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Objectives: To investigate roles of brain carbon monoxide (CO), an endogenous gasotransmitter, in regulation of the rat micturition reflex. Methods: In urethane‐anesthetized (0.8 g/kg, ip) male rats, evaluation of urodynamic parameters was started 1 h before intracerebroventricular administration of CORM‐3 (CO donor) or ZnPP (non‐selective inhibitor of heme oxygenase, a CO producing enzyme) and continued for 2 h after the administration. We also investigated effects of centrally pretreated SR95531 (GABAA receptor antagonist) or SCH50911 (GABAB receptor antagonist) on the CORM‐3‐induced response. Results: CORM‐3 significantly prolonged intercontraction intervals (ICIs) without changing maximal voiding pressure (MVP), while ZnPP significantly shortened ICI and reduced single‐voided volume and bladder capacity without affecting MVP, post‐voided residual volume, or voiding efficiency. The ZnPP‐induced ICI shortening was reversed by CORM‐3. The CORM‐3‐induced ICI prolongation was significantly attenuated by centrally pretreated SR95531 or SCH50911, respectively. Conclusions: Brain CO can suppress the rat micturition reflex through brain γ‐aminobutyric acid (GABA) receptors. [ABSTRACT FROM AUTHOR]

BACKGROUND: The dysfunction of bladder function caused by spinal cord injury is a difficult point in clinical treatment and a hot spot in research. Repairing the injured spinal cord and remodeling the bladder micturition reflex pathway are the fundamental treatment methods. OBJECTIVE: To summarize the reconstruction of the bladder innervation pathway after spinal cord transection injury and its related influencing factors. METHODS: The relevant literature concerning the reconstruction of bladder micturition reflex, neurogenic bladder and urinary reflex and spinal cord repair was retrieved on CNKI, WanFang Data, PubMed and Web of Science. Chinese and English search terms were “neurogenic bladder; spinal cord injury; micturition reflex; spinal cord repair”. RESULTS AND CONCLUSION: In the process of reconstructing the bladder micturition reflex, there are many factors involved, including the repair and reconstruction of the injured spinal cord, the remodeling of micturition center, the changes of bladder tissue and substances and hormones in and out of the body. In this process, there are mainly the following problems: (1) As a complex process, there are many sites involved in the reconstruction of the micturition reflex, so the main sites of action can be selected for in-depth study, so as to break through the doubts existing in the reconstruction of the micturition reflex pathway. (2) The mechanism of the normal micturition reflex is complex. After spinal cord transection injury, whether the central nucleus mass controlling or participating in the micturition reflex is compensated and the corresponding compensatory mechanism needs to be further investigated. (3) Information communication between the center and the bladder is interrupted after spinal cord transection injury. Whether there is a direct information connection between the center and the bladder remains to be further investigated. (4) The relationship between reconstructing micturition reflex and body fluid after spinal cord transection injury needs further study. In the reconstruction of the bladder micturition reflex, the key treatment is to promote spinal cord repair, nerve reflex reconstruction, substance metabolism and bladder tissue structure adjustment through intervention. Chinese medicine and Western medicine have their methods. [ABSTRACT FROM AUTHOR]

Objectives: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel β3‐adrenoceptor agonist approved for the treatment of overactive bladder. However, how β3‐adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease. Methods: In a rat model of Parkinson's disease induced by unilateral 6‐hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity. Results: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter‐contraction interval (p <.05) and reduced voiding pressure (p <.01). However, no significant effects on urethral function were observed. Conclusions: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of β3‐adrenoceptor agonists. [ABSTRACT FROM AUTHOR]

The study included a group of 133 women (average age 55 years) suffering from urinary incontinence and operated on by the synthetic sling method. A number of studies were performed before and after surgery, including non-invasive uroflow monitoring. The processing and analysis of the data obtained, including the results of urodynamic monitoring, made it possible to provide a mechanism of urinary retention, which is based on the activation of the 4th mating reflex of a forced change in the receptive field by an installed synthetic tape. Based on the reflex nature of the described mechanism, one should use any operation from the class of synthetic sling of limiting effectiveness, use an instrument for implantation, and the material itself is not of key importance for eliminating incontinence.

Urinary bladder dysfunction might be related to disturbances at different levels of the micturition reflex arc. The current study aimed to further develop and evaluate a split bladder model for detecting and analysing relaxatory signalling in the rat urinary bladder. The model allows for discrimination between effects at the efferent and the afferent side of the innervation. In in vivo experiments, the stimulation at a low frequency (1 Hz) of the ipsilateral pelvic nerve tended to evoke relaxation of the split bladder half (contralateral side; −1.0 ± 0.4 mN; n = 5), in contrast to high frequency-evoked contractions. In preparations in which the contralateral pelvic nerve was cut the relaxation occurred at a wider range of frequencies (0.5–2 Hz). In separate experiments, responses to 1 and 2 Hz were studied before and after intravenous injections of propranolol (1 mg/kg IV). The presence of propranolol significantly shifted the relaxations into contractions. Also, electrical stimulation of the ipsilateral pudendal nerve evoked relaxations of similar magnitude as for the pelvic stimulations, which were also affected by propranolol. In control in vitro experiments, substances with β-adrenoceptor agonism, in contrast to a selective α-agonist, evoked relaxations. The current study shows that the split bladder model can be used for in vivo studies of relaxations. In the model, reflex-evoked sympathetic responses caused relaxations at low intensity stimulation. The involvement of β-adrenoceptors is supported by the sensitivity to propranolol and by the in vitro observations. [ABSTRACT FROM AUTHOR]

Objective: The present study investigated the inhibitory effects of a novel minimally invasive implanted tibial nerve stimulation device on non-nociceptive bladder reflexes in cats. Materials and methods: A wireless minimally invasive implanted nerve stimulator was implanted adjacent to the left tibial nerve in seven cats. Multiple cystometrograms (CMGs) were obtained to determine the inhibitory effects of tibial nerve stimulation (TNS) at different frequencies and intensities on the micturition reflex by infusing normal saline (NS). Results: TNS at 6 Hz did not significantly change the bladder capacity (BC) compared to the control level at the intensity threshold (T), while TNS significantly (P < 0.05) increased the BC to 158.89 ± 20.57% of the control level at 2 T. When stimulated at 15 Hz, TNS did not significantly (P > 0.05) change the BCs at 1 T and 2 T. Conclusions: The minimally invasive implanted TNS device was shown to be effective in inhibiting the micturition reflex under physiologic conditions. Further studies are warranted to determine the inhibitory effects of TNS on nociceptive bladder reflexes. [ABSTRACT FROM AUTHOR]

We recently reported that hydrogen sulfide (H 2 S) is a possible relaxation factor in the rat bladder. However, there is no available information about the roles of central H 2 S in the micturition reflex, so we investigated the effects of centrally administered GYY4137 (H 2 S donor) and AOAA (H 2 S synthesis inhibitor) on the micturition reflex in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. Cystometry was performed before and after the administration of GYY4137 (3 or 10 nmol/rat, icv) or AOAA (30 or 100 μg/rat, icv). In some rats, SR95531 (GABA A receptor antagonist, 0.1 nmol/rat, icv) or SCH50911 (GABA B receptor antagonist, 0.1 nmol/rat, icv) was administered 30 min before GYY4137 administration (10 nmol/rat, icv). Centrally administered GYY4137 dose-dependently prolonged the intercontraction intervals (ICI) without altering maximum voiding pressure (MVP). On the other hand, centrally administered AOAA dose-dependently shortened ICI without altering MVP. The AOAA (30 μg/rat, icv)-induced ICI shortening was reversed in the central presence of GYY4137 (10 nmol/rat, icv). Centrally pretreated SR95531 or SCH50911 significantly attenuated the GYY4137 (10 nmol/rat, icv)-induced prolongation of ICI, respectively. These findings suggest that endogenous brain H 2 S can inhibit the rat micturition reflex via both GABA A and GABA B receptors in the brain. • Central H 2 S administration by GYY4137 suppressed micturition reflex. • Central inhibition of H 2 S biosynthesis by AOAA promoted micturition reflex. • The AOAA-induced promotion was reversed by GYY4137-induced H 2 S supplementation. • Antagonists of GABAA or GABAB receptors attenuated the GYY4137-induced suppression. [ABSTRACT FROM AUTHOR]

Objectives: To identify the types of serotonin (5‐hydroxytryptamine) receptors of the prefrontal cortex related to the micturition reflex. Methods: Female Sprague–Dawley rats and a microinjection method were used for this study. Stainless steel guide cannulas were implanted bilaterally into the prefrontal cortex, and a polyethylene catheter was inserted into the bladder. Cystometric parameters (intercontraction interval and maximum voiding pressure) were measured before and after injection of any one of six specific antagonists of 5‐hydroxytriptamine receptors (5‐hydroxytryptamine 1A, 5‐hydroxytryptamine 2A, 5‐hydroxytryptamine 2C, 5‐hydroxytryptamine 3, 5‐hydroxytryptamine 4 and 5‐hydroxytryptamine 7) into the prefrontal cortex. The prefrontal cortex was divided into two regions, namely the prelimbic cortex and the infralimbic cortex. The experiments were carried out in conscious and free‐moving rats. Results: The intercontraction interval value increased significantly after injection of the 5‐hydroxytriptamine 2A receptor antagonist, MDL11939, into the prelimbic cortex of the rat prefrontal cortex (7.68 ± 1.28 vs 9.02 ± 1.41 min, P < 0.05), whereas the intercontraction interval value decreased significantly after injection of the 5‐hydroxytriptamine 7 antagonist SB269970 into the prelimbic cortex (9.42 ± 0.39 vs 8.14 ± 0.71 min, P < 0.05). The intercontraction interval was unaffected by injection of either of these two antagonists into the infralimbic cortex. The other four antagonists (5‐hydroxytryptamine 1A, 5‐hydroxytryptamine 2C, 5‐hydroxytryptamine 3 and 5‐hydroxytryptamine 4) had no effect on the intercontraction interval after injection into the prelimbic cortex and the infralimbic cortex. The maximum voiding pressure was unaffected by injection of any one of the six 5‐hydroxytriptamine antagonists into the prelimbic cortex and infralimbic cortex. Conclusions: In the rat prefrontal cortex5‐hydroxytryptamine 2A receptors excite the micturition reflex, whereas 5‐hydroxytryptamine 7 receptors inhibit this reflex. [ABSTRACT FROM AUTHOR]

Aim: Brain nitric oxide (NO) have been reported in regulation of the sympatho‐adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3‐(4‐morpholinyl)sydnonimine, hydrochloride (SIN‐1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho‐adrenomedullary system and on brain N‐methyl‐D‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptors in urethane‐anesthetized (0.8 g/kg, ip) male Wistar rats. Methods: Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN‐1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN‐1 administration or intracerebroventricular pretreatment with other drugs. Results: SIN‐1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN‐1, 0 µg] and 54.9% [SIN‐1, 250 µg] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.59]) without affecting plasma noradrenaline or maximal voiding pressure. SIN‐1 (250 µg/animal) reduced single‐voided volume and bladder capacity without affecting post‐voiding residual volume. The SIN‐1 (250 µg/animal)‐induced adrenaline elevation and ICI reduction were attenuated by 2‐(4‐carboxyphenyl)‐4,4,5,5‐tetramethylimidazoline‐1‐oxyl‐3‐oxide, sodium salt (carboxy‐PTIO) (NO scavenger, icv) (ICI values; 44.7% [vehicle + SIN‐1] and 77.5% [carboxy‐PTIO + SIN‐1] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.51]). Acute bilateral adrenalectomy abolished SIN‐1‐induced adrenaline elevation, while showed no effect on the SIN‐1‐induced ICI reduction. The ICI reduction was attenuated by MK‐801 (NMDA receptor antagonist, icv) (ICI values; 47.0% [vehicle + SIN‐1] and 87.6% [MK‐801 + SIN‐1] during 15 minutes after SIN‐1 administration [P <.05; η2 = 0.61]), but not by DNQX (AMPA receptor antagonist, icv). Conclusion: Brain NO is involved in facilitation of the rat micturition reflex through brain NMDA receptors, independently of the sympatho‐adrenomedullary outflow modulation. [ABSTRACT FROM AUTHOR]

Objectives: Parkinson's disease caused by the loss of dopaminergic neurons induces not only motor dysfunction but also lower urinary tract dysfunction. Patients with Parkinson's disease have recently been reported to experience both urge urinary incontinence (overactive bladder) and stress urinary incontinence, the latter of which occurs when the pressure of the bladder exceeds that of the urethra. Vibegron is a highly selective novel β 3 -adrenoceptor agonist approved for the treatment of overactive bladder. However, how β 3 -adrenoceptor agonists affect urethral function remains unclear. In a clinical report, the urethral function of patients with Parkinson's disease was shown to be degraded. The present study aimed to investigate the effects of vibegron on lower urinary tract activity in a rat model of Parkinson's disease., Methods: In a rat model of Parkinson's disease induced by unilateral 6-hydroxydopamine injection into the substantia nigra pars compacta, we examined the effects of vibegron on bladder and urethral activity., Results: Cystometric analysis revealed that, compared with vehicle injection, intravenous injection of 3 mg/kg vibegron significantly increased the inter-contraction interval (p < .05) and reduced voiding pressure (p < .01). However, no significant effects on urethral function were observed., Conclusions: The results of the present study provide corroborating evidence that bladder dysfunction is suppressed by the administration of vibegron in Parkinson's disease model rats, confirming that vibegron is effective for treating overactive bladder without further worsening urethral function. These findings may contribute to a better understanding of the mechanisms of β 3 -adrenoceptor agonists., (© 2023 John Wiley & Sons Australia, Ltd.)

Abstract ATP in the suburothelial layer is released from the bladder urothelium by mechanical stimuli. ATP directly activates purinergic receptors that are expressed on primary bladder afferent neurons and induces the micturition reflex. Although ATP is also released to the bladder lumen from the bladder urothelium, the role of ATP in the bladder lumen is unknown. Recently, clinical studies have reported that urinary ATP levels are much higher in patients with an overactive bladder than healthy controls. These results suggest that ATP in the bladder lumen is also involved in the micturition reflex. In this study, we performed intravesical ATP instillation in the mouse bladder. We evaluated urinary function with novel reliable methods using improved cystometry and ultrasonography, which we previously established. We found that intravesical ATP instillation induced urinary frequency because of activation of bladder afferent nerves without inflammatory changes in the bladder or an increase in post-void residual urine. These results suggest that not only ATP in the suburothelial layer, but also ATP in the bladder lumen, are involved in enhancement of the micturition reflex. Highlights • Intravesical ATP instillation induces urinary frequency. • Intravesical ATP instillation activates bladder afferent nerves. • Intravesical ATP instillation do not induce bladder inflammatory changes. • ATP in the bladder lumen is involved in enhancement of the micturition reflex. • Our mouse model of ATP-induced urinary frequency is a promising model of OAB. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine if the duration of the micturition reflex modulation could be prolonged by repeated periods of afferent stimulation in the decorticated rat. Methods: Eighteen female Sprague‐Dawley rats were used for the study, 10 for intravesical electrical stimulation (IVES), and 8 for Ano‐genital pudendal afferents stimulation. Repeated constant flow cystometries were performed with body‐warm saline (0.06‐0.1 mL/min) at about 10 min interval. The selected afferents were stimulated continuously for 5 min at maximal intensity. The same stimulation was repeated six times with a pause of 5 min between the stimulations. The mean threshold volume of cystometries performed during one hour before and each hour after the stimulation were compared. Results: After six periods of IVES, the micturition threshold volume decreased to its lowest value (62% of control) during the first hour and remained at 80% 4 h later (n = 10, P < 0.01). Ano‐genital afferent stimulation produced a corresponding increase in the micturition threshold volume. The long‐lasting poststimulation effect was again observed for more than 5 h. During the first hour the mean threshold volume increased to 211% of controls and it remained at about this level for the entire observation period (n = 8, P < 0.01). Conclusions: Repeated short periods of stimulation prolonged the modulatory effect well beyond the stimulation period. The findings provide experimental evidence supporting the clinical application of IVES and ano‐genital stimulation for treatment of neurogenic urinary bladder dysfunction. [ABSTRACT FROM AUTHOR]

We previously reported that brain α7 nicotinic acetylcholine receptors inhibited the rat micturition reflex. To elucidate the mechanisms underlying this inhibition, we focused on the relationship between α7 nicotinic acetylcholine receptors and hydrogen sulphide (H 2 S) because we found that H 2 S also inhibits the rat micturition reflex in the brain. Therefore, we investigated whether H 2 S is involved in the inhibition of the micturition reflex induced by the activation of α7 nicotinic acetylcholine receptors in the brain. Cystometry was performed in male Wistar rats under urethane anesthesia (0.8 g/kg, ip) to examine the effects of icv pre-treated GYY4137 (H 2 S donor, 1 or 3 nmol/rat) or aminooxyacetic acid (AOAA; non-selective H 2 S synthesis inhibitor, 3 or 10 μg/rat) on PHA568487 (α7 nicotinic acetylcholine receptor agonist, icv)-induced prolongation of intercontraction intervals. PHA568487 administration at a lower dose (0.3 nmol/rat, icv) had no significant effect on intercontraction intervals, while under pre-treatment with GYY4137 (3 nmol/rat icv), PHA568487 (0.3 nmol/rat, icv) significantly prolonged intercontraction intervals. PHA568487 at a higher dose (1 nmol/rat, icv) induced intercontraction interval prolongation, and the PHA568487-induced prolongation was significantly suppressed by AOAA (10 μg/rat, icv). The AOAA-induced suppression of the PHA568487-induced intercontraction interval prolongation was negated by supplementing H 2 S via GYY4137 at a lower dose (1 nmol/rat, icv) in the brain. GYY4137 or AOAA alone showed no significant effect on intercontraction intervals at each dose used in this study. These findings suggest a possible involvement of brain H 2 S in inhibiting the rat micturition reflex induced by activation of brain α7 nicotinic acetylcholine receptors. • GYY4137 potentiated icv administered PHA568487-induced micturition inhibition. • AOAA suppressed icv administered PHA568487-induced micturition inhibition. • The AOAA-induced suppression was negated by GYY4137-induced H 2 S supplementation. • Activation of brain α7 nicotinic receptors inhibits micturition via H 2 S. [ABSTRACT FROM AUTHOR]

Gonadotropin-releasing hormone (GnRH) and its synthetic analog leuprolide acetate, a GnRH agonist, have neurotrophic properties. This study was designed to determine whether administration of leuprolide acetate can improve locomotor behavior, gait, micturition reflex, spinal cord morphology and the amount of microglia in the lesion epicenter after spinal cord injury in rats. Rats with spinal cord compression injury were administered leuprolide acetate or saline solution for 5 weeks. At the 5 th week, leuprolide acetate-treated rats showed locomotor activity recovery by 38%, had improvement in kinematic gait and exhibited voiding reflex recovery by 60%, as compared with the 1 st week. By contrast, saline solution-treated rats showed locomotor activity recovery only by 7%, but voiding reflex did not recover. More importantly, leuprolide acetate treatment reduced microglial immunological reaction and induced a trend towards greater area of white and gray matter in the spinal cord. Therefore, leuprolide acetate has great potential to repair spinal cord injury.

Elderly patients suffering from lower urinary tract symptoms with benign prostatic hyperplasia (BPH) are widely prescribed α 1 -adrenoceptor blockers (α 1 -blockers) to improve voiding and storage symptoms. The mechanism of action for improvements in voiding symptoms is well understood; tonus of the urethra and prostate are decreased and urinary flow rate is increased by α 1 -blockers. However, the mechanisms underlying storage symptoms have remained unclear, although detrusor hyperactivity has been identified as a significant factor. Previous investigations have yielded informative results, such as amelioration of reduced blood flow and afferent C-fiber activation, and the importance of the urothelium. Recently, the fascinating role of α 1A - and α 1D -adrenoceptor subtypes have been investigated for bladder function. Furthermore, the scope of this pathology covers both the bladder and that part of the central nervous system related to the micturition reflex. This review describes the beneficial effects of α 1 -blockers on storage symptoms and the pathogenesis of storage symptoms related to BPH, discusses the mechanisms of action for α 1 -blockers with reference to results from cystometry to suggest improvements in management that suppress detrusor hyperactivity, and examines the potential influence of α 1A - and α 1D -adrenoceptor subtypes on bladder activity. [ABSTRACT FROM AUTHOR]

Objective To evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg). Methods A bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings. Results PAG DBS at 2–2.5 V, PnO DBS at 2–2.5 V, and PPTg DBS at 1.75–2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5–5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions. Conclusion PPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions. Significance DBS could be a potential approach to manage bladder function under various conditions. [ABSTRACT FROM AUTHOR]

Summary Objective Pediatric lower urinary tract dysfunction (LUTD) is a common problem in childhood. Lower urinary tract symptoms in children include overactive bladder, voiding postponement, stress incontinence, giggle incontinence, and dysfunctional voiding. Gastrointestinal co-morbidities, including constipation or fecal incontinence, are commonly associated with lower urinary tract (LUT) symptoms in children, often reaching 22–34%. This review summarized the potential mechanisms underlying functional lower urinary and gastrointestinal co-morbidities in children. It also covered the current understanding of clinical pathophysiology in the pediatric population, anatomy and embryological development of the pelvic organs, role of developing neural circuits in regulation of functional co-morbidities, and relevant translational animal models. Materials and methods This was a non-systematic review of the published literature, which summarized the available clinical and translational studies on functional urologic and gastrointestinal co-morbidities in children, as well as neural mechanisms underlying pelvic organ ‘cross-talk’ and ‘cross-sensitization’. Results Co-morbidity of pediatric lower urinary and gastrointestinal dysfunctions could be explained by multiple factors, including a shared developmental origin, close anatomical proximity, and pelvic organ ‘cross-talk’. Daily physiological activity and viscero-visceral reflexes between the lower gastrointestinal and urinary tracts are controlled by both autonomic and central nervous systems, suggesting the dominant modulatory role of the neural pathways. Recent studies have provided evidence that altered sensation in the bladder and dysfunctional voiding can be triggered by pathological changes in neighboring pelvic organs due to a phenomenon known as pelvic organ ‘cross-sensitization’. Cross-sensitization between pelvic organs is thought to be mainly coordinated by convergent neurons that receive dual afferent inputs from discrete pelvic organs. Investigation of functional changes in nerve fibers and neurons sets certain limits in conducting appropriate research in humans, making the use of animal models necessary to uncover the underlying mechanisms and for the development of novel therapeutic approaches for long-term symptomatic treatment of LUTD in the pediatric population. Conclusion Pediatric LUTD is often complicated by gastrointestinal co-morbidities; however, the mechanisms linking bladder and bowel dysfunctions are not well understood. Clinical studies have suggested that therapeutic modulation of one system may improve the other system's function. To better manage children with LUTD, the interplay between the two systems, and how co-morbid GI and voiding dysfunctions can be more specifically targeted in pediatric clinics need to be understood. [ABSTRACT FROM AUTHOR]

ObjectiveTo explore the effectiveness， safety and the possible mechanism of CelecoxibCapsules （Celebrex） in treatment of female stress urinary incontinence．MethodsFrom January 2014 toDecember 2015， 80 female patients with stress urinary incontinence， from the outpatient department of ourhospital，were selected in experimental group，who took celecoxib orally 200 mg，Bid for 3 months．The other 80female patients with stress urinary incontinence were selected in control group，who took placebo （medical starch）orally 1 piece， Bid for 3 months．The two groups of patients were treated with behavioral therapy and functionalexercise of pelvic floor．Both groups of patients were assessed with the urine pad test and quality of life scale 3months later．The study was approved by the Institutional Review Board of the second Hospital of Kunming MedicalUniversity and followed the principles expressed in the Declaration of Helsinki．The written informed consent wasobtained from every patient．ResultsThe difference between the experimental group and the control group in theage， the course of disease had no statistical significance （P＞0.05）．The effectiveness of experimental goup wasbetter than the controlled group．The urine volume in experimental group is less than that in control group in urinepad test．And the score of experimental goup in QOL-36-SF was higher than that of control group both in physicaldimension and the psychological dimension．The overall effective rate was 96.3% in experimental group ［2126.3%） cases were improved markedly， 56 （70%） patients improved， 3 （3.8%） patients was failed] and88.6% in control group ［15 （18.8%） cases were improved markedly，56 （70%） patients improved，3 （3.8%）patients was failed］．Tthe difference has statistical significance （P＜0.05）．No obvious side effects were observedin both groups and no one stooped the treatment by herself．ConclusionCelecoxib can attenuate the symptoms offemale stress urinary incontinence, and has the good safety and tolerability. [ABSTRACT FROM AUTHOR]

Aims To investigate the role of the PFC in the micturition reflex using an in vivo microdialysis study in rats. Methods Adult female Sprague-Dawley rats were used and microdyalysis in the PFC and cystometrography (CMG) were performed under consciousness and free movement in the present study. Experiment 1: Samples including extracellular neurotransmitters were collected by microdyalysis and analyzed by high performance liquid chromatography. At the same time, CMG were performed to measure intercontraction interval (ICI) and maximum voiding pressure (MVP). Experiment 2: SSRI (citalopram, 1 µM) was administered into the PFC, and microdyalysis and cystometrography (CMG) were performed simultaneously. Experiment 3: Following SSRI administration, 5-HT1A agonist (8-OH-DPAT, 300 µM), which has the effect of decreasing the level of serotonin (5-HT) in the PFC, was administered into the PFC, and microdyalysis and CMG were performed simultaneously. Results Experiment 1: Extracellular level of 5-HT in the PFC significantly increased during micturition reflex ( P < 0.05), whereas levels of glutamate or dopamine were not significantly changed. Experiment 2: Local administration of SSRI in the PFC increased the 5-HT level up to approximate 600% of the basal level. It also significantly increased ICI ( P < 0.05), whereas no significant change was found in MVP. Experiment 3: The extracellular level of 5-HT gradually decreased after local administration of 5-HT1A agonist, thereby ICI significantly decreased ( P < 0.05). Conclusions The results of the present study suggest that the PFC has a suppressive effect on neural control of the micturition reflex via serotonin. Neurourol. Urodynam. 35:902-907, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives To elucidate the possible involvement of glutamate and serotonin (5-hydroxytryptamine) neurons in the ventrolateral midbrain periaqueductal gray during noxious stimulation. Methods The study was carried out by evoking a noxious stimulation by acetic acid in an animal model of cystitis. Changes in glutamate and 5-hydroxytryptamine in the periaqueductal gray during the micturition reflex and acetic acid-induced cystitis were determined using in vivo microdialysis combined with cystometry in rats. Results Extracellular glutamate levels slightly, but significantly, increased during the micturition reflex induced by saline infusion into the bladder. Intravesical infusion of acetic acid facilitated the micturition reflex characterized by increases in voiding pressure and decreases in the intercontraction interval. Glutamate levels were markedly increased by acetic acid, and this enhancement was sustained for at least 3 h. 5-Hydroxytryptamine levels, which were not altered during the micturition reflex, were increased after intravesical infusion of acetic acid. Conclusion The results suggest that periaqueductal gray glutamate and 5-hydroxytryptamine neurons differentially participate in the modulation of both nociception and the micturition reflex. Furthermore, periaqueductal gray 5-hydroxytryptamine levels appear to reflect the nociceptive stimuli. [ABSTRACT FROM AUTHOR]

Unlabelled: A growing body of evidence suggests that 5-hydroxytryptamine (5-HT; serotonin) has both physiological and pathological functions in the lower urinary tract. A wide variety of 5-HT receptor subtypes are variably expressed in different organs, both peripheral and central. On urinary bladder smooth muscle, 5-HT1A, 5-HT2, 5-HT3, and 5-HT7 subtypes could function as postjunctional receptors. Postjunctional 5-HT2 receptors induce detrusor contraction of the bladder body. 5-HT1A is suggested to have a similar effect to 5-HT2, while 5-HT3 might suppress detrusor contraction evoked by direct muscle stimulation. Postjunctional 5-HT7 is reported to induce relaxation of the bladder neck, which might be required for efficient voiding. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes also could act as prejunctional receptors in autonomic excitatory nerve terminals. 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, and 5-HT7 subtypes facilitate the neurogenic contraction of the detrusor by enhancing cholinergic or purinergic transmission, whereas 5-HT1A receptors might inhibit the release of acetylcholine in the detrusor. Furthermore, 5-HT1D could be involved in the suppression of ATP release from the urothelium, aiding visceral sensation of the urinary bladder. In the central pathways controlling the micturition reflex, 5-HT1A, 5-HT2A, and 5-HT7 are involved in regulation of bladder and urethral sphincter activities. Their functions, especially that of 5-HT1A, vary in a species- and site (spinal or supraspinal)- dependent manner. In addition to urinary bladder, 5-HT could be involved in prostate contraction and cell proliferation. Evidence indicates that 5-HT receptor subtypes may be novel therapeutic targets for lower urinary tract symptoms.Funding: Grants-in-Aid for Scientific Research (C) (KAKENHI 23590707, 24590722, and 26460694) from the Japan Society for the Promotion of Science. [ABSTRACT FROM AUTHOR]

Background and Objectives: Micturition reflex is long been taught as an interplay of autonomic and somatic nervous system. This reflex is expected to vary with bladder-habits, gender and BMI differences but no study supports this theory sufficiently. The objective of this study is to provide evidence for variation in bladder capacity to hold urine by bladder-habits, gender and BMI. Methods: A total of 69 1st year dentistry students (20 males & 49 females) who consented were asked to empty their bladder naturally followed by drinking measured amounts of mineral water in glass-beaker to the level that they would not be able to hold urine any further. They were advised to note down all their feelings during that process as mentioned in the response form. They also accounted their usual bladder-habit of postponing the visit and lastly expressed that they passed urine in presence of favorable or unfavorable condition. Results: Male students due to comparatively greater mean height and weight had significantly higher maximum capacity of bladder to hold urine independent of BMI. Likewise there was gender-wise significant difference in appearance of 1st desire to micturate, discomfort and pain in terms of filling capacity of bladder. Micturition-postponing-behavior did not affect significantly the maximum capacity to hold urine but played significant role on voluntary control of micturition under unfavorable circumstances. Conclusions: Bladder capacity and voluntary control varies with gender and accommodating behavior respectively. This study may help in establishing a data base in our study population and may add to scientific knowledge. [ABSTRACT FROM AUTHOR]

Aim We investigated the spinal mechanism through which naftopidil inhibits the micturition reflex by comparing the effects of noradrenaline and naftopidil in rats. Methods The following were investigated: the influence of oral naftopidil on plasma monoamine and amino acid levels, the distribution of oral 14C-naftopidil, the effects of intravenous (IV) or intrathecal (IT) injection of noradrenaline or naftopidil on isovolumetric bladder contractions, amino acid levels in the lumbosacral spinal cord after IT noradrenaline or naftopidil, and the effects of IT naftopidil and strychnine and/or bicuculline on isovolumetric bladder contractions. Key findings Oral naftopidil decreased the plasma adrenaline level, while it increased the serotonin and glycine levels. After oral administration, 14C-naftopidil was detected in the spinal cord and cerebrum, as well as in plasma and the prostate gland. When the bladder volume was below the threshold for isovolumetric reflex contractions, IV (0.1 mg) or IT (0.1 μg) noradrenaline evoked bladder contractions, but IV (1 mg) or IT (0.01–1 μg) naftopidil did not. When the bladder volume was above the threshold for isovolumetric reflex contractions, IV or IT noradrenaline transiently abolished bladder contractions. IT noradrenaline decreased the levels of glycine and gamma-aminobutyric acid (GABA) in the lumbosacral cord, while IT naftopidil increased the GABA level. IT strychnine and/or bicuculline blocked the inhibitory effect of IT naftopidil on bladder contractions. Significance Naftopidil inhibits the micturition reflex by blocking α1 receptors, as well as by the activation of serotonergic, glycinergic, and GABAergic neurons in the central nervous system. [ABSTRACT FROM AUTHOR]

Background and Purpose: Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood.Experimental Approach: We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [(3) H]-ACh overflow experiments.Key Results: Instillation of UDP or PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [(3) H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid.Conclusions and Implications: Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors. [ABSTRACT FROM AUTHOR]

Background and purpose Despite the abundant expression of the UDP-sensitive P2Y6 receptor in urothelial cells and sub-urothelial myofibroblasts its role in the control of bladder function is not well understood. Experimental approach We compared the effects of UDP and of the selective P2Y6 receptor agonist, PSB0474, on bladder urodynamics in anaesthetized rats; the voided fluid was tested for ATP bioluminescence. The isolated urinary bladder was used for in vitro myographic recordings and [ 3H]-ACh overflow experiments. Key results Instillation of UDP or PSB0474 into the bladder increased the voiding frequency ( VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions; an effect blocked by the P2Y6 receptor antagonist, MRS2578. Effects mediated by urothelial P2Y6 receptors required extrinsic neuronal circuitry as they were not detected in the isolated bladder. UDP-induced bladder hyperactvity was also prevented by blocking P2X3 and P2Y1 receptors, respectively, with A317491 and MRS2179 applied i.v.. UDP decreased [ 3H]-ACh release from stimulated bladder strips with urothelium, but not in its absence. Inhibitory effects of UDP were converted into facilitation by the P2Y1 receptor antagonist, MRS2179. The P2Y6 receptor agonist increased threefold ATP levels in the voided fluid. Conclusions and Implications Activation of P2Y6 receptors increased the voiding frequency indirectly by releasing ATP from the urothelium and activation of P2X3 receptors on sub-urothelial nerve afferents. Bladder hyperactivity may be partly reversed following ATP hydrolysis to ADP by E-NTPDases, thereby decreasing ACh release from cholinergic nerves expressing P2Y1 receptors. [ABSTRACT FROM AUTHOR]

Highlights: [•] Micturition reflex comprises the action of somatic motor and autonomic activities. [•] Bar nucleus – besides regulating micturition – co-regulates other pelvic viscera. [•] Bar nucleus neurons are involved in stress response mechanisms. [•] Dopaminergic activity involved modulating the micturition reflex. [•] Dopaminergic dysfunction is related to hyperactivity of the micturition reflex. [Copyright &y& Elsevier]

Objective: This study aimed to determine whether a short-term repeated stimulation of tibial nerve afferents induces a prolonged modulation effect on the micturition reflex in a decorticated rat model., Material and Methods: Fifteen female Sprague-Dawley rats (250-350 g) were fully decorticated and paralyzed in the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 mL/min) at approximately ten-minute intervals were performed, and the micturition threshold volume (MTV) was recorded and used as a dependent variable. After four to five stable recordings, the tibial nerves of both sides were stimulated continuously for five minutes at 10 Hz and at an intensity of three times the threshold for α-motor axons. Six same stimulations were applied repeatedly, with an interval of five minutes between each stimulation. Mean MTV was calculated on the basis of several cystometries in each half-hour period before, during, and after the six repeated TNS., Results: During the experiment, all the animals survived in good condition with relatively stable micturition reflexes, and a significant increase in MTV was detected after TNS. The strongest effect (mean = 178%) was observed during the first 30 minutes after six repeated stimulations. This obvious threshold increase remained for at least five hours., Conclusions: A prolonged poststimulation modulatory effect on the micturition reflex was induced by short-term repeated TNS in decorticated rats. This study provides a theoretical explanation for the clinical benefit of TNS in patients with overactive bladder and suggests decorticated rats as a promising model for further investigation of the neurophysiological mechanisms underlying the bladder inhibitory response induced by TNS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: In contrast to the well-known signaling role of urothelial ATP to control bladder function, the hypothesis that uracil nucleotides (UTP and/or UDP) also exert autocrine/paracrine actions only recently gained experimental support. Urothelial cells express UDP-sensitive P2Y6 receptors, yet their role in the control of bladder activity has been mostly neglected. This study was designed to investigate the ability of PSB0474, a stable UDP analogue which exhibits selectivity for P2Y6 receptors, to modulate urodynamic responses in the anaesthetized rat in vivo. Instillation of PSB0474 into the bladder increased the voiding frequency (VF) without affecting the amplitude (A) and the duration (Δt) of bladder contractions. PSB0474-induced bladder overactivity was prevented by the selective P2Y6 antagonist, MRS2578. The increase in the VF produced by PSB0474 was also blocked by inhibitors of pannexin-1 hemichannels, 10Panx or carbenoxolone, when these drugs were applied inside the bladder lumen but not when they were administered intravenously. Reduction of hemichannels pore permeability with H1152 also prevented PSB0474-induced bladder overactivity, but the exocytosis inhibitor, Exo-1, was inactive. PSB0474 increased by 3-fold the urinary ATP content. Implication of hemichannels permeability on PSB0474-induced ATP release was demonstrated by real-time fluorescence video-microscopy measuring the uptake of propidium iodide by intact urothelial cells in the absence and in the presence of MRS2578 or carbenoxolone. Confocal microscopy studies confirmed the co-localization of pannexin-1 and P2Y6 receptors in the rat urothelium. Data indicate that activation of P2Y6 receptors causes bladder overactivity in the anaesthetized rat indirectly by releasing ATP from the urothelium via pannexin-1 hemichannels. [Copyright &y& Elsevier]

Barrington's nucleus ( BN), commonly known as the pontine micturition center, controls micturition and other visceral functions through projections to the spinal cord. In this study, we developed a rat brain slice preparation to determine the intrinsic and synaptic mechanisms regulating pre-sympathetic output ( PSO) and pre-parasympathetic output ( PPO) neurons in the BN using patch-clamp recordings. The PSO and PPO neurons were retrogradely labeled by injecting fluorescent tracers into the intermediolateral region of the spinal cord at T13-L1 and S1-S2 levels, respectively. There were significantly more PPO than PSO neurons within the BN. The basal activity and membrane potential were significantly lower in PPO than in PSO neurons, and A-type K+ currents were significantly larger in PPO than in PSO neurons. Blocking A-type K+ channels increased the excitability more in PPO than in PSO neurons. Stimulting μ-opioid receptors inhibited firing in both PPO and PSO neurons. The glutamatergic EPSC frequency was much lower, whereas the glycinergic IPSC frequency was much higher, in PPO than in PSO neurons. Although blocking GABAA receptors increased the excitability of both PSO and PPO neurons, blocking glycine receptors increased the firing activity of PPO neurons only. Furthermore, blocking ionotropic glutamate receptors decreased the excitability of PSO neurons but paradoxically increased the firing activity of PPO neurons by reducing glycinergic input. Our findings indicate that the membrane and synaptic properties of PSO and PPO neurons in the BN are distinctly different. This information improves our understanding of the neural circuitry and central mechanisms regulating the bladder and other visceral organs. [ABSTRACT FROM AUTHOR]