Micturition Reflex Research Articles

Quantification of effectiveness of bilateral and unilateral neuromodulation in the rat bladder rhythmic contraction model

BackgroundUsing the isovolumetric bladder rhythmic contraction (BRC) model in anesthetized rats, we have quantified the responsiveness to unilateral and bilateral stimulation of the L6 spinal nerve (SN) and characterized the relationship between stimulus intensity and inhibition of the bladder micturition reflex.MethodsA wire electrode was placed under either one or both of the L6 SN roots. A cannula was placed into the bladder via the urethra and the urethra was ligated. Saline infusion induced BRC.ResultsAt motor threshold (Tmot) intensity, SN stimulation of both roots (10 Hz) for 10 min reduced bladder contraction frequency from 0.63 ± 0.04 to 0.17 ± 0.09 contractions per min (26 ± 14% of baseline control; n = 10, p < 0.05). However, the same intensity of unilateral stimulation (n = 15) or sequential stimulation of both SNs (e.g. 5 min per side alternatively for a total of 10 min or 20 min) was less efficacious. The greater sensitivity to bilateral stimulation is not dependent upon precise bilateral timing of the stimulation pulses. Bilateral stimulation also produced both acute and prolonged- inhibition on bladder contractions in a stimulation intensity dependent fashion.ConclusionsUsing the bladder rhythmic contraction model, bilateral stimulation was more effective than unilateral stimulation of the SN. Clinical testing should be conducted to further compare efficacies of unilateral and bilateral stimulation. Bilateral stimulation may allow the use of lower stimulation intensities to achieve higher efficacy for neurostimulation therapies on urinary tract control.

Editorial Comment to Brain activity during bladder filling and pelvic floor muscle contractions: A study using functional magnetic resonance imaging and synchronous urodynamics

The frontal cortex is regarded as the higher center for micturition, because lesions in the frontal cortex; for example, the prefrontal cortex, medial superior/middle frontal gyri, anterior cingulate cortex, insula and supplemental motor area, produce marked lower urinary tract dysfunction in humans. Overactive bladder (urinary urgency and frequency) as a result of detrusor overactivity is a common bladder abnormality in the aforementioned brain areas. Functional neuroimaging in normal volunteers using single-photon emission computed tomography, positron-emission tomography, functional magnetic resonance imaging, and near infrared spectroscopy has been applied to observe brain activation in response to bladder fullness and urination; and the activated areas strikingly overlap the lesions described in clinical studies. Among the brain areas, anterior cingulate cortex and insula are thought to be “primary”, and the prefrontal cortex is “secondary” (presumably modulatory) in regulating micturition. The constellation of these cortical areas seem to “switch on and off” the spino–bulbo–spinal micturition reflex involving the midbrain periaqueductal grey and the pontine micturition center.1-3 Krhut et al. studied 20 healthy female volunteers who participated in bladder push and pull, and pelvic floor contraction paradigm for urodynamics-functional magnetic resonance imaging.4 The results were in agreement with the previously reported results. In addition, that study successfully highlighted the role of the pelvic floor, though already suggested by others,5-7 that bilateral primary motor area (midline medial surface), bilateral supplementary motor area (similar) and left precentral gyrus are significantly activated by pelvic floor contraction. In order to manage patients' pelvic floor, for both diagnosis and treatment, the brain is worth looking at. None declared.

Comparative Cost-Effectiveness Analysis of Sacral Anterior Root Stimulation for Rehabilitation of Bladder Dysfunction in Spinal Cord Injured Patients

Urinary disorders account for 10% of deaths in patients with complete spinal cord injury. Sacral anterior root stimulation (SARS) may be a valuable therapeutic option to restore complete and voluntary micturition (CVM), but questions on its cost-effectiveness remain. To evaluate the cost-effectiveness of SARS to restore CVM in patients with complete spinal cord injury. We conducted a nonrandomized, multicenter, parallel-group cohort study comparing SARS vs. current medical treatments with catheterization or reflex micturition. CVM was assessed at 12 months (end of follow-up) by urodynamic examination. Medical and nonmedical costs were measured in the perspective of the French national health insurance. Linear regression models were used to estimate the incremental net benefit ((Equation is included in full-text article.); λ = willingness-to-pay) adjusted for potential confounders, and P (INB >0) (i.e., probability of SARS being cost-effective vs medical treatment) for different values of λ. Twenty-five patients were included in each group in 2005 to 2009. At inclusion, mean age was 41 years; 45 (90%) patients were male, and 29 (59%) patients were paraplegic. At 12 months, 15 (60%) patients with SARS had a CVM vs. 3 (12%) patients with medical treatment (P < .001). The total mean cost was 42,803 €; and 8762 €, respectively (P < .001). After adjustment for CVM and voiding methods at inclusion, P (INB >0) was 74% at λ = 100,000 €. This probability was 94% in a sensitivity analysis excluding 6 patients presenting a CVM at inclusion. The effectiveness and cost of SARS are much higher than for medical treatment. Our results inform decision makers of the opportunity to reimburse SARS in this vulnerable population.

Novel 'split bladder' model to study micturition reflex in rats

The mechanisms governing development of diseases causing lower urinary tract disorders, such as overactive bladder and bladder pain syndrome/interstitial cystitis, remain unclear. Although several mechanisms have been proposed, currently available experimental models to investigate such mechanisms are insufficient. However, this situation could be set to change with the development of a novel rat model enabling investigation of the effects of stretch, electrical and pharmacological stimulation of the bladder in vivo and in situ.

A novel in situ urinary bladder model for studying afferent and efferent mechanisms in the micturition reflex in the rat

The search for new animal models to investigate both efferent and afferent levels of the micturition reflex, to better understand urinary dysfunctions, is of great importance. Therefore in this study we developed and characterized, by comparisons with a conventional whole bladder model, a novel in situ model. The urinary bladder was carefully prepared and separated, via a midline incision, into two halves all the way to the urethra in pentobarbitone and medetomidine anesthetized male rats. The separated bladder halves (with no direct connection) were immobilized with ligatures to the underlying tissue. The tension could thereafter be recorded at one side, while the other half was occasionally stretched in order to evoke an afferent signal. Also, injections of ATP and methacholine and electric nerve stimulation were employed. Ipsilateral stretch of 30 and 50 mN induced a force-dependent contractile response on the contralateral side. Moreover, electrical stimulation of efferent pelvic nerve fibers, and intravenous injections of methacholine and ATP, evoked dose-dependent contractions, resembling responses observed in the whole bladder model. Here, the threshold frequency at electrical stimulation of the efferent fibers was <2 Hz and the maximum response appeared at 10-20 Hz, while afferent stimulation had a threshold of 5-10 Hz with the maximum response at 40 Hz. In the current study we show that stimulation of afferents at one side of the bladder induces, via impulses from the central nervous system, contractions from the other side. This novel model enables quantitative comparisons of changes occurring within the micturition reflex arc in bladder disorders. Neurourol. Urodynam. 33:550-557, 2014. © 2013 Wiley Periodicals, Inc.

Increased TRPV4 Expression in Urinary Bladder and Lumbosacral Dorsal Root Ganglia in Mice with Chronic Overexpression of NGF in Urothelium

Transient receptor potential vanilloid (TRPV) family member 4 (TRPV4) expression has been demonstrated in urothelial cells and dorsal root ganglion (DRG) neurons, and roles in normal micturition reflexes as well as micturition dysfunction have been suggested. TRP channel expression and function is dependent upon target tissue expression of growth factors. These studies expand upon the target tissue dependence of TRPV4 expression in the urinary bladder and lumbosacral DRG using a recently characterized transgenic mouse model with chronic overexpression of nerve growth factor (NGF-OE) in the urothelium. Immunohistochemistry with image analyses, real-time quantitative polymerase chain reaction, and Western blotting were used to determine TRPV4 protein and transcript expression in the urinary bladder (urothelium + suburothelium, detrusor) and lumbosacral DRG from littermate wild-type (WT) and NGF-OE mice. Antibody specificity controls were performed in TRPV4(-/-) mice. TRPV4 transcript and protein expression was significantly (p ≤ 0.001) increased in the urothelium + suburothelium and suburothelial nerve plexus of the urinary bladder and in small- and medium-sized lumbosacral (L1, L2, L6-S1) DRG cells from NGF-OE mice compared to littermate WT mice. NGF-OE mice exhibit significant (p ≤ 0.001) increases in NGF transcript and protein in the urothelium + suburothelium and lumbosacral DRG. These studies demonstrate regulation of TRPV4 expression by NGF in lower urinary tract tissues. Ongoing studies are characterizing the functional roles of TRPV4 expression in the sensory limb (DRG, urothelium) of the micturition reflex.

Effect of methysergide on pudendal inhibition of micturition reflex in cats

The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P<0.0001) reduced bladder capacity to 27.0±7.4% of saline control capacity. Pudendal nerve stimulation (PNS) at multiples of the threshold (T) intensity for inducing anal sphincter twitching restored bladder capacity to 60.1±8.0% at 1–2T (P<0.0001) and 92.2±14.1% at 3–4T (P=0.001) of the saline control capacity. Methysergide (0.03–1mg/kg, i.v.) suppressed low intensity (1–2T) PNS inhibition but not high intensity (3–4T) inhibition, and also significantly (P<0.05) increased control bladder capacity at the dosage of 0.3–1mg/kg. During saline infusion without AA irritation, PNS significantly increased bladder capacity to 150.8±9.9% at 1–2T (P<0.01) and 180.4±16.6% at 3–4T (P<0.01) of the saline control capacity. Methysergide (0.1–1mg/kg) significantly (P<0.05) increased saline control bladder capacity and suppressed PNS inhibition at the dosage of 0.03–1mg/kg. After methysergide treatment (1mg/kg), naloxone significantly (P<0.05) reduced control bladder capacity during AA infusion but had no effect during saline infusion. Naloxone also had no influence on PNS inhibition. These results suggest that 5-HT2 receptors play a role in PNS inhibition of reflex bladder activity and interact with opioid mechanisms in micturition reflex pathway. Understanding neurotransmitter mechanisms underlying pudendal neuromodulation is important for the development of new treatments for bladder disorders.

Possible mechanism of deep brain stimulation for pedunculopontine nucleus-induced urinary incontinence: a virally mediated transsynaptic tracing study in a transgenic mouse model

To the editor: The case report titled ‘Urinary incontinence following deep brain stimulation of the pedunculopontine nucleus’ by Aviles-Olmos et al. [1] stated that a possible explanation for the detrusor overactivity that developed immediately after right pedunculopontine tegmental nucleus (PPTg) deep brain stimulation (DBS) is the proximity between the caudal PPTg and brainstem structures, which is implicated in the control of micturition. The pontine micturition center (also known as “Barrington’s nucleus”) is widely acknowledged to be involved in the maintenance of high bladder pressure and modulation of urinary tract functions [7, 12, 17]. Understanding of the neuroanatomical sympathetic circuitry and neuronal connections from the pontine micturition center to the kidney is important for studying the possible mechanism of PPTg DBS-induced urinary incontinence. We would like to further complete the discussion of Aviles-Olmos and colleagues by introducing a virally mediated transsynaptic tracing study in a transgenic mouse model. Barrington’s nucleus (BN) has been considered a pontine center related exclusively to the control of micturition and is located in the dorsolateral tegmentum of the pons [2, 9, 14]. Neurourological studies show that neurons within BN are non-noradrenergic and that the nucleus is clearly separated from the noradrenergic (dopamine-β-hydroxylase–immunoreactive) locus coeruleus and subcoeruleus [3]. To clarify the functional role of BN, we characterized projections from the kidney to BN in adult male MC4R-green fluorescent protein (GFP) transgenic mice using retrograde tracing techniques of pseudorabies virus (PRV)-614, expressing a novel monomeric red fluorescent protein (mRFP1) under control of the cytomegalovirus immediate early promoter for direct visualization under a fluorescence microscope [20–23]. We found that injections of PRV-614 into the kidney resulted in retrograde infection of neurons in BN of the pontine, and PRV-614-infecting cells were most heavily concentrated in BN (Fig. 1-A1, B1 and C1), indicating that a direct neuroanatomical pathway between the kidney and BN exists. Otherwise, fluorescence immunohistochemistry revealed that PRV-614/MC4R-GFP, PRV614/tyrosine hydroxylase (TH), PRV-614/tryptophan hydroxylase (TPH) dual-labeled neurons were detected in BN (Fig. 1), indicating that BN is melanocortinergic, catecholaminergic and serotonergic. Based on all these findings, we speculate that BN may be primarily involved in sympathetic regulation of renal functions, except the control of pelvic parasympathetic activity. Animal studies have showed that BN is critically involved in the micturition reflex [16, 18], but little is known about the neuronal mechanisms involved. A considerable amount of literature demonstrated that there is a close interaction between the kidney and the central nervous system [6, 13], and sympathetic influence in kidney functions is under H.<B. Xiang (*) :X.<H. Guan Department of Anesthesiology and Pain Medicine, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People’s Republic of China e-mail: xianghongbing0204@163.com

Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P ≤ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P ≤ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P ≤ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P ≤ 0.01) increased at all monofilament forces tested (0.1-4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P ≤ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity.

Expression and function of CCL2/CCR2 in rat micturition reflexes and somatic sensitivity with urinary bladder inflammation

Chemokines are proinflammatory mediators of the immune response, and there is growing evidence for chemokine/receptor signaling involvement in pronociception. Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder-related with at least one urinary symptom. We have explored the expression and functional roles of CCL2 (monocyte chemoattractant protein-1) and its high-affinity receptor, CCR2, in micturition reflex function and somatic sensitivity in rats with urinary bladder inflammation induced by cyclophosphamide (CYP) treatment of varying duration (4 h, 48 h, chronic). Real-time quantitative RT-PCR, ELISAs, and immunohistochemistry demonstrated significant (P ≤ 0.01) increases in CCL2 and CCR2 expression in the urothelium and in Fast Blue-labeled bladder afferent neurons in lumbosacral dorsal root ganglia with CYP-induced cystitis. Intravesical infusion of RS504393 (5 μM), a specific CCR2 antagonist, reduced voiding frequency and increased bladder capacity and void volume in rats with CYP-induced cystitis (4 h), as determined with open outlet, conscious cystometry. In addition, CCR2 blockade, at the level of the urinary bladder, reduced referred somatic sensitivity of the hindpaw and pelvic region in rats with CYP treatment, as determined with von Frey filament testing. We provide evidence of functional roles for CCL2/CCR2 signaling at the level of the urinary bladder in reducing voiding frequency and somatic sensitivity following CYP-induced cystitis (4 h). These studies suggest that chemokines/receptors may be novel targets with therapeutic potential in the context of urinary bladder inflammation.

Modulation of respiratory motor output during micturition is dependent on level of respiratory drive

The goal of this study was to examine the interaction between micturition reflexes and respiratory motor output in rats. To this end, phrenic nerve, abdominal muscle, and external urethral sphincter activity were recorded in urethane‐anesthetized, vagotomized, ventilated adult female Sprague‐Dawley rats during passive bladder filling and spontaneous bladder contractions (voiding) elicited by infusion of physiological saline into the bladder. Respiratory drive was controlled by altering ventilation rate and monitored through blood gases. Phrenic and abdominal activities were both influenced by micturition particularly during and after active bladder contraction. Specifically, at low to medium levels of respiratory drive (i.e., close to apneic threshold) the amplitude and frequency of phrenic bursts transiently decreased immediately following bladder contraction. At high levels of respiratory drive phrenic bursts were largely unaffected by bladder contraction whereas abdominal muscles were activated exhibiting tonic activity during and phasic (expiratory) activity following bladder contraction. Thus, multiple respiratory motor outputs are modulated during micturition and the degree of modulation is sensitive to the level of respiratory drive. Supported by HL63175 and NS049310.

273 INVOLVEMENT OF 5-HT2 RECEPTOR IN PUDENDAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER ACTIVITY IN CATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology (I)1 Apr 2013273 INVOLVEMENT OF 5-HT2 RECEPTOR IN PUDENDAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER ACTIVITY IN CATS Yosuke Matsuta, Zeyad Schwen, Abhijith Mally, Bing Shen, Jicheng Wang, James Roppolo, William de Groat, and Changfeng Tai Yosuke MatsutaYosuke Matsuta Pittsburgh, PA More articles by this author , Zeyad SchwenZeyad Schwen Pittsburgh, PA More articles by this author , Abhijith MallyAbhijith Mally Pittsburgh, PA More articles by this author , Bing ShenBing Shen Pittsburgh, PA More articles by this author , Jicheng WangJicheng Wang Pittsburgh, PA More articles by this author , James RoppoloJames Roppolo Pittsburgh, PA More articles by this author , William de GroatWilliam de Groat Pittsburgh, PA More articles by this author , and Changfeng TaiChangfeng Tai Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1657AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Understanding the neurotransmitter mechanisms involved in pudendal nerve inhibition of bladder activity could lead to identify new pharmacological targets for overactive bladder (OAB). Currently little is known about the effect of 5-hydroxytryptamine (5-HT)2 receptor on micturition reflex. This study used methysergide, a 5-HT2 receptor antagonist, and naloxone, an opioid receptor antagonist, to examine the involvement of these receptors in the inhibition of micturition reflex induced by pudendal nerve stimulation (PNS). METHODS Experiments were conducted in 20 cats under α-chloralose anesthesia. A tripolar cuff electrode was applied around the right pudendal nerve and connected to a stimulator. Drugs were administered via the right cephalic vein. Pharmacological studies were performed in two experimental groups (i.e. AA and saline group). In both group, cumulative doses (0.01, 0.03, 0.1, 0.3, and 1 mg/kg) of methysergide and then naloxone (1 mg/kg) were given. RESULTS AA irritated the bladder, induced bladder overactivity and significantly (p < 0.0001) reduced bladder capacity (BC) to 27.0 ± 7.4 % of saline control capacity. PNS (5 Hz, 0.2 ms) at 1-2 and 3-4 times the threshold (T) intensity for inducing an observable twitching of anal sphincter suppressed AA-induced bladder overactivity and significantly increased BC to 60.1 ± 8.0 % at 1-2T (p < 0.0001) and 92.2 ± 14.1 % at 3-4T (p = 0.001) of the saline control capacity. Methysergide (0.03-1 mg/kg, i.v.) suppressed PNS inhibition of bladder overactivity at low intensity (1-2T) but not at high intensity (3-4T). During saline infusion PNS increased BC to 150.8 ± 9.9 % at 1-2T (p < 0.01) and 180.4 ± 16.6 % at 3-4T (p < 0.01) of the saline control capacity. Methysergide significantly increased BC at the doses of 0.1-1 mg/kg (p < 0.05) and suppressed pudendal inhibition. After 1 mg/kg dose of methysergide, naloxone significantly (p < 0.05) reduced BC in AA condition, however, PNS-induced inhibition at 3-4T was still observed. On the other hand, naloxone did not change BC and PNS-induced inhibition in saline condition. CONCLUSIONS These results suggest that 5-HT2 receptor antagonist plays an inhibitory role in both nociceptive and non-nociceptive bladder activity. 5-HT2 receptor interacts with opioid receptor in micturition reflex pathway. Our study indicates methysergide (a FDA-approved drug with few side effects) could be a new treatment for OAB. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e111 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yosuke Matsuta Pittsburgh, PA More articles by this author Zeyad Schwen Pittsburgh, PA More articles by this author Abhijith Mally Pittsburgh, PA More articles by this author Bing Shen Pittsburgh, PA More articles by this author Jicheng Wang Pittsburgh, PA More articles by this author James Roppolo Pittsburgh, PA More articles by this author William de Groat Pittsburgh, PA More articles by this author Changfeng Tai Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

542 CHARACTERIZATION OF LUMBOSACRAL NEURAL ORGANIZATION OF MICTURITION REFLEX PATHWAYS WITH BLADDER DYSFUNCTION AFTER COMPLETE THORACIC SPINAL CORD TRANSECTION IN RATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology (II)1 Apr 2013542 CHARACTERIZATION OF LUMBOSACRAL NEURAL ORGANIZATION OF MICTURITION REFLEX PATHWAYS WITH BLADDER DYSFUNCTION AFTER COMPLETE THORACIC SPINAL CORD TRANSECTION IN RATS Hai-Hong Jiang, Fu-Chen Yang, Brian Balog, Kevin Li, Ching-Yi Lin, Margot Damaser, and Yu-Shang Lee Hai-Hong JiangHai-Hong Jiang Cleveland, OH More articles by this author , Fu-Chen YangFu-Chen Yang Cleveland, OH More articles by this author , Brian BalogBrian Balog Cleveland, OH More articles by this author , Kevin LiKevin Li Cleveland, OH More articles by this author , Ching-Yi LinChing-Yi Lin Cleveland, OH More articles by this author , Margot DamaserMargot Damaser Cleveland, OH More articles by this author , and Yu-Shang LeeYu-Shang Lee Cleveland, OH More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1937AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Bladder remodeling after spinal cord injury (SCI) causes related morphologic and functional changes, known as neurogenic bladder. Sacral nervous plasticity also occurs after SCI. These neuroplastic processes may relate to remodeling of the end organs of the bladder and the urethra; however the exact changes and patterns of neuroplasticity after SCI remain unknown. This study aims to identify micturition reflex network at lumbosacral and bladder dysfunction after T8 complete SCI using pseudoabies virus (PRV) transneuronal tracing technology. METHODS Eighty-five adult Sprague-Dawley female rats (225-275g) were used. All rats were divided into 3 groups: naive control, Tx-15 and Tx-45 (15 days and 45 days survival period after complete SCI procedure at the level of T8, respectively). Each group was further subdivided into 2 groups according to PRV injection to bladder body or external urethral sphincter (EUS). Three days after PRV injection to bladder or EUS, animals underwent perfusion followed by tissue harvest of bladder, urethra, and spinal cord. Thirty μm transverse sections were collected from the middle of L4 to the middle of S3 spinal segment for each sample. Animals in Tx-45 group also underwent urodynamic study 3 days before PRV injection. RESULTS Bladder remodeling occurs and becomes exacerbated 15 and 45 days after SCI according to the statistically significant changes of bladder weight. Bladder weight mirrors the bladder dysfunction. The main PRV-positive spinal segment from bladder injection of PRV after SCI moves distal with time from L6-S1 to S1-S2. The number of PRV-labeled neurons was positively correlated with bladder weight 15 days after bladder injection and 45 days after EUS injection, suggesting neuroplasticity after SCI occurs earlier in the pathway involving the bladder than in the pathway involving the urethra. CONCLUSIONS The window of time between bladder and urethra neuroplasticity after T8 complete SCI may indicate the time for full completion of micturition control pathway reorganization at the lumbosacral level. Further studies using specific synaptic stains in the spinal cord will be used to determine the synaptic plasticity and reorganization of the micturition reflex pathway after lumbosacral level SCI. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e222-e223 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hai-Hong Jiang Cleveland, OH More articles by this author Fu-Chen Yang Cleveland, OH More articles by this author Brian Balog Cleveland, OH More articles by this author Kevin Li Cleveland, OH More articles by this author Ching-Yi Lin Cleveland, OH More articles by this author Margot Damaser Cleveland, OH More articles by this author Yu-Shang Lee Cleveland, OH More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

538 THE INHIBITORY EFFECT OF TRANSFORMING GROWTH FACTOR-BETA ON THE PROLIFERATION AND DIFFERENTIATION OF SATELLITE CELLS IN HUMAN URETHRAL RHABDOSPHINCTER

sure or maximum pressure at any doses tested. When AM251 was administered one voiding cycle before VDM11 administration, the increases in intercontraction intervals and threshold pressure induced by VDM11 administration alone were not seen. In contrast, when AM630 was administered before VDM11 administration, increases in intercontraction intervals and threshold pressure were still observed, as they were after VDM11 alone. CONCLUSIONS: These results suggest that anandamide transporters play an important role in the modulation of micturition reflex. Furthermore, these findings indicate that, in urethane-anesthetized rats, inhibition of the uptake of anandamide by VDM11 can inhibit the micturition reflex at least in part via activation of the CB1 receptor, but not the CB2 receptor. Thus, anandamide transporter inhibitors could be effective for the treatment of bladder dysfunction such as overactive bladder.

119 COMBINATION OF TIBIAL NEUROMODULATION AND TRAMADOL TO INHIBIT THE MICTURITION REFLEX

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research (II)1 Apr 2013119 COMBINATION OF TIBIAL NEUROMODULATION AND TRAMADOL TO INHIBIT THE MICTURITION REFLEX Abhijith Mally, Fan Zhang, P. Daffe Ogagan, Jeffrey Larson, Bing Shen, Jicheng Wang, James Roppolo, William de Groat, and Changfeng Tai Abhijith MallyAbhijith Mally Pittsburgh, PA More articles by this author , Fan ZhangFan Zhang Pittsburgh, PA More articles by this author , P. Daffe OgaganP. Daffe Ogagan Pittsburgh, PA More articles by this author , Jeffrey LarsonJeffrey Larson Pittsburgh, PA More articles by this author , Bing ShenBing Shen Pittsburgh, PA More articles by this author , Jicheng WangJicheng Wang Pittsburgh, PA More articles by this author , James RoppoloJames Roppolo Pittsburgh, PA More articles by this author , William de GroatWilliam de Groat Pittsburgh, PA More articles by this author , and Changfeng TaiChangfeng Tai Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1498AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Tibial nerve stimulation (TNS) is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. METHODS Bladder overactivity was induced in alpha-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3?7 mg/kg iv) to examine the interaction between the two treatments. RESULTS AA irritation significantly reduced bladder capacity to 24.8 +/− 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50–60% of the saline control capacity. Tramadol administered alone in low doses (0.3–1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3–7 mg/kg) increased bladder capacity (50–60%). TNS in combination with tramadol (3–7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. CONCLUSIONS The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e48 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhijith Mally Pittsburgh, PA More articles by this author Fan Zhang Pittsburgh, PA More articles by this author P. Daffe Ogagan Pittsburgh, PA More articles by this author Jeffrey Larson Pittsburgh, PA More articles by this author Bing Shen Pittsburgh, PA More articles by this author Jicheng Wang Pittsburgh, PA More articles by this author James Roppolo Pittsburgh, PA More articles by this author William de Groat Pittsburgh, PA More articles by this author Changfeng Tai Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Neural pathways involved in sacral neuromodulation of reflex bladder activity in cats

This study examined the mechanisms underlying the effects of sacral neuromodulation on reflex bladder activity in chloralose-anesthetized cats. Bladder activity was recorded during cystometrograms (CMGs) or under isovolumetric conditions. An S1-S3 dorsal (DRT) or ventral root (VRT) was electrically stimulated at a range of frequencies (1-30 Hz) and at intensities relative to threshold (0.25-2T) for evoking anal/toe twitches. Stimulation of DRTs but not VRTs at 1T intensity and frequencies of 1-30 Hz inhibited isovolumetric rhythmic bladder contractions. A 5-Hz DRT stimulation during CMGs was optimal for increasing (P < 0.05) bladder capacity (BC), but stimulation at 15 and 30 Hz was ineffective. Stimulation of the S1 DRT was more effective (increases BC to 144% and 164% of control at 1T and 2T, respectively) than S2 DRT stimulation (increases BC to 132% and 150% of control). Bilateral transection of the hypogastric or pudendal nerves did not change the inhibitory effect induced by S1 DRT stimulation. Repeated stimulation of S1 and S2 DRTs during multiple CMGs elicited a significant (P < 0.05) increase in BC (to 155 ± 11% of control) that persisted after termination of the stimulation. These results in cats suggest that the inhibition of reflex bladder activity by sacral neuromodulation occurs primarily in the central nervous system by inhibiting the ascending or descending pathways of the spinobulbospinal micturition reflex.

Some thoughts on the effect of non-linearity on innovation in urological surgery.

Nature works in an interconnected, holistic and non–linear way: every part of a system affects another part and also, the system itself. Yet very little is written about non–linearity in medicine or research medicine in mainstream journals. One famous description as to how Nature works was written by Marcus Aurelius, the Roman Emperor and Stoic philosopher [1]. Always think of the Universe as one living organism, with a single substance, and a single soul; and observe how all things are submitted to the single perceptivity of this one whole; all are moved by its single impulse, and all play their part in the causation of every event that happens. Remark the intricacy of the skein, and the complexity of the web. This description emphasizes one fundamental scientific fact: Medicine, like Nature, consists of complex nonlinear systems operating in every part of the body. These systems are balanced and interact with each other. A pure reductionist approach, therefore, has little place in the study of such a system, as it is literally impossible to isolate just one single factor unrelated to anything else. One has to look at the whole picture. One example of this is the practice of using single urodynamic flow rate values in articles on “obstructed” micturition. The flow of urine through the urethra is non–linear in that it is inversely related to the 5th power of the radius [2] for non–laminar flow (doubling the radius increases the resistance to urine flow by a factor of 32); the urethral tube is opened (and closed) by an external striated muscle mechanism reliant on intact suspensory ligaments, so even the slightest difference in tissue tension or timing is exponentially magnified to the 5th power, ensuring that flow rate can never be adequately reproducible [3] he same criticism applies against drawing conclusions from single pressure values of “detrusor overactivity” (“DO”) obtained during urodynamic testing; the instantaneous “DO” pressure recorded ultimately reflects the instantaneous urethral radius and therefore resistance, a resultant of the interplay of the natural urethral closure mechanisms which close the urethral tube [3] and the micturition reflex which opens it out [2]. The characteristic sinuous curve characteristic of “DO” is consistent with the slight time delay taken to switch from domination of the closure reflex (raised urethral pressure) to domination of the micturition reflex (fall in urethral pressure). “DO” as applied today is reductionist, in that it takes a single reading from an exponentially determined dynamic process and draws important conclusions, for instance, in a patient with mixed incontinence, whether to operate or not. First steps in innovation – towards a hypothesis The first step is for an “innovative” scientist is to “discover” how it works, then to apply that knowledge in solving a difficult clinical problem. Popper [4] describes two mechanisms, induction and deduction. Induction, simplistically, takes an idea or observation towards a hypothesis. The hypothesis then has to be tested in a valid way, by deductive experimentation: “if “a” is so, then “b” follows. In 1986, the 1st author, PP, noted a dense collagenous tissue reaction to implanted Teflon tape. PP had previously noted that pressing a hemostat directly upwards immediately behind the pubic bone controlled urine loss on coughing (USI). Two hypotheses were formed, The cause of USI is a loose pubourethral ligament (PUL). Implantation of a tape will reinforce the damaged PUL by creating an artificial collagenous neoligament. How non–linearity (randomness) may inadvertently affect research directions PP obtained permission from the hospital IRB to perform two prototype midurethral sling operations in 1986. Both worked immediately, the patients passed urine immediately, went home the same day and were continent 10 years later. However, when a systematic study was commenced a year later, results in the 1st case series showed only a 50% cure rate. On this basis, the probability of achieving 2/2 success in the initial 1986 operations was only 25%. Conversely, there was an equivalent 25% probability of 2/2 failures. If this had occurred, there would be no midurethral sling today. What this means is that the Innovative Scientist cannot assume the concept is wrong (or correct) on the basis of 2 cases. One needs some luck and a lot of persistence. Marion Sims, the fistula pioneer, had many attempts at fistula repair before he finally succeeded with silver wire. Variation Nonlinearity describes variation and Chaos Theory describes the feedback control mechanisms which drive non–linear systems. The challenge is to create a management system which makes allowance for variation and to avoid the rare “Black Swan” events inherent in Chaotically controlled systems. The Integral Theory System (ITS) is to our knowledge, the only management system to date which recognizes variation and nonlinear dynamics in its diagnostic and surgical systems.

Sudden syncopal attack after postobstructed diuresis under combined spinal epidural anesthesia

Micturition is clinically well-known as a factor that may cause hypotension, bradycardia, and if severe, syncope. However, the mechanism of syncope during micturition is not completely understood. Vasodilatation, bradycardia, and reflex car diovascular depression are all called by various terms including vasovagal syncope, Bazold-Jarisch reflex, and neurocardiogenic syncope [1]. The neurally-mediated syncope includes true and situational syncope that can take place in various situations such as blood loss, cough, sneeze, micturition and lifting up a heavy load. A case of a 71 year-old man under combined spinal epidural anesthesia for total knee replacement, in which the operation were performed without knowing that a Foley catheter installed had been obstructed, and severe bradycardia, hypotension, and loss of consciousness occurred immediately after moving the pa tient to the recovery room following micturition were described. The patient had a history of syncope. Preoperative cardiac test was normal. At the operation room, heart rate and blood pressure were 70 /min and 170/90 mmHg. Beginning with the sufficient administration of fluid, the regional anesthesia was performed and the sensory block was verified up to the T4 der matome. A forced air warmer was used to maintain the body temperature. At the end of operation, 8 ml of 0.15% levobupivacaine was injected through the epidural catheter, and then a mixture of anesthetics was continuously injected. Intraoperative systolic blood pressure were ranged from 110 to 190 mmHg, diastolic pressure 65 to 105 mmHg, heart rate 52 to 70 /min, and estimated blood loss was approximately 500 ml. Although the total amount of fluid was approximately 1,000 ml, no urine out put was observed. Just before leaving the operation room, it was found that the tip of the Foley catheter was obstructed. When the catheter was opened, about 700 ml of urine was discharged. At that time, the vital signs were normal and consciousness clear. Finding that the sensory block level had come down to the T12 dermatome, the patient was moved to the recovery room. Immediately after arriving at the recovery room, the heart rate was drastically reduced from 70 /min to 30 /min or below, the blood pressure was 50/30 mmHg, and consciousness was lost. Promptly, 0.5 mg of atropine sulfate and 10 mg of ephedrine were administered, and the patient-controlled epidural anal gesia (PCEA) was stopped. Following the treatment, the heart rate recovered to 60 /min and the blood pressure to 110/80 mmHg, and subsequently, the consciousness of the patient was recovered. While the patient remained in the recovery room, no abnormal findings were observed. Micturition syncope was con firmed that head-tilt test done after the operation was positive. The main causes of consciousness loss when awakening from anesthesia include metabolic anomalies such as hypoglycemia, hyponatremia, hypoxia and severe cardiovascular collapse. However, based on the fact that the patient had no findings of cardiac abnormalities, the patient in this case might have experienced reflex micturition syncope. Micturition syncope is one type of situational syncope that occurs due to neural mediation, and usually occurs in healthy men after alcohol hyperingestion [2]. Sumiyoshi et al. [2] mentioned sleeping under warm blankets and administration of a vasodilator can be factors that cause a reduction in the peripheral arterial blood resistance in the lower extremities and reported that the Valsalva maneuver is a factor

Polysynaptic connections between Barrington's nucleus and sacral preganglionic neurons

The pontine micturition center, or Barrington's nucleus, is an essential component in the micturition reflex. The purpose of the present study is to examine the connections between Barrington's nucleus and sacral preganglionic neurons with an electrophysiological method using an intracellular recording technique. When the bladder pressure was near 0mmH2O, electrical stimulation of Barrington's nucleus either evoked no postsynaptic potential or evoked very small excitatory postsynaptic potentials (EPSPs) with ambiguous onset, in sacral preganglionic neurons. However, when the bladder showed micturition contraction, electrical stimulation of the nucleus evoked clear EPSPs in sacral preganglionic neurons. Latencies of EPSPs ranged from 21.9 to 47.5ms. The onset of the EPSPs was not fixed in any of the preganglionic neurons, indicating that they were evoked polysynaptically. The results thus demonstrated that the descending pathway from Barrington's nucleus to the sacral preganglionic neurons is polysynaptic. The results also showed that the descending pathway is strongly facilitated during the voiding phase, whereas this facilitatory effect is very weak when the bladder pressure is low. The study supports the idea that continuous firings of Barrington's nucleus are needed to activate the sacral preganglionic neurons that innervate the bladder muscle.

Urinary incontinence – a challenge to the physiologist Joint symposium for the EU/FP7 networks INComb and TRUST in collaboration with the Swedish Enuresis Academy (SEA), Stockholm 2011

Urinary incontinence – a challenge to the physiologist Joint symposium for the EU/FP7 networks <scp>INC</scp>omb and <scp>TRUST</scp> in collaboration with the <scp>S</scp>wedish <scp>E</scp>nuresis <scp>A</scp>cademy (<scp>SEA</scp>), <scp>S</scp>tockholm 2011