Bladder Overactivity In Rats Research Articles

Transient receptor potential ankyrin 1 channels in the bladder mediate low temperature elicited bladder overactivity in rats.

This study aimed to investigate whether pathways involving transient receptor potential ankyrin 1 (TRPA1) channels in the urinary bladder mediate the bladder overactivity elicited by exposure to a low temperature in rats. At postnatal week 10, female Sprague-Dawley (SD) rats were intraperitoneally injected with the TRPA1 channel antagonist, HC030031, at room temperature (RT) and subsequently exposed to low temperature (LT). Bladder specimens treated with HC030031 were evaluated for contractions through cumulative addition of the TRPA1 channel agonist trans-cinnamaldehyde. Two days before cystometric investigation, small interfering RNA (siRNA) targeting TRPA1 was transfected into urinary bladders. Then, cystometric investigations were performed on rats subjected to TRPA1 siRNA transfection at both RT and LT. Expression of TRPA1 channels in the urinary bladder was assessed through immunohistochemistry and real-time reverse transcription-polymerase chain reaction. At RT, micturition patterns were unaffected by HC030031 treatment. However, upon exposure to LT, rats treated with HC030031 exhibited a reduction of LT-elicited bladder overactivity, as evidenced by inhibited decreases in voiding interval, micturition volume, and bladder capacity. Additionally, HC030031 inhibited trans-cinnamaldehyde-induced contractions. Immunohistochemical analysis showed the presence of TRPA1 channels in the urinary bladder. Notably, rats with TRPA1 siRNA-transfected bladders could partially inhibit bladder overactivity during LT exposure. These findings indicate that pathways involving TRPA1 channels expressed in the urinary bladder could mediate the LT-elicited bladder overactivity.

Caftaric Acid Ameliorates Oxidative Stress, Inflammation, and Bladder Overactivity in Rats Having Interstitial Cystitis: An In Silico Study.

Interstitial cystitis (IC) is the principal unwanted effect associated with the use of cyclophosphamide (CYP). It results in increased oxidative stress, overexpression of proinflammatory cytokines, and bladder overactivity. Patients receiving CYP treatment had severely depreciated quality of life, as the treatment available is not safe and effective. The goal of this study was to assess the protective effect of caftaric acid in CYP-induced IC. IC was induced in female Sprague Dawley by injecting CYP (150 mg/kg, i.p.). In the present study, oral administration of caftaric acid (20, 40, and 60 mg/kg) significantly decreased inflammation. Caftaric acid significantly increased SOD (93%), CAT (92%), and GSH (90%) while decreased iNOS (97%), IL-6 (90%), TGF 1-β (83%), and TNF-α (96%) compared to the diseased. DPPH assay showed the antioxidant capacity comparable to ascorbic acid. Molecular docking of caftaric acid with selected protein targets further confirmed its antioxidant and anti-inflammatory activities. The cyclophosphamide-induced bladder overactivity had been decreased possibly through the inhibition of M3 receptors, ATP-sensitive potassium channels, calcium channels, and COX enzyme by caftaric acid. Therefore, our findings demonstrate that caftaric acid has a considerable protective role against CYP-induced IC by decreasing the oxidative stress, inflammation, and bladder smooth muscle hyperexcitability. Thus, caftaric acid signifies a likely adjuvant agent in CYP-based chemotherapy treatments.

Activation of the adenosine A1 receptor in the lumbosacral spinal cord improves bladder overactivity in rats with cystitis induced by cyclophosphamide.

To investigate the effect of intrathecal administration of CCPA, an adenosine A1 receptor agonist, on voiding function in rats with cystitis induced by cyclophosphamide (CYP). Thirty 8-week-old Sprague Dawley rats were randomly divided into a control group (n = 15) and a cystitis group (n = 15). Cystitis was induced by a single intraperitoneal injection of CYP (200mg/kg, dissolved in physiological saline) in rats. Control rats were injected intraperitoneally with physiological saline. The PE10 catheter reached the level of L6-S1 spinal cord through L3-4 intervertebral space for intrathecal injection. Forty-eight hours after intraperitoneal injection, urodynamic tests were conducted to observe the effect of intrathecal administration of 10% dimethylsulfoxide (vehicle) and 1nmol CCPA on micturition parameters, including basal pressure (BP), threshold pressure (TP), maximal voiding pressure (MVP), intercontraction interval (ICI), voided volume (VV), residual volume (RV), bladder capacity (BC), and voiding efficiency (VE). Histological changes of the bladder of cystitis rats were studied through hematoxylin-eosin staining (HE staining). Moreover, Western blot and immunofluorescence were used to study the expression of adenosine A1 receptor in the L6-S1 dorsal spinal cord in both groups of rats. HE staining revealed submucosal hemorrhage, edema, and inflammatory cell infiltration in the bladder wall of cystitis rats. The urodynamic test showed significant increase in BP, TP, MVP and RV in cystitis rats, while ICI, VV, BC and VE decreased significantly, indicating bladder overactivity. CCPA inhibited the micturition reflex in both control and cystitis rats, and significantly increased TP, ICI, VV, BC, and VE, but had no significant effect on BP, MVP and RV. Western blot and immunofluorescence showed that there was no significant difference in the expression of adenosine A1 receptor in the L6-S1 dorsal spinal cord between the control and cystitis rats. The findings of this study suggest that intrathecal administration of the adenosine A1 receptor agonist CCPA alleviates CYP-induced bladder overactivity. Furthermore, our results indicate that the adenosine A1 receptor in the lumbosacral spinal cord may be a promising target for treatment of bladder overactivity.

Impaired insulin signaling at the bladder mucosa facilitates metabolic syndrome-associated bladder overactivity in rats with maternal and post-weaning fructose exposure

Metabolic syndrome (MetS) and overactive bladder might share common pathophysiologies. Environmental fructose exposure during pre- and postnatal periods of rats may program MetS-associated bladder overactivity. We explored the dysregulated insulin signalling at bladder mucosa, as a common mechanism, in facilitating bladder overactivity in rats with MetS induced by maternal and post-weaning fructose diet. Male offspring of Sprague-Dawley rats were subject into 4 groups by maternal and post-weaning diets (i.e., Control/Control, Fructose/Control, Control/Fructose and Fructose/Fructose by diets). Micturition behavior was evaluated. Acidic ATP solution was used to elicit cystometric reflex along with insulin counteraction. Concentration-response curves to insulin were plotted. The canonical signalling pathway of insulin was evaluated in the bladder mucosal using Western blotting. Levels of detrusor cGMP and urinary NO2 plus NO3 were measured. Male offspring with any fructose exposure presents traits of MetS and bladder overactivity. We observed all fructose exposure groups have the poor urodynamic response to insulin during ATP solution stimulation and poor insulin-activated detrusor relaxation in organ bath study. Compared to controls, the Control/Fructose and Fructose/Fructose groups showed the increased phosphorylation levels of IRS1 (Ser307) and IRS2 (Ser731); thus, suppressed the downstream effectors and urinary NOx/detrusor cGMP levels. The Fructose/Control group showed the compensatory increase of phospho-AKT (Ser473) and phospho-eNOS/eNOS levels, but decreased in eNOS, phospho-eNOS, urinary NOx, and detrusor cGMP levels. Our results show dysregulated insulin signalling at bladder mucosa should be a common mechanism of MetS-associated bladder overactivity programmed by pre-and postnatal fructose diet.

Estrogen inhibits bladder overactivity in rats with cyclophosphamide-induced cystitis via downregulating the expression of P2X3 receptors in bladder epithelium cells.

The therapeutic effect of estrogen on interstitial cystitis/bladder pain syndrome is unclear. We aim to explore the effect of estrogen on bladder overactivity in rats with cyclophosphamide-induced cystitis and its underlying mechanism. In vivo cystometry was used to determine the effect of estrogen on bladder excitability. The effect of estrogen on the expression of P2X3 receptors in bladder epithelium was detected by real-time polymerase chain reaction and western blot. Effect of P2X3 receptors in bladder urothelium on stretch-released adenosine triphosphate was performed by a Flexcell FX5000 Compression system and an Enzyme-Linked Immunosorbent Assay Kit. Estrogen deprivation significantly increased the urinary frequency, while supplementation with diarylpropionitrile (DPN), an estrogen receptor β (ERβ) agonist, alleviated the urinary frequency. 17β-Estradiol and DPN decreased the expression of P2X3 receptors in urothelium cells which was partially inhibited by ERβ antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol. Meanwhile, inhibiting the expression of P2X3 receptors by ERβ agonist or antagonizing the function of P2X3 receptors by selective P2X3 receptor antagonist AF-353 or A-317491 significantly reduced the stretch-released ATP from urothelium cells. Estrogen has a direct effect on the regulation of bladder overactivity in rats with cyclophosphamide-induced cystitis by downregulating the expression of bladder epithelial P2X3 receptors through ERβ and reducing the adenosine triphosphate released from urothelium during bladder filling, thereby inhibiting the generation of the micturition reflex.

Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.

The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.

Ba-Wei-Die-Huang-Wan (Hachimi-jio-gan) can ameliorate ketamine-induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model.

We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-β1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.

Modulation of urinary frequency via type 1 lysophosphatidic acid receptors: Effect of the novel antagonist ASP6432 in conscious rats

Bladder dysfunctions associated with benign prostatic hyperplasia are not sufficiently alleviated by current pharmacotherapies. Lysophosphatidic acid (LPA) is a phospholipid with diverse biological effects. LPA modulates prostate and urethral contraction via the type 1 LPA (LPA1) receptor, suggesting the potential of the LPA1 receptor as a therapeutic target. However, the role of LPA and the LPA1 receptor in bladder function has not been studied in vivo. We investigated the effects of LPA and the novel LPA1 receptor antagonist ASP6432 (potassium 1-(2-{[3,5-dimethoxy-4-methyl-N-(3-phenylpropyl)benzamido]methyl}− 1,3-thiazole-4-carbonyl)− 3-ethyl-2,2-dioxo-2λ6-diazathian-1-ide) on the micturition reflex in conscious rats using cystometry. Intravenous infusion of LPA decreased the micturition interval and threshold pressure with no apparent changes in baseline pressure or maximum intravesical pressure. ASP6432 inhibited the LPA-induced decrease in MI. In contrast, ASP6432 had no effect on the LPA-induced decrease in threshold pressure. Similarly, ASP6432 had no effect on either baseline pressure or maximum intravesical pressure. We also evaluated the effect of ASP6432 on the urinary frequency induced by the nitric oxide synthase inhibitor L-Nω-nitro arginine methyl ester (L-NAME). Intravenous L-NAME administration decreased the micturition interval. ASP6432 dose-dependently reversed the L-NAME-induced decrease in micturition interval. Our findings demonstrate for the first time that LPA causes bladder overactivity in rats. ASP6432 inhibited the LPA- and L-NAME-induced decrease in micturition interval, suggesting a significant role for the LPA1 receptor in regulating the functional capacity of the bladder. Our results also suggest the potential of ASP6432 as a novel therapy for the treatment of bladder dysfunction associated with lower urinary tract diseases.

Effects of intravesical administration of sensory neuron-specific receptor agonist on voiding function in rats with cyclophosphamide-induced cystitis

IntroductionThe aim of this study was to investigate the urodynamic effects of intravesical administration of bovine adrenal medulla 8-22 (BAM8-22), a selective rat sensory neuron-specific receptor 1 agonist, on the micturition reflex in normal rats and rats with cyclophosphamide-induced bladder overactivity.Material and methodsContinuous cystometrograms (0.04 ml/min) were performed in urethane-anesthetized rats. After stable micturition cycles were established, vehicle (saline) or BAM8-22 was instilled intravesically and changes in bladder activity were monitored. The experiments using BAM8-22 were also performed in capsaicin-pretreated rats. In another experiment, vehicle (saline) or BAM8-22 was instilled intravesically and changes in bladder activity were monitored in cyclophosphamide-treated rats. Continuous cystometrograms were performed 48 hours after cyclophosphamide injection. Cystometric parameters were recorded and compared before and after intravesical drug administration.ResultsIntravesical administration of BAM8-22 significantly increased the intercontraction interval and threshold pressure in urethane-anesthetized rats, but did not affect the basal pressure or maximum pressure at any doses tested. The inhibitory effects of intravesical administration of BAM8-22 were not inhibited by capsaicin pretreatment. Intravesical administration of BAM8-22 also significantly increased intercontraction interval in the cyclophosphamide-treated rats.ConclusionsThe current results indicate that intravesical administration of a selective rat sensory neuron-specific receptor 1 agonist can inhibit the micturition reflex and can ameliorate cyclophosphamide-induced bladder overactivity in rats.

MP25-05 ENHANCED BLADDER PAIN SENSITIVITY DUE TO THE PROSTATE-TO-BLADDER AFFERENT CROSS SENSITIZATION IN A RAT MODEL OF PROSTATITIS

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Prostate & Genitalia1 Apr 2015MP25-05 ENHANCED BLADDER PAIN SENSITIVITY DUE TO THE PROSTATE-TO-BLADDER AFFERENT CROSS SENSITIZATION IN A RAT MODEL OF PROSTATITIS Tsuyoshi Majima, Yasuhito Funahashi, Katsumi Kadekawa, Momokazu Gotoh, and Naoki Yoshimura Tsuyoshi MajimaTsuyoshi Majima More articles by this author , Yasuhito FunahashiYasuhito Funahashi More articles by this author , Katsumi KadekawaKatsumi Kadekawa More articles by this author , Momokazu GotohMomokazu Gotoh More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1208AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In chronic pelvic pain syndrome/chronic prostatitis (CPPS/CP), patients suffer from pelvic pain derived not only from the prostate, but also from the lower urinary tract (LUT). However, the mechanisms remain unclear; therefore, we investigated whether prostatic inflammation induced enhanced pain sensitivity in the LUT and bladder overactivity using a rat model of prostatitis. METHODS Adult Male SD rats were divided into two groups; control and prostatitis groups. (1) Formalin was injected into the prostate in the prostatitis group, while saline was injected in the control group. The rats were placed in metabolic cages to evaluate the voiding behavior 1 week after injection. Cystometry was also performed 1 week after injection to measure intercontraction intervals (ICI) of the voiding reflex. (2) Resiniferatoxin (RTx) was instilled into the bladder to evaluate nociceptive behavior such as licking behavior (urethral pain) and freezing behavior (bladder pain) at 1 week after injection. (3) Organ-specific afferent neurons were labelled by retrograde axonal transport of fluorescent dyes, Fast Blue (FB) or DiI, injected into the bladder wall or the prostate, respectively. Dye-labelled afferent neurons in S1 DRG were dissected using laser-capture microdissection method, and mRNA levels of TRP and ATP receptors were measured by real-time RT-PCR. RESULTS 1) In the metabolic cage study, the average micturition volume was decreased significantly in prostatitis rats (n=6) (0.46 ± 0.08 to 0.33 ± 0.07 mL, p = 0.005) without changes in control rats (n=6)(0.42 ± 0.03 to 0.41 ± 0.03 mL). In cystometry, the average ICI was significantly shorter in prostatitis rats (n=7) than in control (n=6) (791 ± 139 vs 1175 ± 146 sec, p = 0.026). (2) There were no significant differences in licking events between two groups (n=6, each group). However, the number of freezing events during 10-15mins after RTx administration into the bladder was significantly (p=0.01) increased in the prostatitis group than in the control group (20±1 and 11±2, respectively). (3) TRPV1, TRPA1 and P2X2 mRNA were increased in not only prostate-innervating DiI-labeled neurons, but also double-labeled neurons and FB-labeled bladder neurons from prostatitis rats compared to control rats CONCLUSIONS These results indicate that prostatic inflammation enhances pain sensitivity of the bladder and induces bladder overactivity in rats, as often seen in patients with CPPS/CP. Also, the prostate-to-bladder afferent cross-sensitization could be a mechanism underlying pelvic pain symptoms in CPPS/CP. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e286 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tsuyoshi Majima More articles by this author Yasuhito Funahashi More articles by this author Katsumi Kadekawa More articles by this author Momokazu Gotoh More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

1089 The urodynamic effects of intravesical administration of sensory neuron-specific receptor agonist on cyclophosphamide-induced bladder overactivity in rats

1089 The urodynamic effects of intravesical administration of sensory neuron-specific receptor agonist on cyclophosphamide-induced bladder overactivity in rats

Effects of sensory neuron-specific receptor agonist on bladder function in a rat model of cystitis induced by cyclophosphamide.

To investigate the effects of activation of sensory neuron-specific receptors (SNSRs) on cyclophosphamide (CYP) bladder overactivity in rats. Female Sprague-Dawley rats (235-258 g) were used. Rats were injected with either CYP (200 mg/kg, intraperitoneally) or saline (control). Continuous cystometrograms (0.04 ml/min) were recorded 48 h after CYP or saline injection under urethane anesthesia. After stable micturition cycles were established, a selective rat SNSR1 agonist, bovine adrenal medulla 8-22 (BAM8-22), was administered intravenously or intrathecally. Cyclophosphamide treatment-induced higher baseline pressure and shorter intercontraction intervals compared with the control group. Intravenous administration of BAM8-22 at 10, 30 and 100 μg/kg significantly increased intercontraction intervals in the CYP-treated group. Intrathecal administration of BAM8-22 at 0.03, 0.1 and 0.3 μg also significantly increased intercontraction intervals in the CYP-treated group. Intravenous or intrathecal administration of BAM8-22 did not change baseline pressure or maximum voiding pressure in the CYP-treated group. These findings indicate that activation of SNSRs can suppress CYP-induced bladder overactivity, probably due to suppression of bladder afferent activity.

Inhibition of Peripheral FAAH Depresses Activities of Bladder Mechanosensitive Nerve Fibers of the Rat

FAAH degrades endocannabinoids and fatty acid amides. FAAH inhibition reduces micturition frequency and counteracts bladder overactivity in rats. We studied the effects of the peripherally active selective FAAH inhibitor URB937, and the CB1 and CB2 receptor antagonists rimonabant and SR144528, respectively, on single unit afferent activity of primary bladder afferents in rats. Female Sprague Dawley® rats were anesthetized. Single unit afferent activity of Aδ or C-fibers from the L6 dorsal roots was recorded during bladder filling before and after URB937 administration with or without rimonabant or SR144528. Drugs (1 mg/kg) were given intravenously. FAAH, CB1 and CB2 expression, and expression of the sensory marker CGRP inthe L6 dorsal root ganglion were compared by immunofluorescence. A total of 102 single afferent fibers (48 Aδ and 54 C-fibers) were isolated from 57 rats. URB937 decreased single unit afferent activity of C-fibers to a mean ± SEM of 78% ± 9% and of Aδ-fibers to a mean of 67% ± 7% while increasing bladder compliance to a mean of 116% ± 3%. The effects of URB937 on single unit afferent activity and bladder compliance were counteracted by rimonabant or SR144528. Rimonabant increased single unit afferent activity ofeach fiber type but SR144528 affected only Aδ-fiber activity. CGRP positive L6dorsal root ganglion neurons showed strong FAAH, CB1 and CB2 staining. To our knowledge we report for the first time that inhibiting peripheral FAAH depresses the Aδ and C-fiber activity of primary bladder afferents via CB1 and CB2 receptors. CB antagonists alone exerted facilitatory effects on single unit afferent activity during bladder filling in rats. The endocannabinoid system may be involved in physiological control of micturition as regulators of afferent signals.

Discovery of potent transient receptor potential vanilloid 1 antagonists: Design and synthesis of phenoxyacetamide derivatives

We aimed to discover a novel type of transient receptor potential vanilloid 1 (TRPV1) antagonist because such antagonists are possible drug candidates for treating various disorders. We modified the structure of hit compound 7 (human TRPV1 IC50=411nM) and converted its pyrrolidino group to a (hydroxyethyl)methylamino group, which substantially improved inhibitory activity (15d; human TRPV1 IC50=33nM). In addition, 15d ameliorated bladder overactivity in rats in vivo.

443 Inhibition of spinal cord fatty acid amide hydrolase reduces bladder overactivity in rats

443 Inhibition of spinal cord fatty acid amide hydrolase reduces bladder overactivity in rats

Mechanisms and urodynamic effects of a potent and selective EP4 receptor antagonist, MF191, on cyclophosphamide and prostaglandin E2‐induced bladder overactivity in rats

To investigate the mechanisms and urodynamic effects of a potent and selective prostaglandin E(2) (PGE(2)) receptor subtype 4 (EP4) antagonist, MF191, on cyclophosphamide (CYP) or PGE(2)-induced bladder overactivity in rats. Experimental and control rats were injected with CYP (200 mg/kg i.p.) or saline on day 1. Continuous cystometrogram (CMGs) were performed on day 3. In group 1, MF191 (vehicle 0.1 and 1 mg/kg) was given i.v. The bladder was then harvested for histology and immunohistochemistry. Some bladders were harvested for analysis of EP4 expression by Western blotting without a CMG study. In group 2, MF191 (vehicle 10 nM, and 100 nM) was continuously infused into the bladder. In group 3, bladder overactivity was induced by intravesical instillation of PGE(2) (200 uM) and vehicle or MF191 (1 mg/kg) was given i.v. CYP induced bladder inflammation, overactivity and EP4 upregulation. The CYP effects were suppressed by MF191 (1 mg/kg i.v.; intercontraction interval [ICI]: 39.4% increase, and reduced inflammatory cells infiltration, and EP4 expression). Intravesical instillation of MF191 (100 nM) suppressed CYP-induced bladder overactivity (ICI: 71.8% increase). PGE(2)-induced bladder overactivity was suppressed by MF191 (ICI: 43.2% increase). MF191 had no significant effects on other CMG variables or on control rats. MF191 might affect the bladder urothelium and inflammatory cells and suppresses CYP- or PGE(2)-induced bladder overactivity. Systemic or intravesical MF191 administration for the treatment of overactive bladder merits clinical study.

Suppression of Bladder Overactivity by Adenosine A2A Receptor Antagonist in a Rat Model of Parkinson Disease

Overactive bladder is highly prevalent among patients with Parkinson disease. Adenosine is an important neurotransmitter in the central nervous system but it is not fully clarified how adenosine receptors regulate the micturition reflex. Thus, we examined the effect of an adenosine A2A receptor antagonist on the micturition reflex in a rat model of Parkinson disease. In a rat model of Parkinson disease induced by 6-hydroxydopamine (Tocris Bioscience, Ellisville, Missouri) injection we examined the effects of the adenosine A2A receptor antagonist ZM241385, the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole on bladder activity. Intravenous administration of ZM241385 increased the intercontraction interval in a dose dependent manner in rats with Parkinson disease and sham operated rats but the inhibitory effect was greater in the Parkinson disease group. Intrathecal and intracerebroventricular administration of ZM241385 increased the intercontraction interval in each group. However, in rats with Parkinson disease the inhibitory effects induced by intracerebroventricular administration of ZM241385 were greater than in sham operated rats. Intravenous administration of SKF38393 increased the intercontraction interval in rats with Parkinson disease and subsequent administration of ZM further increased the intercontraction interval. However, SKF38393 did not increase the intercontraction interval after ZM241385 application. Also, ZM241385 increased the intercontraction interval without being affected by pre-administration or post-administration of quinpirole, which decreased the intercontraction interval. Results indicate that the adenosine A2A receptor mediated excitatory mechanism is enhanced at a supraspinal site to induce bladder overactivity and A2A receptor inhibition effectively suppresses bladder overactivity in rats with Parkinson disease. Thus, adenosine A2A receptor antagonists could be useful for bladder dysfunction in Parkinson disease cases.

365 TRPV1 and TRPV4 antagonists have synergistic effect for treating bladder overactivity in rats

365 TRPV1 and TRPV4 antagonists have synergistic effect for treating bladder overactivity in rats

Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder

The anticonvulsant retigabine has previously been reported to inhibit bladder overactivity in rats in vivo but the mechanism and site of action are not known. In the present study we investigated the effect of retigabine in isolated rat bladder tissue. Bladders from Sprague–Dawley rats were cut transversally into rings and mounted on an isometric myograph. The average tension, the amplitude and frequency of bladder muscle twitches were measured. The bladder tissue was stimulated with carbachol, KCl (5, 10 and 60 mM), and by electric field stimulation. Dose–response curves were obtained with increasing concentrations of the KCNQ (2–5) selective positive modulator, retigabine or with the KCNQ (1–5) negative modulator XE991. Retigabine experiments were repeated in the presence of 10 µM XE991. Retigabine reduced both the contractility and the overall tonus of bladder tissue independent of the mode of stimulation with EC 50 values ranging from 3.3 µM (20 mM KCl) to 8.3 µM (0.2 µM carbachol). In support of a KCNQ-specific effect, retigabine had only weak effects after 60 mM KCl pre treatment and all retigabine effects could be reversed by XE991. XE991 increased both the amplitude and mean tension of the bladder but was more potent at increasing the number rather than the size of the stimulated twitches. In conclusion, this study demonstrates an efficacious KCNQ dependent effect of retigabine and XE991 on rat bladder contractility.

1684 EFFECT OF ADENOSINE A 2A RECEPTOR ANTAGONIST ON BLADDER OVERACTIVITY IN RATS WITH CHEMICAL CYSTITIS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Non-Neurogenic Voiding Dysfunction II1 Apr 20101684 EFFECT OF ADENOSINE A2A RECEPTOR ANTAGONIST ON BLADDER OVERACTIVITY IN RATS WITH CHEMICAL CYSTITIS Takeya Kitta, Katsuya Nonomura, and Naoki Yoshimura Takeya KittaTakeya Kitta Pittsburgh, PA More articles by this author , Katsuya NonomuraKatsuya Nonomura Hokkaido, Japan 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.2010.02.1509AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Adenosine is an endogenous neurotransmitter that exerts numerous physiological effects in many organs. Moreover, there is increasing evidence showing therapeutic potentials of adenosine receptor modulation in various disease conditions such as pain. In this study, we examined the effect of adenosine A2A receptor antagonists on bladder activity in normal and cystitis rats. METHODS Female Sprague-Dawley rats were used. Continuous cystometrograms during saline or 0.2% acetic acid (AA) infusion (0.04ml/min) were recorded under urethane anesthesia. After a stabilization period, ZM24138 (ZM, adenosine A2A receptor antagonist) was administered intravenously (iv, 1 mg/kg), intrathecally (it, 10 μg), intracerebroventricularly (icv, 10 μg) or intravesically (after urothelial permeability was increased by DMSO retained in the bladder for 30 min). Micturition parameters (intercontraction interval [ICI] and maximum voiding pressure [MVP]) were recorded and compared pre and post-drug administration. RESULTS In comparison to saline infusion, AA significantly reduced ICI by 67.8%. Intravesical administration of ZM did not change any parameters. However, iv, it or icv administration of ZM significantly increased ICI in both saline and AA infusion groups while no change was detected in MVP. Moreover, during AA infusion, the inhibitory effects induced by iv and it ZM administration were significantly greater than those during saline infusion (post-ZM ICI increase: 103.1±25.2 vs. 26.6±10.0% and 203.4±40.9 vs. 98.5±26.4%, respectively) (Figure). CONCLUSIONS During saline or AA infusion, the A2A antagonist increased ICI without affecting MVP, suggesting an action on bladder afferent rather than efferent pathways. Because the inhibitory effect of iv or it A2A antagonist was enhanced after AA infusion, which induces bladder overactivity mainly due to C-fiber bladder afferent activation, the A2A receptor mediated adenosinergic mechanism in the spinal cord might be enhanced following C-fiber afferent stimulation. Thus adenosine A2A antagonists could be effective for the treatment of overactive bladder and/or bladder hypersensitive disorders such as BPS/IC. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e651 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeya Kitta Pittsburgh, PA More articles by this author Katsuya Nonomura Hokkaido, Japan More articles by this author Naoki Yoshimura Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...