Amplitude Of Bladder Contractions Research Articles

Propranolol, but not naloxone, enhances spinal reflex bladder activity and reduces pudendal inhibition in cats.

This study examined the role of β-adrenergic and opioid receptors in spinal reflex bladder activity and in the inhibition induced by pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS). Spinal reflex bladder contractions were induced by intravesical infusion of 0.25% acetic acid in α-chloralose-anesthetized cats after an acute spinal cord transection (SCT) at the thoracic T9/T10 level. PNS or TNS at 5 Hz was applied to inhibit these spinal reflex contractions at 2 and 4 times the threshold intensity (T) for inducing anal or toe twitch, respectively. During a cystrometrogram (CMG), PNS at 2T and 4T significantly (P < 0.05) increased bladder capacity from 58.0 ± 4.7% to 85.8 ± 10.3% and 96.5 ± 10.7%, respectively, of saline control capacity, while TNS failed to inhibit spinal reflex bladder contractions. After administering propranolol (3 mg/kg iv, a β₁/β₂-adrenergic receptor antagonist), the effects of 2T and 4T PNS on bladder capacity were significantly (P < 0.05) reduced to 64.5 ± 9.5% and 64.7 ± 7.3%, respectively, of the saline control capacity. However, the residual PNS inhibition (about 10% increase in capacity) was still statistically significant (P < 0.05). Propranolol treatment also significantly (P = 0.0019) increased the amplitude of bladder contractions but did not change the control bladder capacity. Naloxone (1 mg/kg iv, an opioid receptor antagonist) had no effect on either spinal reflex bladder contractions or PNS inhibition. At the end of experiments, hexamethonium (10 mg/kg iv, a ganglionic blocker) significantly (P < 0.05) reduced the amplitude of the reflex bladder contractions. This study indicates an important role of β₁/β₂-adrenergic receptors in pudendal inhibition and spinal reflex bladder activity.

Mechanisms of Pelvic Organ Cross-Talk: Impact of Urethral Ligation on the Inhibitory Rectovesical Reflex

The existence of an inhibitory rectovesical reflex elicited by noxious colorectal afferent input was previously documented in an isovolumetric cystometry model with a ligated urethra. We compared the effect of noxious colorectal distension on bladder cystometry with an open and a ligated urethra. We used female Sprague Dawley® rats anesthetized with urethane. The effect of noxious (60 mm Hg) colorectal distension on intermittent and continuous cystometry with an open urethra was studied and then compared to inhibiting isovolumetric bladder contractions in the same rat after ligating the urethra. We evaluated volume, the pressure micturition threshold, the intercontraction interval, bladder contraction frequency and amplitude of micturition contractions. Noxious colorectal distension at 60 mm Hg did not significantly influence volume or the pressure micturition threshold during intermittent cystometry. It also did not influence the pressure micturition threshold, the intercontraction interval or bladder contraction frequency during continuous cystometry. After urethral ligation 60 mm Hg colorectal distension inhibited isovolumetric bladder contraction frequency in the same rat (mean ± SEM 0.363± 0.207 vs 0.886 ± 0.106 contractions per minute, p <0.05). This inhibition persisted a mean of 289.08 ± 91.24 seconds after deflating the rectal balloon. The inhibitory rectovesical reflex elicited by noxious colorectal distension clearly occurred in an isovolumetric bladder model with a ligated urethra but only to a negligible extent in filling related voiding contractions. Ourresults suggest that the inhibitory rectovesical reflex, most likely at the levelof the lumbosacral spinal cord, is the result of an additive noxious urethral and colonic afferent stimulus.

Functional brain interactions during reflexive micturition are absent from spinal cord injured rats with neurogenic bladder

The micturition reflex is initiated by urinary bladder distension triggering afferent pathways and activation of specific brain centers for controlling urine storage and release. We evaluated brain activation patterns using blood oxygenation level dependent functional magnetic resonance imaging (fMRI) during reflexive micturition in normal and spinal cord injury (SCI) rats. Sprague-Dawley female rats, either intact or with complete spinal cord transection, were anesthetized with urethane for simultaneous isovolumetric cystometry (CMG) and fMRI evaluations. A 9.4-Tesla MRI system with a 4-elements receiver array and a quadrature volume transmit coil was used to maximize the sensitivity detection. Gradient echo-planar imaging (EPI) was used to evaluate brain activation during CMG compared to the empty bladder condition. Group analysis was conducted with a cluster threshold of Z > 2.5 and significance threshold of P = 0.05. The amplitude of bladder contractions was 10-fold higher in control rats and inter-contractile intervals were significantly shorter in SCI rats, indicative of neurogenic overactivity. Group analysis in intact rats showed both known and novel activation patterns in hippocampus, dentate gyrus, ectorhinal cortex, thalamic nucleus, septal nucleus, primary and secondary motor cortex, primary somatosensory cortex, and the periaqueductal gray matter. SCI rats did not exceed the Z-threshold during CMG. We standardized a suitable urodynamic protocol to study supraspinal activation during reflexive micturition using simultaneous CMG/fMRI with high spatial resolution. Small contractions in SCI rats may be caused by increased excitability of afferent pathways without brain activation. Our results represent the first fMRI study in SCI rats.

Restoring the glycosaminoglycans layer in recurrent cystitis: Experimental and clinical foundations

Restoring the bladder glycosaminoglycans layer has recently been introduced as prophylactic treatment for recurrent urinary tract infections. Herein, we analyze the latest main clinical and experimental studies to support this therapeutic option. An electronic research was carried out in the most common databases in order to identify any published studies. Retrieved studies were categorized as experimental or clinical according to their setting. For the clinical studies, the evidence level was assigned. A total of 13 laboratory studies showed how bladder glycosaminoglycans instillations act: attenuation of the inflammation process, reduction of bladder contraction amplitude and frequency, reduction of epithelium damage, and lower bacterial growth in urine and tissue samples. Likewise, two randomized clinical trials with grade 2 evidence level and two case series with grade 4 evidence level reported glycosaminoglycans as an alternative to reduce episodes and to prolong recurrence time in patients with recurrent urinary tract infections. At least 12 months of follow up was completed. No serious adverse events were reported. Compared with a placebo, in one randomized study a significantly higher maximum cystometric capacity was obtained, whereas in the other study a significant increase in quality of life scores was reported too. An improvement in the urinary symptoms score was reported by the two randomized trials. Although the clinical use of glycosaminoglycans replacement therapy for recurrent urinary tract infections is supported by a small number of clinical studies with different evidence levels, the laboratory studies show that glycosaminoglycans could have a protective role against inflammatory factors, supporting the idea "to restore the glycosaminoglycans bladder layer to prevent chronic disease course".

Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo

AimsBombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction. Material and methodsIn vivo cystometry experiments were performed in adult female Sprague–Dawley rats under urethane anesthesia. Diabetes was induced by streptozotocin (STZ; 65mg/kg, i.p.) injection. Experiments were performed 9 and 20weeks post STZ-treatment. Drugs included neuromedin B (NMB; BB1 receptor preferring agonist), and gastrin-releasing peptide (GRP; BB2 receptor preferring agonist). Key findingsNMB and GRP (0.01–100μg/kg in sham rats; 0.1–300μg/kg in STZ-treated rats, i.v.) increased micturition frequency, bladder contraction amplitude and area under the curve dose dependently in both sham and STZ-treated rats. In addition, NMB (3, 10μg/kg i.v.) triggered voiding in >80% of STZ-treated rats when the bladder was filled to a sub-threshold voiding volume. NMB and GRP increased mean arterial pressure and heart rate at the highest doses, 100 and 300μg/kg. SignificanceActivation of bombesin receptors facilitated neurogenic bladder contractions in vivo. Single applications of agonists enhanced or triggered voiding in sham rats as well as in the STZ-treated rat model of diabetic voiding dysfunction. These results suggest that BB receptors may be targeted for drug development for conditions associated with poor detrusor contraction such as an underactive bladder condition.

40 SLEEP APNEA CAUSES BLADDER OXIDATIVE STRESS AND NUCTURIA IN RATS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research (1)1 Apr 201340 SLEEP APNEA CAUSES BLADDER OXIDATIVE STRESS AND NUCTURIA IN RATS Kazem Azadzoi, Farzana Nipa, Yedan Li, and Mike Siroky Kazem AzadzoiKazem Azadzoi Boston, MA More articles by this author , Farzana NipaFarzana Nipa Boston, MA More articles by this author , Yedan LiYedan Li Boston, MA More articles by this author , and Mike SirokyMike Siroky Boston, MA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1415AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sleep apnea (SA) is a chronic condition affecting over 18 million adults in the United States where the affected person repeatedly stops breathing during sleep causing blood oxygen levels to drop and then rapidly increase with breathing. This initiates repeating cycles of hypoxia and reoxygenation. The incidence of SA closely correlates with the prevalence of nocturia. Our goal was to assess bladder oxidative stress markers and examine micturition behavior and cystometric parameters in a rat model of SA. METHODS Male Sprague-Dawley rats were divided into treatment (SA, n=8), sham (n=8) and control (n=8) groups. The treatment group was exposed to conditions similar to SA by housing the animals in computerized servo-controlled oxycyclers that produced reductions in ambient oxygen level from 21% to 8% for 8 seconds then rebound to 21% oxygen for 20 seconds. The computer was programed to repeat this cycle every 90 seconds for 8 hours daily for 8 weeks. The sham group was housed under similar oxycycler conditions with air supply alternating slightly from 21% to 20% oxygen 8 hours daily for 8 weeks. The control group was not exposed to oxycycler and used as age-matched control. After 8 weeks, day and night time voiding behavior of animals were assessed in metabolic cages under 12:12 hours light/dark cycles conditions. After this, cystometrograms were obtained then bladder tissues were processed for biochemical assays, ELISA and transmission electron microscopy (TEM). RESULTS Animals exposure to SA conditions significantly increased micturition frequency and diminished voided volume. Cystometrograms showed a significant increase in spontaneous bladder contractions in animals exposed to SA conditions in comparison with sham and control animals. The duration and amplitude of bladder contractions were significantly greater in the SA group. ELISA of bladder samples from SA group showed oxidative tissue damage characterized by increases in protein oxidation and lipid peroxidation products, decrease in antioxidant enzymatic activity, and accumulation of the oxidative product 8-isoprostane PGF2 alpha and nitrosative product nitrotyrosine. TEM of bladder samples from SA group showed swollen mitochondria, loss of mitochondrial cristae, and diffused accumulation of connective tissue. CONCLUSIONS SA exposes the bladder to oxidative stress and may play a role in the development of nocturia. The mechanism appears to involve free radical incursion of the cellular and subcellular elements and oxidative modification of the bladder mitochondrial energy apparatus and smooth muscle contractile component. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e16 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kazem Azadzoi Boston, MA More articles by this author Farzana Nipa Boston, MA More articles by this author Yedan Li Boston, MA More articles by this author Mike Siroky Boston, MA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Mechanisms of Pelvic Organ Crosstalk: 1. Peripheral Modulation of Bladder Inhibition by Colorectal Distention in Rats

Bladder activity can be inhibited by afferent input from the colorectum (inhibitory rectovesical reflex). We evaluated the functional response of the rat bladder to nonnoxious and noxious colorectal distention, and investigated the mechanical and pharmacological peripheral modulation of this response. In 70 female Sprague-Dawley® rats we evaluated the effect of nonnoxious (20 mm Hg) and noxious (40 and 60 mm Hg) colorectal distention on the micturition volume threshold and on bladder activity in a filled bladder. We also studied the effect of rectal balloon size (1.5 vs 3.5 cm long), and rectal administration of 2% lidocaine jelly or 1 mM allyl isothiocyanate solution on the inhibitory rectovesical reflex. Colorectal distention at 60 mm Hg increased the micturition volume threshold (mean ± SE 0.640 ± 0.056 vs 0.448 ± 0.035 ml in controls, p <0.001). Bladder contraction frequency was significantly decreased by 40 and 60 mm Hg colorectal distention vs controls (mean 0.62 ± 0.06 and 0.33 ± 0.05 per minute, respectively, vs 0.77 ± 0.03, each p <0.001). These effects were reversible and pressure dependent (p <0.001), and more pronounced using a large rectal balloon (mean 40 vs 60 mm Hg colorectal distention 0.35 ± 0.12 vs 0.07 ± 0.04 per minute, p = 0.004). We noted no significant graded inhibition of bladder contraction amplitude or duration. The inhibitory rectovesical reflex was reversibly abolished by intrarectal lidocaine administration. Intrarectal allyl isothiocyanate administration significantly increased the effect of noxious colorectal distention on bladder contraction frequency. Only noxious levels of colorectal distention initiated the inhibitory rectovesical reflex. The effect increased with rectal balloon size and with intrarectal administration of allyl isothiocyanate. It was reversibly abolished by lidocaine. Results suggest that spinal interneurons are the mechanism behind the inhibitory rectovesical reflex.

Exogenous activation of muscarinic receptors decreases subsequent non-muscarinic bladder contractions in vivo in the female rat

AimsTo determine if the muscarinic agonist, bethanechol, inhibits the non-cholinergic, atropine-resistant (i.e. putatively purinergic) component of naturally occurring (i.e. reflexogenic) bladder contractions in vivo in the rat, as previously described in vitro. Our second aim was to determine if elevation of endogenous acetylcholine (ACh) with distigmine, an acetylcholine esterase (AChE) inhibitor, could also inhibit non-cholinergic component of reflexogenic bladder contractions. Main methodsCystometry was performed in urethane anesthetized adult female Sprague Dawley rats. The nonselective muscarinic receptor (mAChR) antagonist, atropine, was administered intravenously (i.v.) before and after i.v. administration of the non-selective mAChR agonist, bethanechol, the AChE inhibitor, distigmine or the neurokinin receptor 2 agonist, [βAla8]-Neurokinin A(4–10). Intermicturition interval (IMI), bladder contraction amplitude (BCA), postvoid bladder pressure (PVBP), and voiding efficiency (VE) were measured. Key findingsAtropine (0.4mg/kg; n=11 rats) delivered as the first drug, had insignificant effects on BCA (~15% reduction) or PVBP (~15% increase) and weakly reduced IMI and VE by ~40% (p<0.05) relative to vehicle. Bethanechol and distigmine on their own produced excitatory effects on bladder activity, consistent with mAChR activation. Unexpectedly atropine, administered after bethanechol or after distigmine but not after [βAla8]-Neurokinin A(4–10), completely blocked bladder activity for 3–10min. Partial recovery of bladder activity occurred after that time, but BCA, IMI, and VE remained significantly reduced and PVBP remained significantly increased. SignificanceActivation of mAChRs by an exogenous agonist or elevation of endogenous ACh levels by an AChE inhibitor inhibits the non-cholinergic, atropine-resistant, component of reflexogenic bladder contractions in vivo.

Transient receptor potential vanilloid 1 mediates nerve growth factor‐induced bladder hyperactivity and noxious input

To explore the role of transient receptor potential vanilloid 1 (TRPV1) in the excitatory effects of chronic administration of nerve growth factor (NGF) on bladder-generated sensory input and reflex activity. To explore new therapeutic targets for bladder dysfunction. Wild-type (WT) and TRPV1 knockout (KO) mice received daily intraperitoneal injections of NGF (1 µg/10 g) or saline for a period of 4 days, during which time thermal sensitivity was evaluated daily. On the 5th day, mice were anaesthetized and cystometries were performed. The frequency, amplitude and area under the curve (AUC) of bladder reflex contractions were determined. c-Fos expression was evaluated on L6 spinal cord sections of WT and TRPV1 KO mice treated with saline or chronic NGF by immunohistochemistry. TrkA receptor staining intensity was determined in L6 spinal cord sections and respective dorsal root ganglia of WT and TRPV1 KO mice. Repeated administration of NGF induced thermal hypersensitivity in WT but not in TRPV1 KO mice. The frequency of bladder contractions of saline-treated WT and TRPV1 KO mice was similar, the values respectively being 0.45 ± 0.12/min and 0.46 ± 0.16/min. Treatment with NGF enhanced bladder reflex activity in WT mice to 1.23 ± 0.41/min (P < 0.05). In NGF-treated KO mice, the frequency of bladder contractions was 0.60 ± 0.05/min. Irrespective of treatment, no differences were observed in the amplitude of bladder contractions of WT and TRPV1 KO mice. The AUC was significantly increased in NGF-treated WT-mice, when compared with saline-treated WT-mice. No changes were found in AUC of saline-treated and NGF-treated TRPV1 KO mice. Chronic administration of NGF resulted in a significant increase of spinal c-Fos expression in WT mice (P < 0.05 vs KO animals), but not in TRPV1 KO animals. TrkA expression was similar in WT and TRPV1 KO mice. NGF-induced bladder overactivity and noxious input depend on the interaction of NGF with TRPV1. The lack of bladder overactivity in TRPV1 KO mice treated with NGF does not represent loss of TrkA expression. TRPV1 is essential for NGF-driven bladder dysfunction and represents a bottleneck target in bladder pathologies associated with NGF up-regulation.

Rat detrusor overactivity induced by chronic spinalization can be abolished by a transient receptor potential vanilloid 1 (TRPV1) antagonist

PurposeTo evaluate the effect of a transient receptor potential vanilloid 1 (TRPV1) antagonist GRC 6211 on neurogenic detrusor overactivity (NDO) of spinal origin. Materials and methodsCystometries under urethane anaesthesia were obtained in 14 chronic spinalized rats to confirm NDO. Two groups were created. In the first one (n=10), GRC 6211 (0.01, 0.1 and 1mg/kg weight) was administered via the duodenum in cumulative doses and cystometries performed 150min after the administration of each dose of the drug. In the second group (n=4), used as control, the animals were submitted to cystometries during 12hours, without administration of GRC 6211. Frequency and amplitude of bladder contractions were recorded in both groups. ResultsThe mean (±SDev) bladder detrusor muscle contraction frequency of spinalized rats was 0.7±0.27 contractions/min. GRC 6211 produced a significant dose-dependent effect, with the frequency diminished to 0.53±0.23, 0.40±0.20 and 0.20±0.13 contractions/min, respectively. The mean (± SDev) amplitude of bladder contractions was 48.4±4.4 cmH2O. After administration of 0.01mg/kg, 0.1mg/kg and 1mg/kg of GRC 6211, the amplitude decreased to 47.1±4.3, 45.6±5.6 and 40.2±4.1 cmH2O respectively. The effect was significant at 0.1 and 1mg/kg doses. Cystometries performed in the control group of spinalized rats showed no evidence of detrusor fatigue caused by the urethane anaesthesia and long duration of the experiment. ConclusionTRPV1 antagonists may be very effective in reducing NDO of spinal origin. This finding may have profound implications for the pathogenesis and future treatment options of patients with spinal NDO.

Inhibition of bladder overactivity by stimulation of feline pudendal nerve using transdermal amplitude‐modulated signal (TAMS)

• To develop a non-invasive neuromodulation method targeting the pudendal nerve. • Bladder overactivity induced by acetic acid (AA) irritation was partially suppressed by electrical stimulation of the pudendal nerve in α-chloralose anaesthetized cats using a transdermal amplitude-modulated signal (TAMS). • During cystometrography (CMG), intravesical infusion of 0.25% AA significantly decreased the mean (se) bladder capacity to 28.8 (5.9)% of the capacity measured during saline infusion. • The TAMS stimulation inhibited AA-induced bladder overactivity at 5, 7 and 10 Hz, and significantly increased the mean (se) bladder capacity to 61.8 (9.9)%, 51.3 (14.5)%, 53.6 (14.9)%, respectively, of the control capacity during saline infusion, whereas stimulation at 20-40 Hz had no effect. • Under isovolumetric conditions at a bladder volume ranging between 130 to 160% of the bladder capacity measured during AA infusion, TAMS stimulation at all frequencies (5-40 Hz) significantly suppressed the irritation-induced rhythmic bladder contractions, reduced the area under the bladder pressure curve, and decreased the frequency of bladder contractions. However, the amplitude of rhythmic bladder contractions was only significantly decreased at stimulation frequencies of 5-20 Hz. • At bladder volumes above the AA control capacity, TAMS stimulation with frequencies of 20-30 Hz had an excitatory effect, resulting in large amplitude (>25 cmH(2) O) bladder contractions. • TAMS stimulation targeting the cat pudendal nerve can inhibit C-fibre afferent-mediated bladder overactivity. • Thus, clinical research seems warranted to explore the usefulness of this technology for patients with overactive bladder symptoms.

Nitro-oleic acid targets transient receptor potential (TRP) channels in capsaicin sensitive afferent nerves of rat urinary bladder

Nitro-oleic acid (9- and 10-nitro-octadeca-9-enoic acid, OA-NO 2) is an electrophilic fatty acid nitroalkene derivative that modulates gene transcription and protein function via post-translational protein modification. Nitro-fatty acids are generated from unsaturated fatty acids by oxidative inflammatory reactions and acidic conditions in the presence of nitric oxide or nitrite. Nitroalkenes react with nucleophiles such as cysteine and histidine in a variety of susceptible proteins including transient receptor potential (TRP) channels in sensory neurons of the dorsal root and nodose ganglia. The present study revealed that OA-NO 2 activates TRP channels on afferent nerve terminals in the urinary bladder and thereby increases bladder activity. The TRPV1 agonist capsaicin (CAPS, 1 μM) and the TRPA1 agonist allyl isothiocyanate (AITC, 30 μM), elicited excitatory effects in bladder strips, increasing basal tone and amplitude of phasic bladder contractions (PBC). OA-NO 2 mimicked these effects in a concentration-dependent manner (1 μM–33 μM). The TRPA1 antagonist HC3-030031 (HC3, 30 μM) and the TRPV1 antagonist diaryl piperazine analog (DPA, 1 μM), reduced the effect of OA-NO 2 on phasic contraction amplitude and baseline tone. However, the non-selective TRP channel blocker, ruthenium red (30 μM) was a more effective inhibitor, reducing the effects of OA-NO 2 on basal tone by 75% and the effects on phasic amplitude by 85%. In bladder strips from CAPS-treated rats, the effect of OA-NO 2 on phasic contraction amplitude was reduced by 65% and the effect on basal tone was reduced by 60%. Pretreatment of bladder strips with a combination of neurokinin receptor antagonists (NK1 selective antagonist, CP 96345; NK2 selective antagonist, MEN 10,376; NK3 selective antagonist, SB 234,375, 1 μM each) reduced the effect of OA-NO 2 on basal tone, but not phasic contraction amplitude. These results indicate that nitroalkene fatty acid derivatives can activate TRP channels on CAPS-sensitive afferent nerve terminals, leading to increased bladder contractile activity. Nitrated fatty acids produced endogenously by the combination of fatty acids and oxides of nitrogen released from the urothelium and/or afferent nerves may play a role in modulating bladder activity.

Irritation Induced Bladder Overactivity is Suppressed by Tibial Nerve Stimulation in Cats

We investigated the effects of tibial nerve stimulation on bladder overactivity induced by acetic acid irritation. Cystometry was performed in 10 α-chloralose anesthetized female cats by infusing saline or acetic acid through a urethral catheter that was secured by a ligature around the urethra. Intravesical infusion of 0.25% acetic acid was used to irritate the bladder and induce bladder overactivity. Multiple cystometrograms were done before, during and after tibial nerve stimulation to determine the inhibitory effect on the micturition reflex. Infusion of 0.25% acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to about 20% of control capacity measured during saline infusion. Tibial nerve stimulation at low (5 Hz) or high (30 Hz) frequency significantly increased bladder capacity to about 40% of saline control capacity when it was applied during acetic acid infusion cystometrogram. Bladder contraction amplitude was smaller during acetic acid irritation than during saline distention due to significantly smaller bladder capacity. Tibial nerve stimulation at 5 Hz increased bladder capacity and bladder contraction amplitude. Activation of somatic afferents in the tibial nerve of cats can partially reverse the bladder overactivity induced by intravesical administration of a chemical irritant that activates C-fiber afferent nerves. These data are consistent with clinical studies showing that tibial nerve neuromodulation is effective treatment for overactive bladder symptoms.

Central inhibitory effect of intravesically applied botulinum toxin A in chronic spinal cord injury

We evaluated a putative central inhibitory effect of intravesical botulinum toxin A (BoNT-A) on the activity of lumbosacral spinal neurons in a chronic spinal cord injury (SCI) model of bladder overactivity. Female Sprague-Dawley rats underwent T8 spinal cord transection. Four weeks later, once overactive neuropathic detrusor pathways had developed, the animals underwent intravesical instillation with either saline (1 ml) or BoNT-A (Botox®, 20 U/1 ml) for 1 hr. Two days later, the rats then completed a cystometric evaluation prior to spinal cord harvest. Sections from the L4-S1 spinal cord segments were examined for the total number of c-fos immunoreactive cells. Comparison of the saline and BoNT-A treated groups showed a significant decrease in L6 (i.e., 67%, P < 0.001) and S1 (i.e., 47%, P < 0.01) c-fos expression (43%) in BoNT-A treated rats compared to saline controls. Cystometrogram studies revealed that the frequency of non-voiding bladder contractions was reduced by 73% (P < 0.05) in BoNT-A compared to saline treated rats. No change in the frequency of voiding bladder contractions or amplitude of bladder contraction was observed between the saline and BoNT-A treated groups. In a SCI model of bladder overactivity, intravesical BoNT-A significantly inhibits the response of bladder afferent activated lumbosacral neurons without significantly impairing efferent bladder function.

Urothelial beta‐3 adrenergic receptors in the rat bladder

To investigate the distribution of beta-3 adrenergic receptors (β(3)ARs) in the rat bladder and to examine the contribution of urothelial β(3)ARs to agonist-induced suppression of bladder reflexes and relaxation of smooth muscle. Bladder tissue was collected from 8- to 10-month old female SD rats. In some samples, the urothelium was surgically separated from the smooth muscle. The expression and localization of βAR mRNA and β(3)AR protein were determined using RT-PCR and immunohistochemistry. Contractile responses to the specific β(3)AR agonists TAK-677 and BRL37344 were measured in bladder strips with or without the urothelium. The contribution of urothelial β(3)ARs to the micturition reflex was assessed in continuous cystometry in urethane anesthetized rats using intravesical delivery of β(3)AR agonists. RT-PCR detected mRNA of all βARs in urothelium and smooth muscle. Immunostaining detected β(3)ARs throughout the urothelium, in the smooth muscle, myofibroblast-like cells, and in the peripheral nerves. Ovariectomy did not change the distribution of β(3)ARs in any bladder structure. Intravesical administration of TAK-677 and BRL37344 (1-5 × 10(-4) M) decreased voiding frequency and amplitude of bladder contractions. In bladder strips in vitro both β(3)AR agonists (10(-12) to 10(-4) M) relaxed the smooth muscle in a concentration-dependent manner to the same extent in strips with and without the urothelium. In addition to their presence in bladder smooth muscle, β(3)ARs are present in the urothelium where their activation may alter reflex voiding via release of factor(s) that act on non-myocyte structures including the afferent and/or efferent nerves to influence bladder contractility.

Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder–pelvic afferent nerve preparation of the rat

Effects of a muscarinic receptor agonist oxotremorine-M (oxo-M) on bladder afferent nerve (BAN) activity were studied in an in vitro bladder–pelvic nerve preparation. Distension of the bladder induced rhythmic bladder contractions that were accompanied by multiunit afferent firing. Intravesical administration of 25 and 50 μM oxo-M significantly increased afferent firing from 41 ± 2 spikes/s to 51 ± 4 spikes/s and 60.5 ± 5 spikes/s, respectively, but did not change the maximum amplitude of spontaneous bladder contractions. The afferent nerve firing induced by isotonic distension of the bladder (10–40 cmH 2O) was increased 22–100% by intravesical administration of 50 μM oxo-M. Electrical stimulation on the surface of the bladder elicited action potentials (AP) in BAN. Oxo-M significantly decreased the voltage threshold by 40% (p < 0.05) and increased by 157% (p < 0.05) the area of the AP evoked at a submaximal stimulus intensity. These effects were blocked by intravesical injection of 5 μM atropine methyl nitrate (AMN). Intravesical administration of 5 μM AMN alone did not alter BAN firing or the amplitude of bladder contractions. The facilitatory effects induced by oxo-M on BAN activity were also suppressed (p < 0.05) by intravesical administration of 2′,3′-0-trinitrophenyl-ATP (TNP-ATP) (30 μM). In preparations pretreated with capsaicin (125 mg/kg, s.c.) the facilitatory effects of 50 μM oxo-M on BAN activity were absent. These results suggest that activation of muscarinic receptors facilitates mechano-sensitive, capsaicin-sensitive BAN activity in part by mechanisms involving purinergic receptors located near the luminal surface of the bladder and ATP release which presumably occurs in the urothelium.

Intravesical instillation of botulinum toxin A: an in vivo murine study and pilot clinical trial

The objectives of this study were to compare the urodynamic effects of botulinum toxin A (BoNT-A) delivered via intramural injection into the bladder wall to that of intravesical instillation in a rat model of detrusor overactivity and to evaluate the effects of intravesical instillation of BoNT-A in female patients with idiopathic overactive bladder. Detrusor overactivity was induced in female Wistar rats using partial bladder outflow obstruction. Animals were treated with 5 units (U) of BoNT-A via intramural bladder injection (n = 6) or intravesical instillation (n = 7). Conscious cystometrograms were performed prior to BoNT-A administration and then repeated 7 days and 2 weeks following treatment. In the subsequent pilot clinical study, 16 female patients with overactive bladder refractory to antimuscarinics were treated with 200 units of BoNT-A in 50 mL of 0.9% saline instilled using a 12-F urethral catheter. Treatment outcome was evaluated immediately prior to and 1 month after BoNT-A administration. In the preclinical study, the average intermicturition and threshold pressures, as well as the number and amplitude of non-voiding bladder contractions, decreased significantly in both instillation and injection groups. Micturition pressure decreased significantly only in the intramural injection group. In the pilot clinical study, seven patients reported improvement in symptoms. The average number of incontinence episodes was significantly reduced, and the volume at which the first non-voiding contraction was recorded increased by 52.8%. The results of our urodynamic studies support the hypothesis that BoNT-A instilled into the urinary bladder affects bladder sensation.

1514 CEREBRAL INFARCTION FAILS TO ENHANCE THE SNEEZE-INDUCED CONTINENCE REFLEX AFTER DULOXETINE, A NOREPINEPHRINE AND SEROTONIN REUPTAKE INHIBITOR, IN RATS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Incontinence - Evaluation & Therapy I1 Apr 20101514 CEREBRAL INFARCTION FAILS TO ENHANCE THE SNEEZE-INDUCED CONTINENCE REFLEX AFTER DULOXETINE, A NOREPINEPHRINE AND SEROTONIN REUPTAKE INHIBITOR, IN RATS Minoru Miyazato, Yasuhiro Kaiho, Hideaki Izumi, Naoki Kawamorita, Haruo Nakagawa, Yoichi Arai, Michael Chancellor, William de Groat, and Naoki Yoshimura Minoru MiyazatoMinoru Miyazato Pittsburgh, PA More articles by this author , Yasuhiro KaihoYasuhiro Kaiho Miyagi, Japan More articles by this author , Hideaki IzumiHideaki Izumi Miyagi, Japan More articles by this author , Naoki KawamoritaNaoki Kawamorita Miyagi, Japan More articles by this author , Haruo NakagawaHaruo Nakagawa Miyagi, Japan More articles by this author , Yoichi AraiYoichi Arai Miyagi, Japan More articles by this author , Michael ChancellorMichael Chancellor Royal Oak, MI More articles by this author , William de GroatWilliam de Groat Pittsburgh, PA More articles by this author , and Naoki YoshimuraNaoki Yoshimura Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2358AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Norepinephrine and serotonin reuptake inhibitors such as duloxetine have demonstrated clinical efficacy in the treatment of stress urinary incontinence (SUI). We have previously reported that duloxetine enhances the active urethral closure mechanism during sneezing via activation of both spinal noradrenergic and serotonergic systems in normal rats. However, it is not investigated whether these mechanisms are affected by cerebral infarction (CI). We therefore investigated the effect of duloxetine on the sneeze induced continence reflex as well as bladder function in CI rats. METHODS The left middle cerebral artery was occluded with 4-0 nylon to create CI. (1) Three days later, sneeze-induced urethral responses were examined using a microtransducer-tipped catheter inserted to the middle urethra from the urethral orifice. Sneeze was induced by a rat's whisker cut and inserted into the nostril under urethane anesthesia, and the effect of duloxetine (1 mg/kg i.v.) on the amplitude of urethral responses during sneezing (A-URS) as well as urethral baseline pressure (UBP) was evaluated. (2) In normal and CI rats, continuous cystometry was evaluated before and after duloxetine injection. RESULTS (1) In CI rats, UBP was 43% lower (15.5 cm H2O) compared with normal rats (27.4 cm H2O), but A-URS did not differ in two groups (39.5 cm H2O vs. 36.4 cm H2O). Duloxetine (i.v.) enhanced A-URS and UBP by 32% and 22%, respectively, in normal rats, but did not affect either in CI rats. (2) CI reduced intercontraction intervals without affecting the amplitude of bladder contractions compared with normal rats. Duloxetine prolonged intercontraction intervals in CI rats, but not in normal rats. CONCLUSIONS In CI rats, the sneeze-induced urethral continence reflex is preserved, but urethral baseline pressure is lower compared with normal rats. Duloxetine improves urinary frequency but fails to enhance the sneeze-induced urethral responses (both A-URS and UBP) after CI. These results suggest that: (1) CI induces not only bladder overactivity, but also SUI, which may account for mixed incontinence in CI patients, and (2) norepinephrine and serotonin reuptake inhibition is effective to treat bladder overactivity, but not for SUI due to failed activation of spinal noradrenergic and/or serotonergic systems controlling the urethral continence reflex in CI. Thus, the clinical efficacy of norepinephrine/serotonin reuptake inhibitors for SUI could be reduced in SUI patients with CI while they are useful for the treatment of overactive bladder. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e584 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Minoru Miyazato Pittsburgh, PA More articles by this author Yasuhiro Kaiho Miyagi, Japan More articles by this author Hideaki Izumi Miyagi, Japan More articles by this author Naoki Kawamorita Miyagi, Japan More articles by this author Haruo Nakagawa Miyagi, Japan More articles by this author Yoichi Arai Miyagi, Japan More articles by this author Michael Chancellor Royal Oak, MI More articles by this author William de Groat Pittsburgh, PA More articles by this author Naoki Yoshimura Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function.

NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplakin II (UPII) promoter. NGF mRNA and protein were expressed at higher levels in the bladders of NGF-overexpressing (NGF-OE) transgenic mice compared with wild-type littermate controls from postnatal day 7 through 12-16 wk of age. Overexpression of NGF led to urinary bladder enlargement characterized by marked nerve fiber hyperplasia in the submucosa and detrusor smooth muscle and elevated numbers of tissue mast cells. There was a marked increase in the density of CGRP- and substance P-positive C-fiber sensory afferents, neurofilament 200-positive myelinated sensory afferents, and tyrosine hydroxylase-positive sympathetic nerve fibers in the suburothelial nerve plexus. CGRP-positive ganglia were also present in the urinary bladders of transgenic mice. Transgenic mice had reduced urinary bladder capacity and an increase in the number and amplitude of nonvoiding bladder contractions under baseline conditions in conscious open-voiding cystometry. These changes in urinary bladder function were further associated with an increased referred somatic pelvic hypersensitivity. Thus, chronic urothelial NGF overexpression in transgenic mice leads to neuronal proliferation, focal increases in urinary bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity. NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction.

Acoustical properties of the swimbladder in the oyster toadfish Opsanus tau

Both the swimbladder and sonic muscles of the oyster toadfish Opsanus tau (Linnaeus) increase in size with fish growth making it difficult to distinguish their relative contributions to sound production. We examined acoustics of the swimbladder independent of the sonic muscles by striking it with a piezoelectric impact hammer. Amplitude and timing characteristics of bladder sound and displacement were compared for strikes of different amplitudes. Most of the first cycle of sound occurred during swimbladder compression, indicating that the bladder rapidly contracted and expanded as force increased during the strike. Harder hits were shorter in duration and generated a 30 dB increase in amplitude for a 5-fold or 14 dB range in displacement. For an equivalent strike dominant frequency, damping, bladder displacement and sound amplitude did not change with fish size, i.e. equal input generated equal output. The frequency spectrum was broad, and dominant frequency was driven by the strike and not the natural frequency of the bladder. Bladder displacement decayed rapidly (zeta averaged 0.33, equivalent to an automobile shock absorber), and the bladder had a low Q (sharpness of tuning), averaging 1.8. Sound output of an acoustic source is determined by volume velocity (surface area x velocity), and bladder surface area, muscle dimensions and contraction amplitude increase with fish size. Therefore, larger fish will be capable of producing more intense sound. Because the bladder is a low Q resonator, its output will follow muscle contraction rates independent of its size and natural frequency.