Detrusor Overactivity In Female Rats Research Articles

372 Chronic FAAH inhibition reduces urodynamic signs of detrusor overactivity in female rats

372 Chronic FAAH inhibition reduces urodynamic signs of detrusor overactivity in female rats

800 DEGARELIX REDUCES URODYNAMIC CHANGES IN A RAT MODEL FOR EXPERIMENTAL DETRUSOR OVERACTIVITY AND PRODUCES MORE EFFICIENT VOIDING

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research1 Apr 2011800 DEGARELIX REDUCES URODYNAMIC CHANGES IN A RAT MODEL FOR EXPERIMENTAL DETRUSOR OVERACTIVITY AND PRODUCES MORE EFFICIENT VOIDING Giorgio Gandaglia, Fabio Benigni, Giovanni La Croce, Marco Moschini, Alice Bergamini, Frank Strittmatter, Enrico Colli, Patrizio Rigatti, Francesco Montorsi, and Petter Hedlund Giorgio GandagliaGiorgio Gandaglia Milan, Italy More articles by this author , Fabio BenigniFabio Benigni Milan, Italy More articles by this author , Giovanni La CroceGiovanni La Croce Milan, Italy More articles by this author , Marco MoschiniMarco Moschini Milan, Italy More articles by this author , Alice BergaminiAlice Bergamini Milan, Italy More articles by this author , Frank StrittmatterFrank Strittmatter Munich, Germany More articles by this author , Enrico ColliEnrico Colli Copenhagen, Denmark More articles by this author , Patrizio RigattiPatrizio Rigatti Milan, Italy More articles by this author , Francesco MontorsiFrancesco Montorsi Milan, Italy More articles by this author , and Petter HedlundPetter Hedlund Milan, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.618AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES GnRH antagonists may have beneficial effects on LUTS in patients with BPH. The aim was to study effects of degarelix, a GnRH receptor antagonist, on normal bladder function and experimental detrusor overactivity (DO) in female rats. METHODS After ethical approval, female Sprague-Dawley rats were given degarelix (10μg/kg, n=13) or saline vehicle (controls; n=11) subcutaneously every second day for 5 days. The dose regime chosen was based on the pharmacological profile of degarelix. On day 6, bladder function and responses to intravesical (ives) PGE2 (50 μM) were studied with cystometry in conscious rats. Values are mean ± SEM. ANOVA was used for comparisons. RESULTS Bladder and body weights were similar in both groups. Baseline micturition interval (MI), micturition volume (MV), and bladder capacity (BC), basal pressure (BP), and maximal pressure (MP) were similar in both groups. Degarelix rats had lower residual volumes (RV) of 0.03±0.01 ml (controls 0.10±0.02 ml, p<0.05). Threshold pressure (TP) was 28.3±3.9 (controls) and 15.2±0.8 cmH2O (degarelix, p<0.05). Flow pressure (FP) was 45.9±4.1 (controls) and 31.9±1.9 cmH2O (degarelix, p<0.05). PGE2 (ives) reduced MI, MV, and BC of all rats. RV was not changed in degarelix rats (0.04±0.01 ml) but was increased in controls to 0.15 ± 0.02 ml (p<0.001) after PGE2. Ives PGE2 increased more BP, TP, and FP in controls (p<0.001) than degarelix rats. For controls, BP, TP and FP was 24.1±4.1, 39.2±5.6, and 61.9±5.7 cmH2O, and in degarelix rats 12.1±0.9, 17.7±1.3, and 37.2±2.3 cmH2O. Whereas MP increased in controls, no change was observed for degarelix rats after ives PGE2. After intravesical PGE2, the area under the pressure curve (AUC) was 38.4±6.5 and 18.6±1.7 cmH2O/sec for controls and degarelix rats (p<0.001) and the absolute increase in AUC amounted to 14.0±3.1 (controls) and 5.1± 1.1 (degarelix; p<0.01) cmH2O/sec. In controls, compliance (C) was reduced from 0.09±0.01 at baseline to 0.05±0.01 ml/cmH2O after ives PGE2. In degarelix rats, C was unaffected by ives PGE2 and amounted to 0.15±0.04 ml/cmH2O (p<0.05). CONCLUSIONS Degarelix counteracted urodynamic signs of DO in female rats without affecting maximal bladder pressures. Indicating more efficient emptying of the bladder in this model for DO, rats treated with degarelix had less residual volume and preserved compliance. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e322 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giorgio Gandaglia Milan, Italy More articles by this author Fabio Benigni Milan, Italy More articles by this author Giovanni La Croce Milan, Italy More articles by this author Marco Moschini Milan, Italy More articles by this author Alice Bergamini Milan, Italy More articles by this author Frank Strittmatter Munich, Germany More articles by this author Enrico Colli Copenhagen, Denmark More articles by this author Patrizio Rigatti Milan, Italy More articles by this author Francesco Montorsi Milan, Italy More articles by this author Petter Hedlund Milan, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effects of the Gonadotropin-Releasing Hormone Antagonist Ganirelix on Normal Micturition and Prostaglandin E2–Induced Detrusor Overactivity in Conscious Female Rats

BackgroundGonadotropin-releasing hormone (GnRH) antagonists have been reported to have beneficial effects on lower urinary tract symptoms in patients with benign prostatic hyperplasia. ObjectiveOur aim was to investigate the effects of ganirelix, a GnRH receptor antagonist, on bladder function and detrusor overactivity (DO) in female rats. Design, setting, and participantsFemale Sprague-Dawley rats received 2 wk of daily systemic (0.1mg/kg) or acute intravesical administration (IVES; 0.14mg/l or 1.4mg/l) ganirelix or vehicle (controls). MeasurementsAssessments were obtained using cystometry in awake rats, organ bath studies, enzyme-linked immunosorbent assay, and western blot (WB). Results and limitationsLuteinising hormone levels were lower in rats treated systemically with ganirelix than in controls. No differences were observed in body or bladder weights. Micturition interval (MI), micturition volume (MV), residual volume, and bladder capacity (BC) were similar in both groups at baseline. No differences in urodynamic pressure parameters were observed between groups at baseline. Intravesical prostaglandin E2 reduced MI, MV, and BC, and it increased basal pressure (BP), threshold pressure (TP), flow pressure (FP), and maximum pressure (MP) in all rats. MI, MV, and BC were reduced by 43%±4%, 50%±4%, and 43%±4% (controls) versus 22%±3%, 23%±3%, and 21%±3% (ganirelix-treated rats; p<0.001). TP and FP increased by 38%±8% and 30%±4% (controls) versus 16%±7% and 16%±5% (ganirelix; p<0.05). The maximal force of contractions for carbachol was larger in detrusor from ganirelix-treated rats (231% vs 177% of 60mM K+-induced contractions). At 0.14mg/l, but not 0.14mg/l, IVES ganirelix increased MI, MV, and BC and decreased BP, TP, FP, and MP. In vitro, ganirelix had no effect on detrusor function. The gonadotropin-releasing hormone receptor was expressed (by WB) in the bladder mucosa. ConclusionsSystemic treatment with ganirelix counteracted experimental DO in female rats. Because bladder preparations from these rats exhibited larger contractions to carbachol and because intravesical ganirelix affected both micturition intervals and urodynamic pressure profiles, a peripheral site of action of ganirelix in the urinary bladder cannot be excluded.

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.

Effects of gamma-aminobutyrate B receptor modulation on normal micturition and oxyhemoglobin induced detrusor overactivity in female rats.

Using baclofen (Sigma-Aldrich, Steinheim, Germany), a gamma-aminobutyrate B (GABA(B)) receptor agonist, and CGP62349 (AstraZeneca R & D Mölndal, Sweden), a GABA(B) receptor antagonist, in a rat model of conscious micturition we addressed certain questions, including whether there is a tonic GABA(B) receptor influence on normal bladder function, how baclofen affects normal and C-fiber activated micturition, and where the sites of GABA(B) receptor action are. Nonanesthetized female Sprague-Dawley rats were used. The bladder was catheterized and other catheters were placed intravenously, intrathecally or intracerebroventricularly. At 3 days the rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Overactivity caused by C-fiber activation was induced by intravesical oxyhemoglobin. Drugs were given intravenously, intrathecally or intracerebroventricularly. Micturition parameters were recorded and compared before and after drug administration. Baclofen at doses of 0.5 microg. intrathecally and 0.3 microg. intracerebroventricularly increased bladder capacity and threshold pressure. Overflow incontinence developed in 4 of 7 rats after 0.5 microg. baclofen intrathecally and in 5 of 7 after 1 microg. baclofen intracerebroventricularly. CGP62349 at a dose of 30 microg. intrathecally and intracerebroventricularly had a stimulatory effect on micturition, which was attenuated by baclofen. While intravenous baclofen at 1 mg. (-1)kg. was devoid of effects, intravenous baclofen at 4 mg. kg. (-1)tended to decrease micturition pressure, bladder capacity and micturition volume. Infusion volume decreased significantly, demonstrating a diuretic effect, which was abolished by pretreatment with subcutaneous desmopressin at 25 ng. kg. (-1). CGP62349 at 2 mg. kg. (-1) intravenously had a stimulatory effect on micturition, which was inhibited by baclofen. Intravesical oxyhemoglobin at 250 microM. induced bladder overactivity, which was attenuated by baclofen at 4 mg. kg. (-1) intravenously and abolished by baclofen 0.5 microg intrathecally. In the normal rat stimulation of GABA(B) receptors, mainly in the central nervous system, inhibits micturition. Antagonism of GABA(B) receptors stimulates micturition, suggesting that the receptors are under tonic GABAergic influence. Baclofen intrathecally attenuated oxyhemoglobin induced detrusor overactivity, suggesting that the inhibitory actions of GABA(B) receptor agonists in the spinal cord may be useful for controlling micturition disorders caused by C-fiber activation in the urothelium and/or suburothelium.

DIETARY GLYCINE INHIBITS BLADDER ACTIVITY IN NORMAL RATS AND RATS WITH SPINAL CORD INJURY

The influence of dietary glycine on bladder activity, and on glutamate and glycine levels in the serum and lumbosacral cord was examined in rats with or without spinal cord injury (SCI). A total of 84 female rats were divided into an intact and an SCI group. Each group of rats was divided into 7 subgroups. Two intact and 2 SCI subgroups were fed a standard diet and the remaining subgroups were fed diets containing 0.1% to 3% glycine. After 4 weeks isovolumetric cystometry was performed with rats under urethane anesthesia. Following cystometry glutamate and glycine levels in the serum and lumbosacral cord were measured as well as the glycine receptor alpha1 mRNA level in the lumbosacral cord. Dietary glycine (1% to 3%) prolonged the interval between bladder contractions in intact rats but did not change the amplitude of contractions. On the other hand, dietary glycine (1% to 3%) prolonged the interval and decreased the amplitude of bladder contractions in SCI rats. The glycine levels in the serum and lumbosacral cord of SCI rats on the standard diet were respectively 43% and 45% lower than those in intact rats on the standard diet. Dietary glycine (1% to 3%) increased the serum glycine level in intact and SCI rats but the glycine receptor alpha1 mRNA level in the lumbosacral cord was unchanged. Dietary glycine crosses the blood-brain barrier and inhibits the micturition reflex pathway in the lumbosacral cord but SCI and/or dietary glycine do not influence glycine receptor expression.

Effects of γ-Aminobutyrate B Receptor Modulation on Normal Micturition and Oxyhemoglobin Induced Detrusor Overactivity in Female Rats

Using baclofen (Sigma-Aldrich, Steinheim, Germany), a gamma-aminobutyrate B (GABA(B)) receptor agonist, and CGP62349 (AstraZeneca R & D Mölndal, Sweden), a GABA(B) receptor antagonist, in a rat model of conscious micturition we addressed certain questions, including whether there is a tonic GABA(B) receptor influence on normal bladder function, how baclofen affects normal and C-fiber activated micturition, and where the sites of GABA(B) receptor action are. Nonanesthetized female Sprague-Dawley rats were used. The bladder was catheterized and other catheters were placed intravenously, intrathecally or intracerebroventricularly. At 3 days the rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Overactivity caused by C-fiber activation was induced by intravesical oxyhemoglobin. Drugs were given intravenously, intrathecally or intracerebroventricularly. Micturition parameters were recorded and compared before and after drug administration. Baclofen at doses of 0.5 microg. intrathecally and 0.3 microg. intracerebroventricularly increased bladder capacity and threshold pressure. Overflow incontinence developed in 4 of 7 rats after 0.5 microg. baclofen intrathecally and in 5 of 7 after 1 microg. baclofen intracerebroventricularly. CGP62349 at a dose of 30 microg. intrathecally and intracerebroventricularly had a stimulatory effect on micturition, which was attenuated by baclofen. While intravenous baclofen at 1 mg. (-1)kg. was devoid of effects, intravenous baclofen at 4 mg. kg. (-1)tended to decrease micturition pressure, bladder capacity and micturition volume. Infusion volume decreased significantly, demonstrating a diuretic effect, which was abolished by pretreatment with subcutaneous desmopressin at 25 ng. kg. (-1). CGP62349 at 2 mg. kg. (-1) intravenously had a stimulatory effect on micturition, which was inhibited by baclofen. Intravesical oxyhemoglobin at 250 microM. induced bladder overactivity, which was attenuated by baclofen at 4 mg. kg. (-1) intravenously and abolished by baclofen 0.5 microg intrathecally. In the normal rat stimulation of GABA(B) receptors, mainly in the central nervous system, inhibits micturition. Antagonism of GABA(B) receptors stimulates micturition, suggesting that the receptors are under tonic GABAergic influence. Baclofen intrathecally attenuated oxyhemoglobin induced detrusor overactivity, suggesting that the inhibitory actions of GABA(B) receptor agonists in the spinal cord may be useful for controlling micturition disorders caused by C-fiber activation in the urothelium and/or suburothelium.

Effects of ??-Aminobutyrate B Receptor Modulation on Normal Micturition and Oxyhemoglobin Induced Detrusor Overactivity in Female Rats

Effects of ??-Aminobutyrate B Receptor Modulation on Normal Micturition and Oxyhemoglobin Induced Detrusor Overactivity in Female Rats