UNASSIGNED: Mirabegron is available for treatment of overactive bladder (OAB). However, mechanisms underlying symptom improvements and long-term effects on bladder smooth muscle cells are uncertain. Contractility and growth of bladder smooth muscle contribute to OAB, and depend on smooth muscle phenotypes, and on muscarinic receptor expression. Here, we examined prolonged exposure to mirabegron (20-48 h) on phenotype markers, muscarinic receptor expression, and phenotype-dependent functions in human bladder smooth muscle cells (hBSMC).
UNASSIGNED: Expression of markers for contractile (calponin, MYH11) and proliferative (MYH10, vimentin) phenotypes, proliferation (Ki-67), and of muscarinic receptors were assessed by RT-PCR. Proliferation, viability, actin organization and contractions in cultured hBSMC were examined by EdU, CCK-8, phalloidin staining and matrix contraction assays.
UNASSIGNED: Calponin-1 mRNA decreased with 100 nM and 150 nM mirabegron applied for 20 h (0.56-0.6 fold of controls). Decreases were resistant to the β3-AR antagonist L-748,337 (0.34-0.55 fold, 100-150 nM, 20 h). After 40 h, decreases occured in the presence of L-748,337, but not without L-748,337. MYH11 mRNA increased with 150 nM mirabegron (40 h, 1.9 fold). This was partly preserved with L-748,337, but not observed after 20 h mirabegron exposure. Vimentin mRNA reduced with 150 nM mirabegron after 20 h, but not after 40 h, with and without L-748,337 (0.71-0.63 fold). MYH10 mRNA expression remained unaffected by mirabegron. Exposure to 150 nM mirabegron increased Ki-67 mRNA after 20 h in the presence of, but not without L-748,337, and after 40 h without, but not with L-748,337. Proliferation rates and actin organization were stable with 50-150 nM mirabegron (24 h, 48 h). Viability increased significantly after mirabegron exposure for 20 h, and by trend after 40 h, which was fully sensitive to L-748,337. M2 mRNA was reduced by 20 h mirabegron, which was resistant to L-748,337. Carbachol (3 µM) enhanced time-dependent contractions of hBSMC, which was inhibited by mirabegron (150 nM) in late phases (24 h), but not in early phases of contractions. Conclusion: Mirabegron induces dynamic phenotype alterations and M2 downregulation in hBSMC, which is paralleled by time-shifted anticontractile effects. Phenotype transitions may be involved in improvements of storage symptoms in OAB by mirabegron.

The β3-adrenoceptor agonist mirabegron is available for the treatment of storage symptoms of overactive bladder, including frequency, urgency, and incontinence. The off-target effects of mirabegron include binding to α1-adrenoceptors, which are central in the treatment of voiding symptoms. Here, we examined the structure-function relationships in the binding of mirabegron to a cryo-electron microscopy structure of α1A. The binding was simulated by docking mirabegron to a 3D structure of a human α1A-adrenoceptor (7YMH) using Autodock Vina. The simulations identified two binding states: slope orientation involving 10 positions and horizontal binding to the receptor surface involving 4 positions. No interactions occurred with positions constituting the α1A binding pocket, including Asp-106, Ser-188, or Phe-312, despite the positioning of the phenylethanolamine moiety in transmembrane regions close to the binding pocket by contact with Phe-288, -289, and Val-107. Contact with the unique positions of α1A included the transmembrane Met-292 during slope binding and exosite Phe-86 during horizontal binding. Exosite binding in slope orientation involved contact of the anilino part, rather than the aminothiazol end, to Ile-178, Ala-103, and Asn-179. In conclusion, contact with Met-292 and Phe-86, which are unique positions of α1A, accounts for mirabegron binding to α1A. Because of its lack of interactions with the binding pocket, mirabegron has lower affinity compared to α1A-blockers and no effects on voiding symptoms.

OBJECTIVE: To investigate the protective effect of intravesical glucosamine in treating overactive bladder (OAB).
METHODS: Ninety-two female Sprague-Dawley (SD) rats were divided into 4 groups i.e. protamine sulfate (PS), N-acetylcysteine (NAC), and glucosamine-treated PS (GPS), and normal saline control (NC) were used. We induced hyperactivity in rats via intravesical infusion of PS and potassium chloride (KCl), whereas the NC group underwent a sustained intravesical saline infusion for 1 h. N-acetylcysteine (NAC), a potential antioxidant as well as anti-inflammatory agent was employed as positive control. Cystometrography (CMG) was then conducted to determine urodynamic parameters, i.e., leak point pressure (LPP, n = 48) and inter-contractile interval, the duration between two voids (ICI, n = 32).
RESULTS: LPP was significantly elevated in the GPS group (mean ± SD: 110.9 ± 6.2 mmHg) compared to the NC (81.0 ± 32.5 mmHg), PS (40.3 ± 10.9 mmHg), and NAC group (70.3 ± 19.4 mmHg). The cystometrogram data also reveals a prolonged ICI in the GPS group (241.3 ± 40.2 s) compared to the NC group (216.0 ± 41.7 s), PS group (128.8 ± 23.6 s), and NAC group (193.8 ± 28.3 s).
CONCLUSIONS: This preliminary study implies the ameliorative impact of GPS treatment on OAB in terms of improved urodynamic parameters, including LPP and ICI.

BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC).
METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization.
CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

This paper explores a practical approach to pelvic floor health called the Skilling technique. Unlike the commonly recommended \"squeezing upwards\" method which teaches a woman to voluntarily squeeze upwards (a learnt technique), the Skilling method is entirely reflex: the squatting-based exercises on which it is based, strengthen the three reflex pelvic muscle forces which pull against the suspensory ligaments pubourethral ligament (PUL) and uterosacral ligament (USL) to: close the urethra during effort (control of stress incontinence), open the urethra during micturition, and stretch the vagina in opposite directions to control inappropriate activation of the micturition reflex [overactive bladder (OAB)]. The strengthened ligaments better support the pelvic visceral plexuses (VPs), which unsupported, can fire off de novo impulses which the brain interprets as \"chronic pelvic pain\". This review investigates the impact of the Skilling technique on pain, bladder and bowel symptoms in women. In premenopausal women, results show a 50% symptom improvement in 68% to 82% of women who have chronic pelvic pain, urge, frequency, nocturia, abnormal emptying, and post-void residual urine. A modified Skilling technique was applied in children aged 6-11 years with day/night enuresis. Remarkably, an 86% cure rate was achieved over 4 months. It was hypothesized that this accelerated cure, which is achieved naturally with age, may be connected to the reinforcement of collagen which occurs with the increase in pubertal hormones. In summary, the Skilling technique is a promising and accessible method to enhance pelvic floor health for both women and children, offering a practical alternative to traditional approached like Kegel exercises.

OBJECTIVE: Pelvic organ prolapse (POP) and overactive bladder (OAB) commonly affect the aging female population. We aimed to investigate the possible relationship between the two, as reflected by urodynamic studies.
METHODS: A retrospective analysis was conducted on women who underwent urodynamic studies at a university-affiliated tertiary medical center from January 2018 to January 2021. Women presenting with urge incontinence and diagnosed with detrusor overactivity (DO) were included in the study. Based on the presence or absence of a modified POP-Q ≥ grade 2, these women were categorized into two groups. Data on general demographics, clinical symptoms, and urodynamic findings were extracted and compared using SPSS.
RESULTS: During the study period, 949 urodynamic evaluations were performed. Of these, 303 (31.92%) reported urge incontinence. Out of this subset, 151 (49.83%) were diagnosed with DO. Within this group, 18 (11.9%) had POP, while 134 (88.1%) did not. The POP group had a notably higher incidence of prior vaginal hysterectomy and anterior colporrhaphy (p = 0.02 and p = 0.01, respectively). While most urodynamic parameters were similar between groups, there was a significant increase in hesitancy in the POP group (13 s vs 8 s, p = 0.03). There was a trend indicating a reduced median Q max (12 ml/s vs. 18 ml/s, p = 0.06) and an increased flow time (55 s vs 40 s, p = 0.08) in the POP group.
CONCLUSIONS: The urodynamic profile of the POP group suggests an obstructive voiding pattern. Further longitudinal research is essential to fully understand the relationship between POP and OAB.

UNASSIGNED: Managing overactive bladder (OAB) symptoms in Parkinson\'s disease (PD) is challenging. This study aimed to investigate the medical management of OAB symptoms in patients with PD.
UNASSIGNED: Patients with OAB symptoms who were newly treated with tolterodine and/or tamsulosin were screened from a database of 187 PD patients. Before treatment, the Hoehn-Yahr scale, International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), and urodynamic evaluation were evaluated. On day 21 of treatment, the IPSS and OABSS were re-evaluated. The changes of these scores and urinary symptoms were analyzed.
UNASSIGNED: Seventy patients with a mean age of 62.2±7.9 years and median Hoehn-Yahr stage of 2 (IQR 2-3) were enrolled. Tolterodine, tamsulosin, and tolterodine + tamsulosin were used in 43, 20, and 7 patients, respectively. The IPSS storage symptoms (9.4±3 vs. 3.5±2.3) and OABSS (9±2.8 vs. 4.8±3.3) improved significantly after treatment (both P<0.01). However, 28 (40%) patients displayed moderate urinary symptoms, and nocturia and urgency still affected more than half of the patients after treatment.
UNASSIGNED: Tolterodine and/or tamsulosin can significantly improve OAB symptoms in PD patients. Nocturia and urgency remain common after treatment.

OBJECTIVE: A small, but growing literature links stressors and mental health disorders (MHDs) across the life course to overactive bladder (OAB) and urinary incontinence symptoms. Mechanisms by which stressors and MHDs may impact bladder health are not fully understood, limiting novel prevention and treatment efforts. Moreover, potential biopsychosocial mechanisms involving the brain and gut have not been considered in an integrated, comprehensive fashion.
METHODS: Members of the prevention of lower urinary tract symptoms Research Consortium developed conceptual models to inform research on biopsychosocial mechanisms through which stress and MDHs may impact bladder health among girls and women, focusing on brain and gut physiology.
RESULTS: Two conceptual models were developed-one to explain central (brain-based) and peripheral (gut-based) mechanisms linking stressors and MHDs to OAB and bladder health, and one to highlight bidirectional communication between the brain, gut, and bladder. Traumatic events, chronic stressors, and MHDs may lead to a maladaptive stress response, including dysregulated communication and signaling between the brain, gut, and bladder. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters, amino acids, short-chain fatty acids, and inflammatory immune response molecules that mediate communication between the gut and brain. Microbiota signal neurogenesis, microglia maturation, and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission and synaptogenesis, potentially influencing bladder symptom development. Life course trajectories of risk may be prevented or interrupted by central and peripheral resources for neuropsychological resilience.
CONCLUSIONS: Depicted pathways, including brain-gut-bladder communication, have implications for research and development of novel prevention and treatment approaches.

The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to examine the potential link between urinary metabolites of organophosphate esters and OAB.
Data from the National Health and Nutrition Examination Survey (NHANES) database of the 2011-2016 cycles were utilized. Four urinary metabolites of organophosphate esters: diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) were included in the study. Multivariate logistic regression and restricted cubic spline (RCS) were used to evaluate the relationship between urinary OPEs metabolites and OAB. Interaction analysis was conducted on subgroups to confirm the findings.
A total of 3,443 United States (US) adults aged 20 years or older were included in the study, of whom 597 participants were considered to have OAB. After adjusting for potential confounding factors, we found a positive association between DPHP and the risk of overactive bladder. The risk of overactive bladder increased with increasing DPHP concentrations compared with quartile 1 (quartile 2, OR = 1.19, 95% CI, 0.82-1.73, P = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, P = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, P = 0.002). However, after dividing the participants by gender, only the female group retained consistent results. Additionally, restricted cubic spline analysis revealed a nonlinear dose-response correlation between DPHP and OAB in female participants. In the subgroup analysis based on age, race, body mass index (BMI), recreational activity, smoking status, drinking status, hypertension, diabetes, and stroke, the interaction analysis revealed that the findings were uniform.
Our findings indicate that exposure to DPHP could elevate the risk of OAB in US adult females. Further experimental studies are needed to explore the underlying mechanism in the future.

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