Inhibition Of Bladder Contractions Research Articles

MP52-10 CHRONIC, NON-INVASIVE NERVE STIMULATION THERAPY TO TREAT INCONTINENCE IN PEOPLE WITH NEUROGENIC BLADDER

You have accessJournal of UrologyCME1 Apr 2023MP52-10 CHRONIC, NON-INVASIVE NERVE STIMULATION THERAPY TO TREAT INCONTINENCE IN PEOPLE WITH NEUROGENIC BLADDER Seth Meade, Dennis Bourbeau, Steven Brose, Kenneth Gustafson, Cesar Colasante, and Kevin Suarez Seth MeadeSeth Meade More articles by this author , Dennis BourbeauDennis Bourbeau More articles by this author , Steven BroseSteven Brose More articles by this author , Kenneth GustafsonKenneth Gustafson More articles by this author , Cesar ColasanteCesar Colasante More articles by this author , and Kevin SuarezKevin Suarez More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003300.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Reduction of urinary urgency and incontinence is a top priority for individuals with neurogenic bladder (NB). Multiple clinical studies show non-invasive genital nerve stimulation (GNS) can modulate sympathetic reflexes to inhibit bladder contractions acutely and is well-tolerated. To translate GNS as an effective adjunct therapy for managing neurogenic bladder, further evidence of chronic efficacy and feasibility is needed. METHODS: In this “before-and-after” prospective cohort study, participants acted as their own controls. 9 individuals with NB were enrolled (8/9 (88.9%) male) and confirmed to: 1) have NB by urodynamics examination and 2) have bladder contractions inhibited by GNS. 5 participants (100% male) who tolerated GNS without additional medications and were adherent to voiding diaries tested the efficacy of at-home, self-administered GNS using a commercial TENS unit. Participants completed voiding diaries, each detailing at least 1 continuous week of tracked voiding, leak, and urgency events. Diaries were completed once at study initiation during a control period without GNS or medications, and then for 3 separate periods during prolonged use of GNS to manage incontinence (baseline, 6 months, 1 year). Participants also completed a bladder-related quality of life questionnaire (Qualiveen) at their initial evaluation, as well as 6 and 12 months later. RESULTS: Preliminary findings show that GNS increased bladder capacity for all 9 individuals tested by an average of 58%, and 3/5 individuals tested chronically maintained an increased bladder capacity after 6 months of GNS. 4/5 individuals reported increased bladder-related QOL by total Qualiveen after 6 months of at-home GNS. Of 2 individuals who experienced leakage with chronic voiding data one reduced their leaks/day by 90% at 6 months of use and the other by 30% at 1 year of GNS. Of 2 individuals with the primary goal of reducing bladder urgency, neither was able to reduce their urgency events/day but were able to reduce their voiding frequency by 65% and 15% after more than 1 month of use. The primary reason individuals reported for dropping from the study was difficulty placing the electrodes and keeping them in place. CONCLUSIONS: GNS can provide a durable reduction in leakage events for individuals with incontinence due to neurogenic bladder up to 6 months. Multiple subjects reported issues with electrode placement and adhesion as well as associated wires from the TENS unit leading to less-than-ideal GNS for some. Source of Funding: -RX002512 Department of Veterans Affairs -642810 Craig H. Neilsen Foundation (CHNF) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e706 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Seth Meade More articles by this author Dennis Bourbeau More articles by this author Steven Brose More articles by this author Kenneth Gustafson More articles by this author Cesar Colasante More articles by this author Kevin Suarez More articles by this author Expand All Advertisement PDF downloadLoading ...

Reviving Cav1.2 as an attractive drug target to treat bladder dysfunction.

Inhibition of bladder contraction with antimuscarinics is a common approach to treat bladder hyperactivity, and the L-type voltage-gated calcium channel α1C (Cav1.2) is crucial for bladder contractility. Therefore, strategies aimed at inhibiting Cav1.2 appear warranted. However, multiple clinical trials that attempted to treat bladder overactivity with calcium channel blockers (CCBs) have been unsuccessful, creating an unsolved mystery. In contrast, cardiologists and epidemiologists have reported strong associations between CCB use and bladder hyperactivity, opposing expectations of urologists. Recent findings from our lab offer a potential explanation. We have demonstrated that ketamine which can cause cystitis, functions, like nifedipine, as a Cav1.2 antagonist. We also show that a Cav1.2 agonist which potentiates muscle contraction, rather than antagonizing it, can increase the volume of voids and reduce voiding frequency. This perspective will discuss in detail the unsuccessful urological trials of CCBs and the promise of Cav1.2 agonists as potential novel therapies for bladder dysfunctions.

The frequency spectrum of bladder non-voiding activity as a trigger-event for conditional stimulation: Closed-loop inhibition of bladder contractions in rats.

To test the hypothesis that the frequency of bladder non-voiding contractions (NVCs) can be used as a trigger event for closed-loop conditional inhibition of detrusor contractions via tibial nerve (TN) or dorsal penile nerve (DPN) stimulation. In urethane anaesthetized male Wistar rats, the bladder was filled continuously with saline to evoke contractions. To test the plausibility of conditional inhibition via the TN, electrical stimulation was switched on manually when the pressure increased above a threshold of 10 cmH2 0 above the baseline. For testing conditional stimulation via the DPN, the pressure signal was continuously stored and a baseline threshold, the area under the curve (AUC) of the amplitude spectrum in the 0.2-20 Hz range of a 5 s window at the beginning of filling was calculated. When the AUC of subsequent pressure windows superseded the baseline threshold, the DPN was automatically stimulated. TN stimulation failed to inhibit evoked voiding contractions. The NVC frequency spectrum based DPN stimulation successfully inhibited 70% of the evoked contractions and resulted in a 45% increase in bladder capacity (BC). While, conditional TN stimulation failed to suppress bladder contractions, DPN stimulation, automatically triggered by an increased frequency of bladder non-voiding activity, resulted in bladder inhibition, and a consequential increase in BC. This study demonstrates the plausibility of using the frequency of NVCs as a trigger event for conditional inhibition of detrusor contractions.

Comparison of Bladder Inhibitory Effects of Patterned Spinal Nerve Stimulation With Conventional Neuromodulation in the Rat

The present study compared the effectiveness of patterned frequency of spinal nerve stimulation (SNS) with continuous, fixed-frequency nerve stimulation in an animal model of the bladder reflex contraction (BRC). In anesthetized female rats, wire electrodes were placed under each of the L6 spinal nerve to produce bilateral SNS. A cannula was placed into the bladder via the urethra, and the urethra was ligated to ensure an isovolumetric bladder. Using motor threshold intensity, continuous stimulation at fixed frequencies of 4 Hz (n = 5) and 10 Hz (n = 7) decreased the frequency of BRC of 71 ± 24% (mean, SEM) and 85 ± 18% of controls, respectively (vs. no stimulation, n = 10, p < 0.05, two-way analysis of variance [ANOVA]). Fixed-frequency stimulation at 0.01, 0.1, 1, 40, and 100 Hz, did not demonstrate a trend change on BRC. When stimulation frequency is delivered with a 4-6 pulse/burst pattern every 1-100 sec, neuromodulation has demonstrated a trend toward effectiveness, with a four-pulse 40 Hz burst stimulation per second showing the most difference, reducing the BRC frequency of 74 ± 8% of control (n = 8, p < 0.05, two-way ANOVA). However, it is not more effective than continuous neuromodulation at a fixed frequency of 4 Hz or 10 Hz at BRC inhibition. Burst stimulations may inhibit bladder contractions; however, they are not more effective than continuous neuromodulation. Without further knowledge regarding mechanisms and potential benefit of burst stimulation on bladder control in patients with neuropathological conditions, applications should utilize continuous fixed 10 Hz stimulation for maximal clinical outcomes.

Modulation of the rat micturition reflex with transcutaneous ultrasound.

Low intensity focused ultrasound has recently been identified as a novel method of stimulating targeted neurons. We hypothesized that ultrasound stimulation of the posterior tibial nerve would inhibit bladder contractions in an established rat model of rhythmic bladder contractions. Cyclical detrusor contractions were initiated by placing a transurethral catheter in female rats and infusing saline into the bladder. Transcutaneous ultrasound pulses were then delivered to the lower extremity of a rat (overlying the posterior tibial nerve) using a single element spherically focused 250 kHz transducer. Sixty-three cycles were repeated at 2 kHz for 300 ms at peak negative pressure of 900 kPa pulsed at 0.5 Hz. We report successful suppression of bladder contractions using ultrasound stimulation in 10 animals. The average latency between the initiation of ultrasound and suppression of bladder contractions was 3 min 23 s (±51 s), the average time of contraction suppression was 13 min and 50 s (±2 min 25 s) and the average time from the end of ultrasound to return of contractions was 9 min 37 s (±2 min and 30 s). In this work, we demonstrate the ability of targeted transcutaneous ultrasound to inhibit rhythmic bladder contractions in anesthetized rats. Due to its non-invasive nature and ease of application, we believe ultrasound mediated suppression of the micturition reflex is potentially an ideal outpatient treatment of overactive bladder and dysfunctional elimination.

Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats.

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective β-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a β-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.

Gentle Mechanical Skin Stimulation Inhibits Micturition Contractions via the Spinal Opioidergic System and by Decreasing Both Ascending and Descending Transmissions of the Micturition Reflex in the Spinal Cord.

Recently, we found that gentle mechanical skin stimulation inhibits the micturition reflex in anesthetized rats. However, the central mechanisms underlying this inhibition have not been determined. This study aimed to clarify the central neural mechanisms underlying this inhibitory effect. In urethane-anesthetized rats, cutaneous stimuli were applied for 1 min to the skin of the perineum using an elastic polymer roller with a smooth, soft surface. Inhibition of rhythmic micturition contractions by perineal stimulation was abolished by naloxone, an antagonist of opioidergic receptors, administered into the intrathecal space of the lumbosacral spinal cord at doses of 2–20 μg but was not affected by the same doses of naloxone administered into the subarachnoid space of the cisterna magna. Next, we examined whether perineal rolling stimulation inhibited the descending and ascending limbs of the micturition reflex. Perineal rolling stimulation inhibited bladder contractions induced by electrical stimulation of the pontine micturition center (PMC) or the descending tract of the micturition reflex pathway. It also inhibited the bladder distension-induced increase in the blood flow of the dorsal cord at L5–S1, reflecting the neural activity of this area, as well as pelvic afferent-evoked field potentials in the dorsal commissure at the lumbosacral level; these areas contain long ascending neurons to the PMC. Neuronal activities in this center were also inhibited by the rolling stimulation. These results suggest that the perineal rolling stimulation activates the spinal opioidergic system and inhibits both ascending and descending transmissions of the micturition reflex pathway in the spinal cord. These inhibitions would lead to the shutting down of positive feedback between the bladder and the PMC, resulting in inhibition of the micturition reflex. Based on the central neural mechanisms we show here, gentle perineal stimulation may be applicable to several different types of overactive bladder.

A spinal GABAergic mechanism is necessary for bladder inhibition by pudendal afferent stimulation.

Electrical stimulation of pudendal afferents can inhibit bladder contractions and increase bladder capacity. Recent results suggest that stimulation-evoked bladder inhibition is mediated by a mechanism other than activation of sympathetic bladder efferents in the hypogastric nerve, generating α-adrenergic receptor-mediated inhibition at the vesical ganglia and/or β-adrenergic receptor-mediated direct inhibition of the detrusor muscle. We investigated several inhibitory neurotransmitters that may instead be necessary for stimulation-evoked inhibition and found that intravenous picrotoxin, a noncompetitive GABAA antagonist, significantly and reversibly blocked pudendal afferent stimulation-evoked inhibition of bladder contractions in a dose-dependent manner. Similarly, intravenous picrotoxin also blocked pudendal afferent stimulation-evoked inhibition of nociceptive bladder contractions evoked by acetic acid infusion. Furthermore, intrathecal administration of picrotoxin at the lumbosacral spinal cord also blocked bladder inhibition by pudendal afferent stimulation. On the other hand, glycinergic, adrenergic, or opioidergic mechanisms were not necessary for bladder inhibition evoked by pudendal afferent stimulation. These results identify a lumbosacral spinal GABAergic mechanism of bladder inhibition evoked by pudendal afferent stimulation.

Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats.

The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P < 0.01) reduced the amplitude of the reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions.

Differentiation of Bilateral Neuromodulation for Bladder Control Using a Preclinical Model

Therapy,applies electrical stimulation unilaterally to the sacral spinal nerve(SN, S3) as an established clinical treatment modality forpatients with overactive bladder [1]. Scheepens and colleagues [2]reported that bilateral stimulation was superior to unilateral sacralneuromodulation in only 2 out of 25 patients. Retrospective stud-ies, however, have also suggested that patients receiving bilateralstimulation are more likely to show a significant symptomaticimprovement [3–5]. Preclinical testing is consistent with thisclinical finding. Bilateral stimulation results in a stronger bladderinhibition than unilateral stimulation when tested in cats [6,7] andpigs [8].In the present study we attempt to define and characterizeresponses to several forms of bilateral SN neuromodulation usingend-points related to bladder control. We characterize the effec-tiveness of three stimulation modalities: 1) bilateral stimulationwith phase-matched individual pulses, 2) bilateral stimulationwith phase-mismatched pulses, and 3) unilateral stimulation of asingle SN root sequentially with stimulation of the alternate side.For all testing stimulation was applied at a fixed frequency of10 Hz which has been shown to be optimal for inhibition of blad-der contractions in the rat using both low and high intensity stimu-lation [9].

The role of pelvic and perineal striated muscles in urethral function during micturition in female rabbits

To evaluate the role of pelvic and perineal striated muscles on urethral function during micturition. Pubococcygeus, or both bulbospongiosus and ischiocavernosus muscles were electrically stimulated during the voiding phase of micturition, and bladder and urethral pressure were simultaneously recorded in urethane anesthetized female rabbits. Bladder and urethral function were assessed measuring urodynamic and urethral pressure variables obtained before and during the stimulation of muscles. Two-tail paired t-tests were carried out in order to determine significant differences (P < 0.05) between groups. Electric stimulation of the pubococcygeus during voiding decreased voiding efficiency and voided volume, whereas residual volume, the duration of voiding, the interval between bladder contraction and urethral resistance increased. Simultaneously, there was an increase in maximum urethral pressure, as well as an increase in the pressure to return to baseline and in the pressure required to close the urethra. Electrical stimulation of bulbospongiosus and ischiocavernosus muscles increased voiding efficiency, voiding duration, and the maximal pressure in bladder. Meanwhile, the maximal urethral pressure, the time related to the rise of urethral pressure, and the urethral pressure required to close the urethra decreased. The stimulation of pelvic and perineal muscles have opposing roles in urethral function during micturition. Pubococcygeus muscles facilitate urethral closure, while they inhibit bladder contraction. In contrast, bulbospongiosus and ischiocavernosus muscles prevent urethral contraction while they promote bladder contraction.

T‐ and L‐Type Voltage‐Gated Calcium Channels: Their Role in Diabetic Bladder Dysfunction

We investigated the mechanisms of diabetic bladder dysfunction (BD) through analysis of the roles of L- and T-type voltage-gated calcium channels (VGCCs), with the ultimate goal of identifying potential drug targets for diabetic BD. Bladder function of db/db (type 2 diabetes) and wild type (Wt) mice was evaluated by behavioral tests and in vivo cystometry. Contractile responses of bladder strips to carbachol were measured with or without pre-treatment with nifedipine (a L-type VGCC blocker) or mibefradil (a T-type VGCC blocker). Furthermore, the effects of mibefradil and nifedipine on the proliferation of human bladder smooth muscle cells (BSMCs) were studied. db/db mice had significantly increased voiding frequency, bladder weight, bladder compliance and capacity, and heightened contractile response to carbachol, compared to Wt mice. Nifedipine, but not mibefradil, dramatically suppressed bladder tissue contraction in Wt mice. Whereas nifedipine nearly completely inhibited bladder contraction in db/db mice, mibefradil "normalized" the heightened bladder contractility of db/db mice to the level of Wt mice. In culture, mibefradil, but not nifedipine, inhibited the proliferation of human BSMCs. Our results indicate that while L-type VGCCs play a major role in the contraction of both diabetic and non-diabetic bladders, T-type VGCCs are involved in the contraction of diabetic bladders and mediate BSMC proliferation. This study provides support for further investigations on the effect of blockade of T-type VGCC or combined blockade of both types of VGCCs in the treatment of diabetic BD.

Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury.

During childbirth, a combinatorial injury occurs and can result in stress urinary incontinence (SUI). Simulated childbirth injury, consisting of vaginal distension (VD) and pudendal nerve crush (PNC), results in slowed recovery of continence, as well as decreased expression of brain-derived neurotrophic factor (BDNF), a regenerative cytokine. Electrical stimulation has been shown to upregulate BDNF in motor neurons and facilitate axon regrowth through the increase of β(II)-tubulin expression after injury. In this study, female rats underwent selective pudendal nerve motor branch (PNMB) stimulation after simulated childbirth injury or sham injury to determine whether such stimulation affects bladder and anal function after injury and whether the stimulation increases BDNF expression in Onuf's nucleus after injury. Rats received 4 h of VD followed by bilateral PNC and 1 h of subthreshold electrical stimulation of the left PNMB and sham stimulation of the right PNMB. Rats underwent filling cystometry and anal pressure recording before, during, and after the stimulation. Bladder and anal contractile function were partially disrupted after injury. PNMB stimulation temporarily inhibited bladder contraction after injury. Two days and 1 wk after injury, BDNF expression in Onuf's nucleus of the stimulated side was significantly increased compared with the sham-stimulated side, whereas β(II)-tubulin expression in Onuf's nucleus of the stimulated side was significantly increased only 1 wk after injury. Acute electrical stimulation of the pudendal nerve proximal to the crush site upregulates BDNF and β(II)-tubulin in Onuf's nucleus after simulated childbirth injury, which could be a potential preventive option for SUI after childbirth injury.

Comparison of neural targets for neuromodulation of bladder micturition reflex in the rat

Spinal nerve (SN) stimulation inhibits the bladder rhythmic contraction (BRC) in anesthetized rats. This preparation was used to study the effects of electrical stimulation of the tibial nerve (TN) and the dorsal nerve of the clitoris (DNC) on BRC. Stimulation of the TN and DNC for 10 min produced a frequency- and intensity-dependent attenuation of the frequency of bladder contractions. As observed with the SN, 10-Hz stimulation of either TN or DNC produced the greatest degree of inhibition, with lower or higher frequencies being either less efficacious or inactive. In contrast to the prolonged inhibition produced by SN stimulation, both TN and DNC stimulation produced "short" lasting inhibition of bladder contractions and the maximal inhibition occurred during stimulation. TN stimulation was effective over only a narrow range of current intensities [3-4 × motor threshold current for inducing a toe twitch (T(mot))] and only at a frequency of 10 Hz. Stimulation of TN at 10 Hz, 3 × T(mot) inhibited BRC to 23% of control. Ten-hertz DNC stimulation at 2 × T(EAS), the threshold current for evoking a reflex anal sphincter contraction, decreased the frequency of contractions to 4% of control. Although compared with the respective threshold current the BRC response was more sensitive to DNC compared with TN stimulation, the absolute current required to reduce BRC using DNC stimulation appeared to be higher. Comparing the effects of TN and DNC stimulation to our previous results with SN stimulation, SN stimulation produces the largest duration and efficacy of bladder inhibition.

253 INVOLVEMENT OF METABOTROPIC GLUTAMATE RECEPTOR MGLU5 IN PUDENDAL INHIBITION OF BLADDER OVERACTIVITY IN CATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2012253 INVOLVEMENT OF METABOTROPIC GLUTAMATE RECEPTOR MGLU5 IN PUDENDAL INHIBITION OF BLADDER OVERACTIVITY IN CATS Jeffrey Larson, P. Dafe Ogagan, Jicheng Wang, Bing Shen, James Roppolo, Changfeng Tai, and William C. de Groat Jeffrey LarsonJeffrey Larson Pittsburgh, PA More articles by this author , P. Dafe OgaganP. Dafe Ogagan Pittsburgh, PA More articles by this author , Jicheng WangJicheng Wang Pittsburgh, PA More articles by this author , Bing ShenBing Shen Pittsburgh, PA More articles by this author , James RoppoloJames Roppolo Pittsburgh, PA More articles by this author , Changfeng TaiChangfeng Tai Pittsburgh, PA More articles by this author , and William C. de GroatWilliam C. de Groat Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.310AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Neuromodulation is a useful treatment modality in patients with refractory lower urinary tract symptoms, but the mechanisms of action are poorly understood. Metabotropic glutamate receptors are implicated in neuropathic pain syndromes but their involvement in micturition is poorly understood. We hypothesized that pudendal inhibition of bladder overactivity could be due to activation of the mGlu5 receptor. We used a selective mGluR5 antagonist (MTEP) to assess this receptor's function during neuromodulation. METHODS MTEP was administered to 11 cats in increasing cumulative doses. Saline (n=5) or 0.25% acetic acid (n=6) were utilized to irritate the bladder and induce overactivity. Bladder capacity and the degree of inhibition of bladder activity induced by pudendal nerve stimulation were assessed by cystometrogram. RESULTS In the absence of pudendal nerve stimulation, MTEP significantly increased saline bladder capacity. Infusion of acetic acid (AA) significantly reduced bladder capacity compared to saline. During saline CMGs, pudendal nerve stimulation significantly inhibited bladder contraction and increased bladder capacity by 196 ±37.4%; a smaller increase in bladder capacity was observed with AA infusion (98.4 ± 55.2%). Administration of MTEP doses of ≥ 1mg/kg significantly blocked the pudendal nerve inhibition of bladder contractions during AA infusion. At all doses tested during saline infusion, MTEP significantly increased baseline bladder capacity without neuromodulation. CONCLUSIONS MTEP can suppress reflex micturition as well as pudendal nerve stimulation induced inhibition of bladder activity. These results indicate that glutamic acid is an excitatory transmitter in the micturition pathway essential to the pudendal nerve stimulation evoked inhibitory mechanism. The mGlu5 receptor could serve as a novel and important potential new target for the treatment of OAB. Potential mGluR5 locations include spinal cord inhibitory interneurons, spinal tract neurons, or upper tract CNS. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e102-e103 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jeffrey Larson Pittsburgh, PA More articles by this author P. Dafe Ogagan Pittsburgh, PA More articles by this author Jicheng Wang Pittsburgh, PA More articles by this author Bing Shen Pittsburgh, PA More articles by this author James Roppolo Pittsburgh, PA More articles by this author Changfeng Tai Pittsburgh, PA More articles by this author William C. de Groat Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

497 DIFFERENTIAL ROLE OF OPIOID RECEPTORS IN TIBIAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER REFLEXES IN CATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology II1 Apr 2012497 DIFFERENTIAL ROLE OF OPIOID RECEPTORS IN TIBIAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER REFLEXES IN CATS Abhijith Mally, Jeffrey Larson, P. Dafe Ogagan, Changfeng Tai, Bing Shen, Jicheng Wang, James Roppolo, and William C. de Groat Abhijith MallyAbhijith Mally Pittsburgh, PA More articles by this author , Jeffrey LarsonJeffrey Larson Pittsburgh, PA More articles by this author , P. Dafe OgaganP. Dafe Ogagan Pittsburgh, PA More articles by this author , Changfeng TaiChangfeng Tai 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 , and William C. de GroatWilliam C. de Groat Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.567AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Electrical stimulation of somatic afferent pathways in the tibial nerve can inhibit bladder activity and therefore aid in the management of overactive bladder symptoms. Opioid peptides have a well known role in controlling pain mechanisms and are involved in somatic afferent inhibition of non-nociceptive bladder reflexes. We hypothesized that inhibition of irritation-induced bladder overactivity by tibial nerve stimulation could be due to activation of opioid receptors. We used naloxone to block the opioid receptors and assess the receptor function during tibial neuromodulation. METHODS Naloxone was administered to 20 cats in increasing cumulative doses. Saline (n=10) or .25% acetic acid (n=10) were utilized to irritate the bladder and induce overactivity. Bladder capacity and the degree of inhibition of bladder activity induced by tibial nerve stimulation were assessed by cystometrogram. RESULTS Infusion of acetic acid (AA) significantly reduced bladder capacity compared to saline. During CMG, tibial nerve stimulation (TNS) significantly inhibited bladder contraction and increased bladder capacity by 41.5±9.9% and 46.1±7.9% of the saline control capacity. Naloxone completely eliminated TNS inhibition of bladder overactivity. Naloxone did not change bladder capacity during AA irritation. However, during saline infusion, naloxone significantly reduced bladder capacity to 66.5±8.1% of the control capacity. During saline infusion TNS induced an acute increase in bladder capacity and an increase that persisted following stimulation. Naloxone administered during the post-stimulation inhibition still decreased bladder capacity. CONCLUSIONS These results indicate that opioid receptors have different roles in modulation of bladder reflexes induced by nociceptive and non-nociceptive stimuli and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e204 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhijith Mally Pittsburgh, PA More articles by this author Jeffrey Larson Pittsburgh, PA More articles by this author P. Dafe Ogagan Pittsburgh, PA More articles by this author Changfeng Tai 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 C. de Groat Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effects of stimulation site and stimulation parameters on bladder inhibition by electrical nerve stimulation

What's known on the subject? and What does the study add? Electrical stimulation of the dorsal nerve of the penis, the compound pudendal nerve and the S1 sacral nerve have been used clinically to treat the symptoms of overactive bladder, but the relative efficacy of the three locations was unclear and the optimal stimulation parameters across locations had not been determined. In the present paper we quantified the effects of acute electrical stimulation location, frequency and amplitude on isovolumetric reflex bladder contractions and maximum cystometric capacity in anaesthetized male cats. Our results could influence the selection of anatomical targets for clinical neuromodulation and how neuromodulation devices are programmed. To quantify the effects of acute electrical stimulation frequency and amplitude at the dorsal nerve of the penis (DNP), pudendal nerve (PN) and S1 sacral nerve (S1) on isovolumetric reflex bladder contractions and maximum cystometric capacity in anaesthetized male cats. Experiments were conducted in 14 adult male cats anaesthetized with α-chloralose. The effects of stimulation on the pressure - time integral of reflex bladder contractions were evaluated using a randomized block design with the following factors randomized: stimulation intensity (0.8, 1, or 2 × the threshold for evoking a reflex electromyogram response in the external anal sphincter [T]), frequency (2 Hz, 5 Hz, 7.5 Hz, 10 Hz, 15 Hz, 20 Hz, or 33 Hz) and location (PN, S1 or DNP). The effects of stimulation (with parameters that produced maximum inhibition of isovolumetric bladder contractions) on cystometric capacity were evaluated using a randomized block design, with the order of stimulation location randomized and control trials interleaved with stimulation trials. Inhibition of isovolumetric bladder contractions was significantly dependent on stimulation location, frequency, amplitude and the interactions between any two of these variables. Stimulation of the DNP, at 5 Hz, 7.5 Hz or 10 Hz, and at 2T caused greater reductions in normalized bladder contraction area than any other location, frequency or amplitude tested. Stimulation of the PN or S1 at 7.5 Hz or 10 Hz and 2T, or of the DNP at 5 Hz, 7.5 Hz or 10 Hz and 0.8T, 1T or 2T generated maximum inhibition of isovolumetric bladder contractions. Cystometric capacity was significantly larger with stimulation (10 Hz, 1T-2T) than control. There was no significant difference in cystometric capacity based upon stimulation location. There was no significant difference in the maximum degree to which the respective optimum parameters inhibited bladder contractions or increased cystometric capacity by location. The range of amplitudes and frequencies that caused maximum inhibition was larger for DNP stimulation than for PN or S1 stimulation. These findings have implications on the selection of anatomical target and device programming for clinical neuromodulation for treatment of the symptoms of overactive bladder.

Acute effect of electrical stimulation of the dorsal genital nerve on rectal capacity in patients with spinal cord injury

Constipation and fecal incontinence are considerable problems for most individuals with spinal cord injury (SCI). Neurogenic bowel symptoms are caused by several factors including abnormal rectal wall properties. Stimulation of the dorsal genital nerve (DGN) can inhibit bladder contractions and because of common innervation inhibitory effects are anticipated in the rectum too. Therefore, DNG could have a future role in the treatment of neurogenic fecal incontinence. To study the effect of acute DGN stimulation on the rectal cross sectional area (CSA) in SCI patients. Seven patients with complete supraconal SCI (median age 50 years) were included. Stimulation was applied via plaster-electrodes using an amplitude of twice the genito-anal reflex threshold (pulse width: 200 μs; pulse rate: 20 Hz). A pressure controlled phasic (10, 20 and 30 cmH(2)O) rectal distension protocol was repeated four times with subjects randomized to stimulation during 1st and 3rd distension series or 2nd and 4th distension series. The rectal CSA and pressure were measured using impedance planimetry and manometry. All patients completed the investigation. Median stimulation amplitude was 51 mA (range 30-64). CSA was smaller during stimulation and differences reached statistical significance at distension pressures of 20 cmH(2)O (average decrease 9%; P = 0.02) and 30 cmH(2)O (average decrease 4%; P = 0.03) above resting rectal pressure. Accordingly, rectal pressure-CSA relation was significantly reduced during stimulation at 20 (P=0.03) and 30 cmH(2)O distension (P=0.02). DGN Stimulation in patients with supraconal SCI results in an acute decrease of rectal CSA and the rectal pressure-CSA relation.

67 Dental caries prevalence of diabetes mellitus type 2 and non diabetes patients in Dental Clinic of Hospital Universiti Sains Malaysia

67 Dental caries prevalence of diabetes mellitus type 2 and non diabetes patients in Dental Clinic of Hospital Universiti Sains Malaysia

Achieving urinary continence in children

Achievement of urinary continence is an important developmental step that most children attain with the assistance of their parents and caregivers. Debate continues as to the best time to toilet train; in some Asian and African cultures children are trained as infants, while training at age 2-3 years is more typical in Western cultures. Infant voiding is not merely a spinal reflex, as the sensation of bladder filling is relayed to the brain. However, the ability of the brain to inhibit bladder contractions, and to achieve coordinated bladder contraction with sphincter relaxation, matures over time. While there is a concern that later toilet training may be responsible for an increase in urinary incontinence in children, no controlled studies on early versus late toilet training exist to evaluate this hypothesis. A number of medical conditions such as spina bifida, posterior urethral valves, cerebral palsy and autism can cause incontinence and difficulties in toilet training. The decision to start toilet training a child should take into account both the parents' expectation of how independent the child will be in terms of toileting, and the child's developmental readiness, so that a realistic time course for toilet training can be implemented.