Bladder Contraction Duration Research Articles

Extracorporeal Shock Wave Therapy Protected the Functional and Architectural Integrity of Rodent Urinary Bladder against Ketamine-Induced Damage.

This study tested the hypothesis that extracorporeal-shock-wave (ECSW) protected the functional and anatomical integrity of rat urinary-bladder against ketamine-induced damage. In in vitro study, the rat bladder smooth muscle cells (RBdSMCs) were categorized into G1 (sham-control), G2 (RBdSMCs + menadione), G3 (RBdSMCs + ECSW) and G4 (RBdSMCs + menadione + ECSW). The results showed protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), inflammatory markers (MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-6/IL-1ß/MMP-9/iNOS), and cell-stress response signalings (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38/p-53) were significantly increased in G2 than in G1 and G3, and those were significantly reversed in G4 (all p < 0.0001). Adult-male SD rats (n = 24) were equally categorized into group 1 (sham-control), group 2 (ketamine/30 mg/kg/daily i.p. injection for four weeks), group 3 [ketamine/30 mg/kg + ECSW/optimal energy (0.12 mJ/mm2/120 impulses/at 3 h and days 3/7/14/21/28 after ketamine administration)] and group 4 [(ketamine/30 mg/kg + ECSW/higher energy (0.16 mJ/mm2/120 impulses)] and animals were euthanized by day 42. The results showed the urine levels of pro-inflammatory cytokines (TNF-α/IL-6) were lowest in group 1, highest in group 2 and significantly higher in group 3 than in group 4 at days 1/7/14/28 (all p < 0.0001). The duration of urinary bladder contraction was lowest in group 2, highest in group 1 and significantly higher in group 4 than in group 3, whereas the maximal pressure of urinary bladder exhibited an opposite pattern of bladder contraction among the groups (all p < 0.0001). The histopathological findings of fibrosis/inflammation/keratinization and protein expressions of oxidative-stress/mitochondrial-damaged biomarkers (NOX-1/NOX-2/oxidized protein/cytosolic-cytochrome-C/cyclophilin-D), and inflammatory (TLR-2/TLR-4/MyD88/TRAF6/p-IKB-α/NF-κB/TNF-α/IL-1ß/MMP-9/iNOS) and cell-stress response (ASK1/p-MKK4/p-MKK7/ERK1/2//p-JNK/p-p38) signalings and apoptotic/fibrotic biomarkers (cleaved-caspas3/cleaved-PARB/Smad3/TFG-ß) exhibited an identical pattern of urine proinflammatory cytokine among the groups (all p < 0.0001). ECSW effectively attenuated ketamine-induced bladder damage and dysfunction.

Bladder underactivity induced by prolonged pudendal afferent activity in cats.

The purpose of this study was to determine the effects of pudendal nerve stimulation (PNS) on reflex bladder activity and develop an animal model of underactive bladder (UAB). In six anesthetized cats, a bladder catheter was inserted via the urethra to infuse saline and measure pressure. A cuff electrode was implanted on the pudendal nerve. After determination of the threshold intensity (T) for PNS to induce an anal twitch, PNS (5 Hz, 0.2 ms, 2 T or 4 T) was applied during cystometrograms (CMGs). PNS (4-6 T) of 30-min duration was then applied repeatedly until bladder underactivity was produced. Following stimulation, control CMGs were performed over 1.5-2 h to determine the duration of bladder underactivity. When applied during CMGs, PNS (2 T and 4 T) significantly (P < 0.05) increased bladder capacity while PNS at 4 T also significantly (P < 0.05) reduced bladder contraction amplitude, duration, and area under contraction curve. Repeated application of 30-min PNS for a cumulative period of 3-8 h produced bladder underactivity exhibiting a significantly (P < 0.05) increased bladder capacity (173 ± 14% of control) and a significantly (P < 0.05) reduced contraction amplitude (50 ± 7% of control). The bladder underactivity lasted more than 1.5-2 h after termination of the prolonged PNS. These results provide basic science evidence supporting the proposal that abnormal afferent activity from external urethral/anal sphincter could produce central inhibition that underlies nonobstructive urinary retention (NOUR) in Fowler's syndrome. This cat model of UAB may be useful to investigate the mechanism by which sacral neuromodulation reverses NOUR in Fowler's syndrome.

Changes in bladder function with time following cystostomy in rats.

To investigate bladder function patterns following cystostomy and determine the best time window for cystometric evaluation of bladder function in conscious rats. Cystostomy was performed in rats of the first seven groups; thereafter, cystometry was performed in the designed time interval. Noncystostomy rats of group 8 voided freely as control. Basal bladder pressure (Pves.basal ), maximum bladder pressure (Pves.max ), bladder threshold pressure (Pves.thre ), voiding interval (VI), bladder contraction duration (CD), bladder compliance (ΔC), voided volume (VV), postvoiding residual urine (PVR), and bladder capacity (BC) were recorded and compared with cystostomy groups, with VV, PVR, BC compared with the control values. Bladders were collected after the urodynamic study for weighing, hematoxylin-eosin, and Masson staining to investigate pathological changes. Pves.basal , Pves.max , and Pves.thre trended downward, while BC, VI, VV, and ΔC trended upward on days 1 to 5 postcystostomy. BC and VV significantly decreased on days 1 to 3 postcystostomy compared with control values; on days 5 to 15 postcystostomy, Pves.basal , Pves.max , Pves.thre , VI, VV, BC, and PVR were stable, and BC, VV, and PVR showed no significant differences from the control values. However, on day 21 postcystostomy, BC increased significantly compared with the controls. Bladder weight increased in the cystostomy groups compared with the controls. Pathological analysis showed severe acute bladder inflammation on days 1 to 3, mild inflammation on days 5 to 15, and increased collagen deposition in bladder tissue on day 21 postcystostomy. Cystometric evaluation of bladder function in conscious rats is best performed on days 5 to 15 postcystostomy.

Time-Dependent Changes of Urethral Function in Diabetes Mellitus: A Review.

This article reviewed the current knowledge on time-course manifestation of diabetic urethral dysfunction (DUD), and explored an early intervention target to prevent the contribution of DUD to the progression of diabetes-induced impairment of the lower urinary tract (LUT). In the literature search through PubMed, key words used included “diabetes mellitus,” “diabetic urethral dysfunction,” and “diabetic urethropathy.” Polyuria and hyperglycemia induced by diabetes mellitus (DM) can cause the time-dependent changes in functional and morphological manifestations of DUD. In the early stage, it promotes urethral dysfunction characterized by increased urethral pressure during micturition. However, the detrusor muscle of the bladder tries to compensate for inducing complete voiding by increasing the duration and amplitude of bladder contractions. As the disease progresses, it can induce an impairment of coordinated micturition due to dyssynergic activity of external urethra sphincter, leading to detrusor-sphincter dyssynergia. The impairment of relaxation mechanisms of urethral smooth muscles (USMs) may additionally be attributable to decreased responsiveness to nitric oxide, as well as increased USM responsiveness to α1-adrenergic receptor stimulation. In the late stage, diabetic neuropathy may play an important role in inducing LUT dysfunction, showing that the decompensation of the bladder and urethra, which can cause the decrease of voiding efficiency and the reduced thickness of the urothelium and the atrophy of striated muscle bundles, possibly leading to the vicious cycle of the LUT dysfunction. Further studies to increase our understandings of the functional and molecular mechanisms of DUD are warranted to explore potential targets for therapeutic intervention of DM-induced LUT dysfunction.

An excitatory reflex from the superficial peroneal nerve to the bladder in cats.

This study in α-chloralose-anesthetized cats discovered an excitatory peroneal nerve-to-bladder reflex. A urethral catheter was used to infuse the bladder with saline and record bladder pressure changes. Electrical stimulation was applied to the superficial peroneal nerve to trigger reflex bladder activity. With the bladder distended at a volume ~90% of bladder capacity, superficial peroneal nerve stimulation (PNS) at 1-3 Hz and threshold (T) intensity for inducing muscle twitching on the posterior thigh induced large-amplitude (40-150 cmH2O) bladder contractions. PNS (1-3 Hz, 1-2T) applied during cystometrograms (CMGs) when the bladder was slowly (1-3 ml/min) infused with saline significantly (P < 0.01) reduced bladder capacity to ~80% of the control capacity and significantly (P < 0.05) enhanced reflex bladder contractions. To determine the impact of PNS on tibial nerve stimulation (TNS)-induced changes in bladder function, PNS was delivered following TNS. TNS of 30-min duration produced long-lasting poststimulation inhibition and significantly (P < 0.01) increased bladder capacity to 140.5 ± 7.6% of the control capacity. During the post-TNS inhibition period, PNS (1-3 Hz, 1-4T) applied during CMGs completely restored bladder capacity to the control level and significantly (P < 0.05) increased the duration of reflex bladder contractions to ~200% of control. The excitatory peroneal nerve-to-bladder reflex could also be activated by transcutaneous PNS using skin surface electrodes attached to the dorsal surface of the foot. These results raise the possibility of developing novel neuromodulation therapies to treat underactive bladder and nonobstructive urinary retention.

The influence of duloxetine on detrusor overactivity in rats with depression induced by 13-cis-retinoic acid

Introduction and hypothesisThe aim of this study was to assess the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression.MethodsAfter 6 weeks of 13-cis-retinoic acid administration at a dose of 1 mg/kg/day, rats were given duloxetine at a dose of 1 mg/kg. This was followed by conscious cystometry, a forced swim test, and locomotor activity measurement. The levels of corticotropin-releasing factor (CRF) in the hypothalamus, amygdala and plasma were also determined.ResultsDuloxetine treatment led to a reduction in detrusor overactivity symptoms induced by the retinoid. Decreases were observed in cystometric parameters including the detrusor overactivity index, and the amplitude and frequency of nonvoiding contractions, while increases were seen in bladder compliance and the volume threshold to elicit nonvoiding contractions. No statistically significant differences were found in basal pressure, threshold pressure, micturition voiding pressure, postvoid residual , volume threshold, voiding efficiency, intercontraction interval, bladder contraction duration or relaxation time. Duloxetine also reduced the immobility time to that observed in control animals, while it did not affect locomotor activity. Its effects also included lowering of the CRF levels in the hypothalamus, amygdala and plasma, which increased following the prior administration of the retinoid. The plasma level of 13-cis-retinoic acid in rats corresponded to the levels found in humans.ConclusionsThis is the first study showing the efficacy of duloxetine in an animal model of detrusor overactivity induced by depression. Further studies in patients with detrusor overactivity and coexisting depression are warranted to confirm these experimental results.

P2Y6-deficiency increases micturition frequency and attenuates sustained contractility of the urinary bladder in mice

The role of the P2Y6 receptor in bladder function has recently attracted a great deal of attention in lower urinary tract research. We conducted this study to determine contributions of the P2Y6 receptor in lower urinary tract function of normal phenotypes by comparing P2Y6-deficient mice and wild-type mice. In in vivo experiments, P2Y6-deficient mice had more frequent micturition with smaller bladder capacity compared to wild-type mice; however, there was no difference between these groups in bladder-filling pressure/volume relationships during cystometry under decerebrate, unanaesthetized conditions. Analysis of in vivo bladder contraction revealed significant difference between the 2 groups, with P2Y6-deficient mice presenting markedly shorter bladder contraction duration but no difference in peak contraction pressure. However, analysis of in vitro experiments showed no P2Y6 involvements in contraction and relaxation of bladder muscle strips and in ATP release by mechanical stimulation of primary-cultured urothelial cells. These results suggest that the P2Y6 receptor in the central nervous system, dorsal root ganglion, or both is involved in inhibition of bladder afferent signalling or sensitivity in the pontine micturition centre and that the receptor in the detrusor may be implicated in facilitation to sustain bladder contraction force.

Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats

Hemorrhagic cystitis often develops in patients treated with cyclophosphamide (CYP). Studies have indicated that Rho kinase (ROCK) inhibitors may suppress detrusor overactivity symptoms and possess anti-inflammatory properties. The aim of the present study was to investigate whether inhibition of ROCK reduces cystometric and histopathological changes associated with CYP-induced cystitis. The rats received GSK 269962, a ROCK inhibitor, at a dose of 30 mg/kg daily, or vehicle for 7 days. Then, acute chemical cystitis leading to bladder overactivity was induced by CYP injection (200 mg/kg i.p.). Following CYP injection, cystometric studies with physiological saline were performed. Moreover, bladder edema (by the Evans Blue dye leakage technique) and urothelium thickness were measured. CYP injection resulted in a significant increase in cystometric parameters: basal pressure, threshold pressure, bladder contraction duration, relaxation time, detrusor overactivity index, non-voiding contractions amplitude, and non-voiding contractions frequency as well as increased Evans Blue extravasation into bladder tissue, whereas micturition voiding pressure, voided volume, post-void residual, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit non-voiding contractions as well as urothelium thickness were significantly decreased in CYP-injected rats. Administration of GSK 269962 normalized the abovementioned CYP injection-induced changes. Inhibition of ROCK was found to ameliorate CYP-induced detrusor overactivity and bladder inflammation. Our data indicate uroprotective effects following ROCK inhibition, which further suggests that this strategy may become an interesting pharmacological tool to prevent urinary adverse effects in patients treated with chemotherapy using CYP.

The effect of combined treatment with a β3 AR agonist and a ROCK inhibitor on detrusor overactivity.

The objective of the study was to evaluate the efficacy and safety of the combined treatment with the β3 AR agonist and ROCK inhibitor in the rat model of detrusor overactivity induced by retinyl acetate instillation. The ROCK inhibitor (GSK 269962) and/or the β3 AR agonist (BRL 37344) were administered in single doses and a cystometry was carried out, along with a 24 hr measurement of cardiovascular parameters and diuresis. The combined use of GSK 269962 and BRL 37344 in doses ineffective in monotherapies, ameliorated DO. An increase was found in voided volume, voiding efficiency, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions, accompanied by a decrease in basal pressure, threshold pressure, detrusor overactivity index, nonvoiding contractions amplitude, and frequency. The combination therapy in question proved to have no effect on micturition voiding pressure, post-void residual, bladder contraction duration, or relaxation time. A 24 hr observation of female rats who received GSK 269962 and/or BRL 37344 did not show any significant changes in urine production. BRL 37344 increased heart rate and blood pressure proportionately to the applied dose. The assessment of the combined treatment with GSK 269962 and BRL 37344 revealed a significant drop of cardiovascular parameters when compared to the rats which only received BRL 37344. The combined use of β3 AR agonists and ROCK inhibitors may improve overactive bladder treatment efficacy and minimize side effects. This polytherapy appears to improve urine storage with no impairment of voiding function. Neurourol. Urodynam. 36:580-588, 2017. © 2016 Wiley Periodicals, Inc.

The influence of Rho-kinase inhibition on acetic acid-induced detrusor overactivity.

Accumulating evidence has shown that Rho-kinase (ROCK) is involved in the regulation of bladder contraction. Our objective was to examine whether the ROCK inhibitor, GSK 269962, could prevent acetic acid (AA)-induced detrusor overactivity and to assess its influence on urine production (UP) and mean arterial pressure (MAP). The bladder was catheterized from the external urethral orifice. 0.25 % (AA) solution was infused into the bladder for 5 min. In the same session a catheter was inserted into the apex of the bladder dome. In order to measure the blood pressure, the carotid artery was cannulated. Three days after the intravesical instillation of AA, the ROCK-GSK 269962 inhibitor was administered in a single dose of 10 mg/kg and a cystometry was carried out, along with a 24 hr measurement of UP and MAP. GSK 269962 reversed the changes induced by AA causing a drop in basal pressure, threshold pressure, micturition voiding pressure, bladder contraction duration, relaxation time, detrusor overactivity index, amplitude, and frequency of nonvoiding contractions while an increase in voided volume, post-void residual, volume threshold, voiding efficiency, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. ROCK inhibition did not show any significant changes in UP and MAP. The results obtained indicate that ROCK inhibition may ameliorate AA-induced bladder overactivity. ROCK inhibitors appear to represent a potentially attractive pharmacological option for the treatment of lower urinary tract disorders associated with changes in detrusor contractility. Neurourol. Urodynam. 36:263-270, 2017. © 2015 Wiley Periodicals, Inc.

A new model of detrusor overactivity in conscious rats induced by retinyl acetate instillation.

A credible animal overactive bladder model used in basic research is an indispensable harbinger of safe and ethical clinical trials on human subjects. Our objective was to develop a new animal model of a hyperactive bladder that will be void of inflammatory urothelium lesions and display significant sensitivity to muscarinic receptor antagonists. To examine the influence of 0.75% retinyl acetate solution on cystometric parameters, it was infused into the bladder for 5min. Cystometric studies with physiological saline were performed in conscious unrestrained rats 3days later. To examine the influence of retinyl acetate, acetic acid or cyclophosphamide on morphology of urinary bladders, the bladders were subjected to histopathological examination. We demonstrated that in rats subject to previous 5-minute bladder instillations with retinyl acetate, an increase of basal pressure, threshold pressure, micturition voiding pressure, bladder contraction duration, relaxation time, detrusor overactivity index, nonvoiding contraction frequency and amplitude occurs. On the other hand, a decrease in voided volume, post-void residual, volume threshold, voiding efficiency, intercontraction interval, bladder compliance and volume threshold to elicit nonvoiding contractions was observed. Administration of oxybutynin chloride (0.5mg/kg, i.v.) reversed changes of cystometric parameters evoked by retinyl acetate. Contrary to acetic acid and cyclophosphamide, bladders subjected to retinyl acetate infusion had no signs of bladder inflammation. The results obtained indicate that transient infusion of 0.75% retinyl acetate can induce detrusor overactivity, which is often observed in patients with overactive bladder syndrome (OAB). In addition, it was demonstrated that stimulating afferent C-fibres using retinyl acetate did not induce evident histopathological inflammatory lesions in the urinary bladder wall. It appears that in the future this model can prove useful in gaining more knowledge on the pathophysiology of OAB, and contribute to the preparation of new, more effective options of OAB pharmacotherapy.

Somatomotor and sensory urethral control of micturition in female rats.

In rats, axons of external urethral sphincter (EUS) motoneurons travel through the anastomotic branch of the pudendal nerve (ABPD) and anastomotic branch of the lumbosacral trunk (ABLT) and converge in the motor branch of the sacral plexus (MBSP). The aim of the present study was to determine in female rats the contribution of these somatomotor pathways and urethral sensory innervation from the dorsal nerve of the clitoris on urinary continence and voiding. EUS electromyographic (EMG) activity during cystometry, leak point pressure (LPP), and voiding efficiency (VE) were assessed in anesthetized virgin Sprague-Dawley female rats before and after transection of the above nerve branches. Transection of the MBSP eliminated EUS EMG, decreased LPP by 50%, and significantly reduced bladder contraction duration, peak pressure, intercontraction interval, and VE. Transection of the ABPD or ABLT decreased EUS EMG discharge and LPP by 25% but did not affect VE. Transection of the dorsal nerve of the clitoris did not affect LPP but reduced contraction duration, peak pressure, intercontraction interval, and VE. We conclude that somatomotor control of micturition is provided by the MBSP with axons travelling through the ABPD and ABLT. Partial somatomotor urethral denervation induces mild urinary incontinence, whereas partial afferent denervation induces voiding dysfunction. ABPD and ABLT pathways could represent a safeguard ensuring innervation to the EUS in case of upper nerve damage. Detailed knowledge of neuroanatomy and functional innervation of the urethra will enable more accurate animal models of neural development, disease, and dysfunction in the future.

Detrusor Underactivity and Detrusor Hyperactivity with Impaired Contractility

Detrusor underactivity (DU) is a condition of impaired bladder contraction strength or duration resulting in impaired bladder emptying. In contrast, detrusor hyperactivity with impaired contractility (DHIC) is a condition in which patients paradoxically exhibit detrusor overactivity during storage yet are unable to mount a sufficient detrusor contraction during voiding to completely empty the bladder. Both conditions are often mistaken for bladder outlet obstruction. These conditions are more commonly seen in institutionalized elderly patients with either urinary retention or incontinence. To date, the exact etiologies of DU and DHIC remain unclear. Accurate diagnosis is based on clinical suspicion, complete history and physical exam, and videourodynamic evaluation. However, in certain patients, such as frail elderly patients, a full workup may not be warranted if it will not influence treatment decisions. Treatment of these disorders is primarily based on patient bother, with behavior modification first implemented, followed by pharmacotherapy with addition of CIC or indwelling catheter as indicated.

Activation of P2Y6 receptors increases the voiding frequency in anaesthetized rats by releasing ATP from the bladder urothelium.

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

MP17-01 ACID-SENSING ION CHANNELS ARE INVOLVED IN AFFERENT EXCITATORY TRANSMISSION CONTROLLING REFLEX BLADDER ACTIVITY IN MICE

You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology1 Apr 2014MP17-01 ACID-SENSING ION CHANNELS ARE INVOLVED IN AFFERENT EXCITATORY TRANSMISSION CONTROLLING REFLEX BLADDER ACTIVITY IN MICE Mitsuharu Yoshiyama, Hideki Kobayashi, Isao Araki, and Masayuki Takeda Mitsuharu YoshiyamaMitsuharu Yoshiyama More articles by this author , Hideki KobayashiHideki Kobayashi More articles by this author , Isao ArakiIsao Araki More articles by this author , and Masayuki TakedaMasayuki Takeda More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.522AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Acid-sensing ion channels (ASICs) have been proposed as transducers of sensory stimuli. ASIC subunits mRNAs are largely expressed in the central nervous systems (CNS), the peripheral nervous system including dorsal root ganglia (DRG) that innervate the bladder, and the bladder (both mucosa and detrusor), suggesting the possibility that ASICs are involved in regulation of lower urinary tract (LUT) activity. In this study, we examined effects of A-317567, a non-amiloride blocker of ASICs, on activity of LUT with or without acid irritation. METHODS C57BL/6 female mice (12-13 week-old) were anesthetized with sevoflurane during surgery including precollicular decerebration. A PE-50 tube was inserted into the bladder dome to record intravesical pressure. Cystometrogram (CMG) recordings under unanesthetized conditions were performed by continuously infusing (30 μl/min) saline alone or saline followed by dilute acetic acid (A/A, pH 3). CMG parameters were: pressure threshold for inducing micturition (PT); maximal voiding pressure (MVP), bladder compliance (BCP), bladder contraction duration (BCD), and inter-contraction interval (ICI). A-317567 was infused intravesically (100 μM) or injected i.p. (30 mg/kg), and effects of the drug were compared with those of the vehicle. All values are expressed as mean ± S.E.M. For statistical analysis, two-way repeated measures ANOVA and Wilcoxon matched-pairs signed rank test were used, and P ≤ 0.05 was considered significant. RESULTS I.p. administration of A-317567 increased PT and ICI and decreased BCP during saline infusion CMG, whereas it produced no changes in MVP and BCD (Fig. 1A). The i.p. dose ameliorated bladder hyperactivity (i.e., exhibited as decreased ICI) induced by intravesical A/A perfusion (Fig. 1B). However, intravesical infusion of the drug had no effects on activity of the LUT either with or without acid irritation. Neither intravesical infusion nor i.p. injection of the vehicle produced significant effects on both normal LUT activity and A/A-induced bladder hyperactivity. CONCLUSIONS ASICs participate in afferent excitatory transmission controlling reflex bladder activity under conditions of the LUT either with or without acid irritation. ASICs in the DRG, the CNS or both, but not in the bladder, play the essential role. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e135-e136 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Mitsuharu Yoshiyama More articles by this author Hideki Kobayashi More articles by this author Isao Araki More articles by this author Masayuki Takeda More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

ATP released via pannexin-1 hemichannels mediates bladder overactivity triggered by urothelial P2Y6 receptors

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

The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice.

Diabetes is associated with both dysfunction of the lower urinary tract (LUT) and overactivity of the renin-angiotensin system (RAS). Although it is well known that the RAS affects normal LUT function, very little is known about RAS effects on the diabetic LUT. Accordingly, we investigated the effects of chronic angiotensin II (AngII) treatment on the LUT in a model of type 1 diabetes. Ins2(Akita) diabetic mice (20 weeks old) and their age-matched background controls underwent conscious cystometric evaluation after 4 weeks of chronic AngII treatment (700 ng/kg/min by osmotic pump) or vehicle (saline). Diabetic mice had compensated LUT function with bladder hypertrophy. Specifically, micturition volume, residual volume, and bladder capacity were all increased, while voiding efficiency and pressure generation were unchanged as bladder mass, contraction duration, and phasic urethral function were increased. AngII significantly increased voiding efficiency and peak voiding pressure and decreased phasic frequency irrespective of diabetic state and, in diabetic but not normoglycemic control mice, significantly decreased residual volume and increased contraction duration and nonphasic contraction duration. The Ins2(Akita) diabetic mice had compensated LUT function at 20 weeks of age. Even under these conditions, AngII had beneficial effects on LUT function, resulting in increased voiding efficiency. Future studies should therefore be conducted to determine whether AngII can rescue the decompensated LUT function occurring in end-stage diabetic uropathy.

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.

An animal study to compare the degree of the suppressive effects on the afferent pathways of micturition between tamsulosin and sildenafil

BackgroundTamsulosin, an α1-adrenoceptor antagonist, and sildenafil, a phosphodiesterase (PDE) inhibitor, are reported to improve lower urinary tract symptoms including overactive bladder (OAB). This study is aimed at investing the effects of tamsulosin and sildenafil and comparing the degree of the suppressive effects on the afferent pathways of micturition between them using an animal model of OAB, the spontaneously hypertensive rat (SHR).ResultsThe cystometric parameters, the basal pressure and duration of bladder contraction, were significantly increased in the SHR group as compared with the Wistar-Kyoto (WKY) group. The intercontraction interval also significantly decreased in the SHR group. In the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group, however, the basal pressure and duration were significantly reduced and the intercontraction interval was significantly prolonged. Moreover, the degree of the expression of c-Fos and NGF was significantly higher in the SHR group as compared with the WKY group. But it was significantly reduced in the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group. Furthermore, tamsulosin had a higher degree of effect as compared with sildenafil.ConclusionsIn conclusion, α1-adrenergic receptor antagonists and PDE-5 inhibitors may have an effect in improving the voiding functions through an inhibition of the neuronal activity in the afferent pathways of micturition.