Amplitude Of Non-voiding Contractions Research Articles

The intracerebroventricular injection of lipopolysaccharide may induce neurogenic detrusor overactivity symptoms in mice.

We aimed to explore if the intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS) was able to evoke the cognitive and locomotive impairment and detrusor overactivity (DO) symptoms in mice. This study compared the bladder function of mice that received the i.c.v. injection of LPS or saline. Specifically, basal pressure (BP), threshold pressure (TP), micturition pressure (MP), bladder capacity (BC), micturition volume (MV), bladder compliance (COM), frequency of micturition (MF), detrusor overactive index (DOI), frequency of non-voiding contractions (FNVCs), and amplitude of non-voiding contractions (ANVCs) were assessed by cystometry. The spontaneous voiding spot assay (VSA) was exerted to further assess the micturition patterns of mice. The Morris water maze (MWM) and the open field test (OFT) were used to detect the cognition and locomotive behaviors, respectively. Hematoxylin and eosin staining was conducted to evaluate the changes in morphology and histology of mice. The extent of injury in the prefrontal cortex was tested by using Nissl staining. The LPS-treated mice exhibited evidently DOcharacterized by the increase of MF, FNVCs, ANVCs, and DOI and the decrease of BC. The VSA further suggested that LPS induced urinary frequency and urinary incontinence in mice. Furthermore, neither signs of bladder inflammation nor the damage of bladder smooth muscle and urothelium in LPS-exposed mice was observed. LPS induced deficits in spatial learning, memory, and locomotor activity in mice. Neuronal cells in the prefrontal cortex were obviously lost in the LPS-treated mice. Acute neuroinflammation induced the cognitive and locomotive impairment and the neurogenic overactive bladder (NOAB) symptoms in mice. This novel animal model may contribute to further study the mechanisms of NOAB in neurodegenerative patients and assess the novel therapeutic strategies in the future.

Blebbistatin reveals beneficial effects on the cystometric parameters in an animal model of detrusor overactivity

The aims of the study were to determine the effectiveness of blebbistatin (BLEB) on detrusor overactivity (DO) in an animal model induced by retinyl acetate (RA) and, because of potential urothelial permeability, to evaluate the degenerative impact of BLEB on the urothelium. Three days after RA instillation into the urinary bladder, BLEB was administered into the bladder and immediately after cystometric assessment was performed. Furthermore, Evans Blue extravasation into bladder tissue and urothelium thickness were measured. Sixty female Wistar rats were used and randomly assigned to one of four groups (n = 15 in each group): (1) control, (2) RA, (3) BLEB, and (4) RA + BLEB. RA administration induced changes in cystometric parameters reflecting DO, as previously reported. Treatment with BLEB did not significantly alter cystometric parameters in rats which did not receive RA. Administration of BLEB to rats pretreated with RA reversed changes in cystometric parameters induced by RA in basal pressure, threshold pressure, detrusor overactivity index, amplitude of nonvoiding contractions, frequency of nonvoiding contractions, voided volume, volume threshold, intercontraction interval, bladder compliance, and volume threshold to elicit nonvoiding contractions. There were no significant differences in Evans Blue extravasation into bladder tissue or urothelium thickness between the groups. The current research provides new data on the possible utility of blebbistatin in the pharmacotherapy of DO, which is an important feature of overactive bladder (OAB). Further studies in human patients with DO/OAB are warranted to confirm these preclinical results.

Effects of cathodal trans-spinal direct current stimulation on lower urinary tract function in normal and spinal cord injury mice with overactive bladder

Objective. Lower urinary tract (LUT) dysfunction is a monumental problem affecting quality of life following neurotrauma, such as spinal cord injury (SCI). Proper function of the bladder and its associated structures depends on coordinated activity of the neuronal circuitry in the spinal cord and brain. Disconnection between the spinal and brain centers controlling the LUT causes fundamental changes in the mechanisms involved in the micturition and storage reflexes. We investigated the effects of cathodal trans-spinal direct current stimulation (c-tsDCS) of the lumbosacral spine on bladder and external urinary sphincter (EUS) functions. Approach. We used cystometry and electromyography (EMG), in mice with and without SCI. Main results. c-tsDCS caused initiation of the micturition reflex in urethane-anesthetized normal mice with depressed micturition reflexes. This effect was associated with normalized EUS-EMG activity. Moreover, in urethane-anesthetized normal mice with expressed micturition reflexes, c-tsDCS increased the firing frequency, amplitude, and duration of EUS-EMG activity. These effects were associated with increased maximum intravesical pressure (Pmax) and intercontraction interval (ICI). In conscious normal animals, c-tsDCS caused significant increases in Pmax, ICI, threshold pressure (Pthres), baseline pressure (Pbase), and number and amplitude of non-voiding contractions (NVCnumb and Pim, respectively). In conscious mice with severe contusive SCI and overactive bladder, c-tsDCS increased Pmax, ICI, and Pthres, but decreased Pbase, NVCnumb, and Pim. c-tsDCS reduced the detrusor-overactivity/cystometry ratio, which is a measure of bladder overactivity associated with renal deterioration. Significance. These results indicate that c-tsDCS induces robust modulation of the lumbosacral spinal-cord circuitry that controls the LUT.

AB321. SPR-48 The effects of myrbetriq on detrusor overactivity associated with suprasacral spinal cord injury (SCI) in rats

Objectiveβ3-adrenoceptor agonists (BARA) represent a novel mechanism of action for direct relaxation of urinary bladder smooth muscle. Myrbetriq (MYR) is an FDA approved BARA developed by Astellas Pharma, and has proven to be very useful for treating overactive bladder. Preliminary data from this laboratory demonstrated a remarkable effect of a rat-specific BARA, CL-316,243 (CL), on the hallmark attributes of neurogenic bladder subsequent to spinal cord injury (SCI). This included an increase in true bladder capacity (TBC), a decrease in the number and amplitude of non-voiding contractions (NVC) and an increased filling compliance (C). The current report reflects a formalized preclinical study of both the rat specific BARA, CL, and MYR, in order to provide preclinical support for utilization of MYR in treating SCI patients with neurogenic detrusor overactivity.MethodsFemale rats (4 weeks post-SCI at T9–10, n=43, 10–11/group) were anesthetized with isoflurane and fitted with femoral vein, ureteral diversion and transvesical catheters. The animals were mounted in Ballman restraint cages to which they had been previously acclimated. Conscious cystometry was performed before and after 3 repeated vehicles (Veh 1–3) and 3 escalating 1/2 log doses of either CL or MYR, and their paired repeated vehicle controls (Veh 4–6) at 30-minute intervals. See figure for testing scheme protocol. Data were analyzed using ANOVA with repeated measures. P<0.05 was considered significant.ResultsBoth CL and MYR significantly increased TBC and NVC count, MYR decreased maximal NVC amplitude, and CL increased C, relative to their respective repeated vehicle controls.ConclusionsThe results of these studies support the use BARA for the treatment of NDO secondary to SCI, as at least one of the drugs tested was able to distinguish themselves from their repeated vehicle control groups as having a positive effect for each of the four measures.Funding Source(s)an IIR grant from Astellas

Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia and urinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis

The aim of this study was to investigate the involvement of the transient receptor potential ankyrin 1 (TRPA1) in haemorrhagic cystitis, the main side effect of cyclophosphamide-based chemotherapy. Hannover female rats received intraperitoneal (i.p.) injection of cyclophosphamide (three doses of 100mg/kg, every other day, in a total of five days). This treatment was followed by the treatment with TRPA1 antagonist HC 030031 (50mg/kg, p.o.). The threshold for hindpaw withdrawal or abdominal retraction to von Frey Hair and the locomotor activity were measured. The treatment with the TRPA1 antagonist HC 030031 significantly decreased mechanical hyperalgesia induced by cyclophosphamide without interfere with locomotor activity. Urodynamic parameters were performed by cystometry 24h after a single treatment with cyclophosphamide (200mg/kg, i.p.) in control and HC 030031 treated rats. Analyses of the urodynamic parameters showed that a single dose of cyclophosphamide was enough to significantly increase the number and amplitude of non-voiding contractions and to decrease the voided volume and voiding efficiency, without significantly altering basal, threshold or maximum pressure. The treatment with HC 030031 either before (100mg/kg, p.o.) or after (30mg/kg, i.v.) cyclophosphamide inhibited the non-voiding contractions but failed to counteract the loss in voiding efficiency. Our data demonstrates that nociceptive symptoms and urinary bladder overactivity caused by cyclophosphamide, in part, are dependent upon the activation of TRPA1. In this context, the antagonism of the receptor may be an alternative to minimise the urotoxic symptoms caused by this chemotherapeutic agent.

Effect of mirabegron, a novel β3-adrenoceptor agonist, on bladder function during storage phase in rats

Mirabegron, a selective β(3)-adrenoceptor agonist, facilitates urine storage function by exerting a relaxing effect on bladder smooth muscle. Here, we investigated the effect of mirabegron on bladder function during the storage phase. We assessed the effect of mirabegron on the resting intravesical pressure in anesthetized rats and also tested antimuscarinics (oxybutynin and tolterodine) under the same experimental conditions. Mirabegron dose-dependently decreased the resting intravesical pressure, while oxybutynin and tolterodine showed no statistically significant effects on resting intravesical pressure. We also investigated the effect of mirabegron on bladder function using cystometry technique in conscious rats with bladder outlet obstruction. While mirabegron dose-dependently decreased the frequency of nonvoiding contractions, considered an index of abnormal response in bladder storage, no significant effects were noted on the amplitude of nonvoiding contractions, micturition pressure, threshold pressure, voided volume, residual volume, or bladder capacity. Neither oxybutynin nor tolterodine affected the frequency of nonvoiding contractions; however, oxybutynin increased residual volume and tended to decrease voided volume in a dose-dependent manner, and tolterodine dose-dependently decreased voided volume. Taken together, these results shed light on the suggestion of mirabegron as a therapeutic agent, compared with antimuscarinics, with its most prominent effect being the facilitation of bladder storage.

1646 EFFECT OF A SELECTIVE β3-ADRENERGIC AGONIST (CL-316,243) ON CYSTOMETRIC PARAMETERS IN CONSCIOUS NORMAL AND SPINAL CORD INJURED FEMALE RATS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Neurogenic Voiding Dysfunction1 Apr 20121646 EFFECT OF A SELECTIVE β3-ADRENERGIC AGONIST (CL-316,243) ON CYSTOMETRIC PARAMETERS IN CONSCIOUS NORMAL AND SPINAL CORD INJURED FEMALE RATS Jean-Baptiste Beauval, Veronique Guilloteau, Monica Capellini, Marc Guerard, Timothy D. Westfall, Xavier Gamé, Stefano Palea, and Philippe Lluel Jean-Baptiste BeauvalJean-Baptiste Beauval Toulouse, France More articles by this author , Veronique GuilloteauVeronique Guilloteau Toulouse, France More articles by this author , Monica CapelliniMonica Capellini Toulouse, France More articles by this author , Marc GuerardMarc Guerard Toulouse, France More articles by this author , Timothy D. WestfallTimothy D. Westfall Toulouse, France More articles by this author , Xavier GaméXavier Gamé Toulouse, France More articles by this author , Stefano PaleaStefano Palea Toulouse, France More articles by this author , and Philippe LluelPhilippe Lluel Toulouse, France More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1478AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In rats with detrusor overactivity secondary to bladder outlet obstruction, β3-adrenergic agonists were shown to increase bladder capacity and decrease non-voiding contractions (NVC). The aim of this study was to determine the effect of CL-316,243 (CL) a selective β3-adrenergic agonist on cystometric parameters in conscious normal rats and to evaluate its effects in a model of bladder overactivity in conscious female rats after spinal cord injury (SCI). METHODS Adult female Wistar rats were used. Cystometry was performed in two different sets of experiments, one in conscious normal animals and the other in conscious rats after SCI at the T8 level for 5 weeks (or sham). Briefly, under anesthesia the jugular vein and urinary bladder were catheterized. 2 days later the bladder was continuously infused with saline. After stabilization (basal cystomeric values), vehicle or CL were administered intravenously. Then, intravesical pressure was recorded for 1 hour. Micturition frequency (MF), intercontraction interval (ICI) and amplitude of micturition (AM) were analyzed and averaged for the 60 min period post-administration. For each parameter, results were compared to baseline. CL was tested at 0.01, 0.03 and 0.1 mg/kg in normal rats and at 0.01 mg/kg in rats with SCI. RESULTS Normal rats. CL significantly increased ICI and decreased MF in a dose dependent manner (-39±4, -46±5, -50±6% at 0.01, 0.03 and 0.1 mg/kg, respectively). No effect on AM was observed with low doses of CL (0.01 and 0.03 mg/kg), while at the highest dose (0.1 mg/kg) AM was significantly decreased (-19±6%). SCI rats. In comparison to sham, SCI rats presented with increased ICI (475±38 vs. 318±53 sec, p=0.025), decreased MF (4±0.3 vs. 8±1.4 pics/30 min, p=0.024), increased AM (p=0.0004) and increased bladder weight (435±39 vs. 147±6 g, p<0.0001). During the filling phase NVCs were also observed. CL (0.01 mg/kg) significantly increased ICI in sham and SCI rats (42±17% and 49±17%, respectively). MF was significantly reduced by 38±10% in SCI rats (p=0.007) while no effect on AM was observed in either group. At this dose, CL specifically reduced the frequency (-53±14%) but not the amplitude of NVCs. CONCLUSIONS This is the first demonstration that stimulation of β3-adrenoceptors produces a decrease in MF and NVCs in SCI rats. These effects are observed at low doses without deleterious effects on AM. Our results suggest that β3-adrenergic agonists could be useful for the treatment of neurogenic bladder overactivity. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e665 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jean-Baptiste Beauval Toulouse, France More articles by this author Veronique Guilloteau Toulouse, France More articles by this author Monica Capellini Toulouse, France More articles by this author Marc Guerard Toulouse, France More articles by this author Timothy D. Westfall Toulouse, France More articles by this author Xavier Gamé Toulouse, France More articles by this author Stefano Palea Toulouse, France More articles by this author Philippe Lluel Toulouse, France More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Nonvoiding Activity of the Guinea Pig Bladder

Detrusor nonvoiding contractions occur in up to 70% of healthy individuals. These contractions increase in those with pathological detrusor function and may be associated with afferent activity. We examined nonvoiding contractions in the urethane anesthetized guinea pig bladder and studied the effect of filling rate and intravesical volume. A total of 14 guinea pigs were anesthetized and underwent bladder catheterization at the dome. In 6 guinea pigs bladder infusion was continuous and 2 physiological filling rates were used, including 25 (0.75 HD) and 50 μl per minute (1.5 HD). In another 8 guinea pigs isovolumetric cystometry was done by filling the bladder incrementally and recording at low, medium and high intravesical volume. Nonvoiding contractions were apparent in all animals. Contractions increased in frequency and amplitude as the bladder filled. Different phases were identified. Immediately after a void no nonvoiding contractions were observed, followed by continuous activity, first with small contractions, and later with small and large contractions. Small nonvoiding contractions showed a phasic pattern in frequency while the frequency of large nonvoiding contractions slowly increased or remained stable. The frequency and amplitude of nonvoiding contractions were higher at a faster filling rate and a higher intravesical volume. Nonvoiding contractions are present in the anesthetized guinea pig. Under normal physiological conditions they increase in amplitude and frequency with the increase in the filling rate and in intravesical volume. Small and large nonvoiding contractions differ in frequency pattern and occur at different bladder filling periods. This may illustrate different afferents functioning during bladder filling, which could be important for understanding bladder pathology.

TRPA1 receptor modulation attenuates bladder overactivity induced by spinal cord injury

The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. Moreover, SCI caused upregulation of TRPA1 protein and mRNA levels, in bladder and in dorsal root ganglion (DRG; L6-S1), but not in corresponding segment of spinal cord. Alteration in bladder contractility following SCI was evidenced by enhancement in cinnamaldehyde-, capsaicin-, or carbachol-induced bladder contraction as well as in its spontaneous phasic activity. Of relevance to voiding behavior, SCI induced increase in the number of nonvoiding contractions (NVCs), an important parameter associated with the OAB etiology, besides alterations in other urodynamic parameters. HC-030031 (TRPA1 antagonist) treatment decreased the number and the amplitude of NVCs while the TRPA1 antisense oligodeoxynucleotide (AS-ODN) treatment normalized the spontaneous phasic activity, decreased the cinnamaldehyde-induced bladder contraction and the number of NVCs in SCI rats. In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI.

194 RHO-KINASE INHIBITION IMPACTS NEUROGENIC DETRUSOR OVERACTIVITY IN CHRONIC SPINALIZED RATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2010194 RHO-KINASE INHIBITION IMPACTS NEUROGENIC DETRUSOR OVERACTIVITY IN CHRONIC SPINALIZED RATS Dong Broqueres-You, Stephanie Oger, Delphine Behr-Roussel, Sandrine Compagnie, Stephanie Caisey, Pierre Denys, Emmanuel Chartier-Kastler, and Francois Giuliano Dong Broqueres-YouDong Broqueres-You Orsay, France More articles by this author , Stephanie OgerStephanie Oger Orsay, France More articles by this author , Delphine Behr-RousselDelphine Behr-Roussel Orsay, France More articles by this author , Sandrine CompagnieSandrine Compagnie Orsay, France More articles by this author , Stephanie CaiseyStephanie Caisey Orsay, France More articles by this author , Pierre DenysPierre Denys Garches, France More articles by this author , Emmanuel Chartier-KastlerEmmanuel Chartier-Kastler Paris, France More articles by this author , and Francois GiulianoFrancois Giuliano Garches, France More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.250AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Spinal cord injury (SCI) severely disrupts normal bladder function by inducing neurogenic detrusor overactivity (NDO). First line SCI-induced NDO treatments i.e. antimuscarinics often associated with intermittent catheterization are somewhat limited by a mild to moderate clinical efficacy and a significant incidence of side effects. Thus the development of new effective drugs for the treatment of NDO is of crucial importance. Rho-kinase has a central role in the regulation of detrusor smooth muscle contraction since components of the rhoA/rho-kinase signalling pathway are involved in the Ca2+-sensitization of the smooth muscle. Moreover, in vitro and in vivo data from animal models of overactive bladder (OAB) indicate that rho-kinases are involved in pathophysiological mechanisms responsible for OAB. Thus, we aimed to evaluate the effects of a rho-kinase inhibitor (Y-27632) on urodynamic parameters in rats with chronic SCI. METHODS Complete T7-T8 spinal cord transection was performed in 17 female adult Sprague-Dawley rats. At 3-4 weeks post-SCI, cystometry was performed in conscious rats to determine the effects of Y-27632 (150μg/kg, intravenous injection, iv, n=7) and vehicle (saline, iv, n=10) on the following urodynamic parameters: maximal amplitude of micturition pressure (MP); baseline intravesical pressure (BP); delta pressure threshold for inducing micturition (delta PT); intercontraction interval, (ICI); voided volume; amplitude of non-voiding contractions (NVC) and the volume threshold necessary to initiate NVC. The effects of Y-27632 or vehicle were observed during a treatment period of 60 min. The results were expressed as percentage of baseline value during the control period i.e before Y-27632 or saline injection. RESULTS Y-27632 significantly increased voided volume whereas it did not modify MP, BP, delta PT and ICI. Voided volume reached 117±9% of baseline at 60 min after Y-27632 injection versus 96±4% of baseline for vehicle. The amplitude of NVC was significantly decreased by 43.1% and 17.6% at 30 min and 60 min after Y-27632 administration, respectively when compared to vehicle. In addition, Y-27632 significantly increased the volume threshold of NVC. At 30 min and 60 min after Y-27632 injection, it was increased by 117.4% and by 166.3% when compared with vehicle. CONCLUSIONS The present study demonstrates that inhibition of rho-kinase alters the urodynamic parameters related to NVC and enables a better bladder emptying in SCI-induced NDO rats. This supports the potential development of rho-kinase inhibitors for the treatment of NDO. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e76-e77 Peer Review Report Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Dong Broqueres-You Orsay, France More articles by this author Stephanie Oger Orsay, France More articles by this author Delphine Behr-Roussel Orsay, France More articles by this author Sandrine Compagnie Orsay, France More articles by this author Stephanie Caisey Orsay, France More articles by this author Pierre Denys Garches, France More articles by this author Emmanuel Chartier-Kastler Paris, France More articles by this author Francois Giuliano Garches, France More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord-injured rats

We examined whether replication-defective herpes simplex virus (HSV) vectors encoding the 67 kDa form of the glutamic acid decarboxylase (GAD(67)) gene product, the gamma-aminobutyric acid (GABA) synthesis enzyme, can suppress detrusor overactivity (DO) in rats with spinal cord injury (SCI). One week after spinalization, HSV vectors expressing GAD and green fluorescent protein (GFP) (HSV-GAD) were injected into the bladder wall. Rats with SCI without HSV injection (HSV-untreated) and those injected with lacZ-encoding reporter gene HSV vectors (HSV-LacZ) were used as controls. Three weeks after viral injection, continuous cystometry was performed under awake conditions in all three groups. In the HSV-GAD group, the number and amplitude of non-voiding contractions (NVCs) were significantly decreased (40-45% and 38-40%, respectively) along with an increase in voiding efficiency, compared with HSV-untreated and HSV-LacZ groups, but micturition pressure was not different among the three groups. Intrathecal application of bicuculline partly reversed the decreased number and amplitude of NVCs, and decreased voiding efficiency in the HSV-GAD group. In the HSV-GAD group, GAD(67) mRNA and protein levels were significantly increased in the L6-S1 dorsal root ganglia (DRG) compared with the HSV-LacZ group, while 57% of DRG cells were GFP-positive, and these neurons showed increased GAD(67)-like immunoreactivity compared with the HSV-LacZ group. These results indicate that GAD gene therapy effectively suppresses DO after SCI predominantly through the activation of spinal GABA(A) receptors. Thus, HSV-based GAD gene transfer to bladder afferent pathways may represent a novel approach for treatment of neurogenic DO.

The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction

To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.). IC485 (5-50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63-88% and 49-83%, respectively; IC485 also increased bladder capacity by 28-37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38-74% and 29-44%, respectively, and increased bladder capacity by 19-51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35-67% and 19-34%, respectively. Both IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non-voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO.

Urodynamic Effects of a Novel EP 1 Receptor Antagonist in Normal Rats and Rats With Bladder Outlet Obstruction

Prostaglandin E(2) and its EP(1) receptor were suggested as endogenous modulators of bladder function in the normal physiological state and under pathophysiological conditions. We investigated if the new EP(1) receptor antagonist PF-2907617-02 would influence the regulation of normal micturition in rats, and if it affects bladder function in animals with partial bladder outlet obstruction. The study was performed in normal female Sprague-Dawley rats and in rats with moderate, experimentally induced bladder outlet obstruction 2 weeks in duration. All animals underwent continuous cystometry in the awake state. PF-2907617-02 was given intravenously at doses of 0.1 and 1.0 mg/kg(-1) in normal rats, and at 1.0 mg/kg(-1) in bladder outlet obstructed animals. In a group of normal rats detrusor overactivity was produced by intravesical instillation of prostaglandin E(2). In normal rats PF-2907617-02 (1 mg/kg(-1)) significantly increased bladder capacity, micturition volume and the micturition interval but it had no effect on other urodynamic parameters. The lower dose of PF-2907617 (0.1 mg/kg(-1)) showed no effect. Intravesical prostaglandin E(2) (50 muM) induced detrusor overactivity. The antagonist significantly decreased the stimulatory effects of prostaglandin E(2) at 0.1 and 1.0 mg/kg(-1). In obstructed animals PF-2907617-02 significantly increased the micturition interval but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions. EP(1) receptor is involved in initiation of the micturition reflex in normal rats and in animals with bladder outlet obstruction. It may also contribute to the generation of detrusor overactivity after bladder outlet obstruction. Thus, EP(1) receptor antagonists may have potential as treatment for detrusor overactivity in humans.

DECREASE IN BLADDER OVERACTIVITY WITH REN1820 IN RATS WITH CYCLOPHOSPHAMIDE INDUCED CYSTITIS

Studies suggest that nerve growth factor (NGF) contributes to bladder overactivity stemming from bladder inflammation. Studies were performed to determine the NGF dependence of cyclophosphamide (CYP) induced changes in bladder function using the recombinant NGF sequestering protein REN1820. Urodynamic testing and behavioral observations were made in female rats treated with CYP (4 or 48 hours) and REN1820 or vehicle. Rats examined 4 or 48 hours after CYP treatment plus REN1820 showed significantly fewer nonvoiding contractions with smaller amplitude (p </=0.01). Rats examined 48 hours after CYP treatment plus REN1820 showed decreased voiding frequency (p </=0.01). No changes in filling, threshold or micturition pressure were observed with REN1820 treatment. Rats treated with CYP plus REN1820 showed greater mobility and normal resting postures compared with rats treated with CYP plus vehicle. These studies demonstrate that the use of the NGF sequestering protein REN1820 in rats with CYP induced cystitis decreases bladder overactivity. This is characterized by 1) a decrease in the number and amplitude of nonvoiding contractions and 2) decreased voiding frequency. Rats treated with REN1820 showed greater mobility and normal resting postures, which may reflect improved overall health or well-being. REN1820 may prove to be a novel therapeutic in individuals with the chronic inflammatory bladder syndrome interstitial cystitis.

Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions

BackgroundAntimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity.ResultsIntravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 μM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed.In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC.In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant.In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment.Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume.ConclusionDespite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.