density. An experimentally testable prediction arising from our study is that spontaneous release frequency of neurotransmitter may be implicated in the generation of detrusor overactivity. Set against histological observations, we also conjecture possible changes in the electrical activity of the detrusor during pathology involving patchy denervation. Our model thus provides a physiologically realistic, heuristic framework to investigate the spread and integration of passive potentials in an innervated syncytial tissue under normal conditions and in pathophysiology. [ABSTRACT FROM AUTHOR]