| 1. |
- Buono, Roberta, et al.
(författare)
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Silodosin and tadalafil have synergistic inhibitory effects on nerve-mediated contractions of human and rat isolated prostates
- 2014
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 744, s. 42-51
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Tidskriftsartikel (refereegranskat)abstract
- Lower urinary tract symptoms (CUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUIS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of siloclosin, a highly selective alpha(1A)-adrenoceptor antagonist, alone or in combination with the phosphocliesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of siloclosin (1 nM-1 mu M) and tadalafil (100 nM-100 mu M) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P less than 0.05), 40-58% (10 nM silodosin+1 mu M tadalafil; P less than 0.001-0.05), 56-67% (100 nM silodosin+10 mu M tadalafil; P less than 0.01-0.05), and 33-55% (1 mu M silodosin+100 mu M tadalafil P less than 0.01-0.05), Similar findings were obtained in rat prostate preparations. In human and rat prostate tissue, the drug combination exerted similar inhibitory effect on phenylephrine contractions as silodosin alone. Silodosin plus tadalafil had greater potency than each drug alone to inhibit prostate contractions to electrical field stimulation but not to phenylephrine. This study supports the clinical application of a combination of an (alpha(1A)-adrenoceptor antagonist and a phosphodiesterase 5 inhibitor for symptomatic BPH and suggests that the drug combination requires endogenous nerve-activity for optimal effect.
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| 2. |
- Castiglione, Fabio, et al.
(författare)
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Perioperative Betamethasone Treatment Reduces Signs of Bladder Dysfunction in a Rat Model for Neurapraxia in Female Urogenital Surgery
- 2012
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 62:6, s. 1076-1085
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Information on autonomic neurapraxia in female urogenital surgery is scarce, and a model to study it is not available.OBJECTIVE:To develop a model to study the impact of autonomic neurapraxia on bladder function in female rats, as well as to assess the effects of corticosteroid therapy on the recovery of bladder function in this model.DESIGN, SETTING, AND PARTICIPANTS:Female Sprague-Dawley rats were subjected to bilateral pelvic nerve crush (PNC) and perioperatively treated with betamethasone or vehicle. Bladder function and morphology of bladder tissue were evaluated and compared with sham-operated rats.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Western blot, immunohistochemistry, organ bath experiments, and cystometry.RESULTS AND LIMITATIONS:Sham-operated rats exhibited regular micturitions without nonvoiding contractions (NVCs). Crush of all nerve branches of the pelvic plexus or PNC resulted in overflow incontinence and/or NVCs. Betamethasone treatment improved recovery of regular micturitions (87.5% compared with 27% for vehicle; p<0.05), reduced lowest bladder pressure (8 ± 2 cm H(2)O compared with 21 ± 5 cm H(2)O for vehicle; p<0.05), and reduced the amplitude of NVCs but had no effect on NVC frequency in PNC rats. Compared with vehicle, betamethasone-treated PNC rats had less CD68 (a macrophage marker) in the pelvic plexus and bladder tissue. Isolated bladder from betamethasone-treated PNC rats exhibited better nerve-induced contractions, contained more cholinergic and sensory nerves, and expressed lower amounts of collagen III than bladder tissue from vehicle-treated rats.CONCLUSIONS:PNC causes autonomic neurapraxia and functional and morphologic changes of isolated bladder tissue that can be recorded as bladder dysfunction during awake cystometry in female rats. Perioperative systemic betamethasone treatment reduced macrophage contents of the pelvic plexus and bladder, partially counteracted changes in the bladder tissue, and had protective effects on micturition function.
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| 3. |
- Fuellhase, Claudius, et al.
(författare)
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Spinal Cord FAAH in Normal Micturition Control and Bladder Overactivity in Awake Rats
- 2013
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 189:6, s. 2364-2370
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We assessed whether spinal inhibition of the cannabinoid degrading enzyme FAAH would have urodynamic effects in normal rats and rats with bladder overactivity induced by partial urethral obstruction or prostaglandin E2. We also determined the expression of FAAH, and the cannabinoid receptors CB1 and CB2 in the sacral spinal cord. Materials and Methods: We used 44 rats for functional (cystometry) and Western blot experiments. The FAAH inhibitor oleoyl ethyl amide (3 to 300 nmol) was administered intrathecally (subarachnoidally) or intravenously. The expression of FAAH and CB1/CB2 receptors was determined by Western blot. Results: Oleoyl ethyl amide given intrathecally affected micturition in normal rats and rats with bladder overactivity but effects were more pronounced in the latter. In normal rats oleoyl ethyl amide only decreased micturition frequency, while it decreased frequency and bladder pressures in rats with bladder overactivity. Intravenous oleoyl ethyl amide (3 to 300 nmol) had no urodynamic effect. FAAH and CB1/CB2 receptors were expressed in the rat sacral spinal cord. The expression of CB1/CB2 receptors but not FAAH was higher in obstructed than in normal rats. Conclusions: FAAH inhibition in the sacral spinal cord by oleoyl ethyl amide resulted in urodynamic effects in normal rats and rats with bladder overactivity. The spinal endocannabinoid system may be involved in normal micturition control and it appears altered when there is bladder overactivity.
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| 4. |
- Mistretta, Francesco A., et al.
(författare)
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DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats
- 2016
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS. - 0022-3565 .- 1521-0103. ; 356:1, s. 200-211
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Tidskriftsartikel (refereegranskat)abstract
- The transient receptor potential melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity is available. This study characterizes a new TRPM8-selective antagonist (DFL23448 [5-(2-ethyl-2H-tetrazol-5-yl)-2-(3-fluorophenyl)-1,3-thiazol-4-ol]) and evaluates it in cold-induced behavioral tests and tests on bladder function and experimental bladder overactivity in vivo in rats. DFL23448 displayed IC50 values of 10 and 21 nM in hTRPM8 human embryonic kidney 293 cells activated by Cooling Agent 10 or cold, but it had limited activity (IC50 > 10 mu M) at transient receptor potential vanilloids TRPV1, TRPA1, or TRPV4 or at various G protein-coupled receptors. In rats, DFL23448 administered intravenously or orally had a half-life of 37 minutes or 4.9 hours, respectively. DLF23448 (10 mg/kg i.v.) reduced icilin-induced "wet dog-like" shakes in rats. Intravesical DFL23448 (10 mg/l), but not vehicle, increased micturition intervals, micturition volume, and bladder capacity. During bladder overactivity by intravesical prostaglandin E-2 (PGE(2)), vehicle controls exhibited reductions in micturition intervals, micturition volumes, and bladder capacity by 37%-39%, whereas the same parameters only decreased by 12%-15% (P < 0.05-0.01 versus vehicle) in DFL23448-treated rats. In vehicle-treated rats, but not in DFL23448-treated rats, intravesical PGE(2) increased bladder pressures. Intravenous DFL23448 at 10 mg/kg, but not 1 mg/kg DFL23448 or vehicle, increased micturition intervals, micturition volumes, and bladder capacity. During bladder overactivity by intravesical PGE(2), micturition intervals, micturition volumes, and bladder capacity decreased in vehicle- and 1 mg/kg DFL23448-treated rats, but not in 10 mg/kg DFL23448-treated rats. Bladder pressures increased less in rats treated with DFL23448 10 mg/kg than in vehicle-or 1 mg/kg DFL23448-treated rats. DFL23448 (10 mg/kg i.v.), but not vehicle, prevented cold stress-induced bladder overactivity. Our results support a role for bladder TRPM8-mediated signals in experimental bladder overactivity.
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| 5. |
- Mistretta, Francesco A, et al.
(författare)
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DFL23448, a novel TRPM8-selective ion channel antagonist, modifies bladder function and reduces bladder overactivity in awake rats.
- 2016
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 1521-0103. ; 356:1, s. 200-211
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Tidskriftsartikel (refereegranskat)abstract
- The transient receptor potential (TRP) melastin 8 ion channel (TRPM8) is implicated in bladder sensing but limited information on TRPM8 antagonists in bladder overactivity (BO) is available. This study characterizes a new TRPM8-selective antagonist (DFL23448) and evaluates it in cold-induced behavioral tests and on bladder function and experimental BO in vivo in rats. DFL23448 displayed IC50 values of 10 and 21nM in hTRPM8 HEK-293 cells activated by Cooling Agent 10 or cold, but had limited activity (IC50 > 10μM) at TRPV1, TRPA1, TRPV4, or at various G-protein-coupled receptors. In rats, DFL23448 had a half-life of 37 minutes (intravenous; i.v.) or 4.9 hours (oral). DLF23448 (10mg/kg, i.v) reduced icilin-induced wet-dog shakes in rats. Intravesical (i.ves.) DFL23448 (10mg/L) but not vehicle increased micturition intervals (MI), micturition volumes (MV) and bladder capacity (BC). During BO by i.ves. PGE2, vehicle controls exhibited reductions of MI, MV and BC by 37-39%, whereas the same parameters only decreased by 12-15% (p<0.05-0.01 vs. vehicle) in DFL23448-treated rats. In vehicle-treated rats but not in DFL23448-treated rats, i.ves. PGE2 increased bladder pressures. Intravenous DFL23448 at 10mg/kg, but not 1mg/kg DFL23448 or vehicle, increased MI, MV, and BC. During BO by i.ves. PGE2, MI, MV, and BC decreased in vehicle- and in DFL23448 1mg/kg-treated rats, but not in DFL23448 10mg/kg-treated rats. Bladder pressures increased less in rats treated with DFL23448 10mg/kg than in vehicle- or DFL23448 1mg/kg- treated rats. DFL23448 (10mg/kg, i.v.), but not vehicle, prevented cold-stress BO. Our results support a role for bladder TRPM8-mediated signals in experimental BO.
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| 6. |
- Russo, Andrea, et al.
(författare)
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Effects of the Gonadotropin-Releasing Hormone Antagonist Ganirelix on Normal Micturition and Prostaglandin E-2-Induced Detrusor Overactivity in Conscious Female Rats
- 2011
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Ingår i: EUROPEAN UROLOGY. - : ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS. - 0302-2838 .- 1873-7560. ; 59:5, s. 868-874
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gonadotropin-releasing hormone (GnRH) antagonists have been reported to have beneficial effects on lower urinary tract symptoms in patients with benign prostatic hyperplasia. Objective: Our 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 participants: Female Sprague-Dawley rats received 2 wk of daily systemic (0.1 mg/kg) or acute intravesical administration (IVES; 0.14 mg/l or 1.4 mg/l) ganirelix or vehicle (controls). Measurements: Assessments were obtained using cystometry in awake rats, organ bath studies, enzyme-linked immunosorbent assay, and western blot (WB). Results and limitations: Luteinising 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 E-2 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 andlt; 0.001). TP and FP increased by 38% +/- 8% and 30% +/- 4% (controls) versus 16% +/- 7% and 16% +/- 5% (ganirelix; p andlt; 0.05). The maximal force of contractions for carbachol was larger in detrusor from ganirelix-treated rats (231% vs 177% of 60 mM K+-induced contractions). At 0.14 mg/l, but not 0.14 mg/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. Conclusions: Systemic 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.
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| 7. |
- Castiglione, Fabio, et al.
(författare)
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Adipose-derived Stem Cells Counteract Urethral Stricture Formation in Rats
- 2016
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 70:6, s. 1032-1041
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Tidskriftsartikel (refereegranskat)abstract
- Background: A medical treatment for urethral stricture (US) is not yet available. Objective: To evaluate if local injection of human adipose tissue-derived stem cells (hADSC) prevents urethral fibrosis in a rat model of US. Design, setting, and participants: Male rats were divided into three groups: sham, US, and hADSC (n = 12 each). Sham rats received a vehicle injection in the urethral wall. US and hADSCs were incised and injected with the fibrosis-inducer transforming growth factor-β1 in the urethral wall. Intervention: One day later, hADSCs were injected in the urethral wall of hADSC rats whereas sham and US rats were injected with the vehicle. After 4 wk, the rats underwent cystometries and tissues were then harvested for functional and molecular analyses. Outcome measurements and statistical analysis: Cystometry, microultrasound, histochemistry, organ bath studies, reverse transcription polymerase chain reaction, and western blot. Results and limitations: US rats exhibited 49-51% shorter micturition intervals, 35-51% smaller micturition volumes and bladder capacity, 33-62% higher threshold pressures and flow pressures, and 35-37% lower bladder filling compliance compared with hADSC-treated rats and sham rats (p
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| 8. |
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| 9. |
- Castiglione, Fabio, et al.
(författare)
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Inhibition of Phosphodiesterase 4 Enhances Clitoral and Vaginal Blood Flow Responses to Dorsal Clitoral Nerve Stimulation or PGE1 in Anesthetized Female Rats
- 2013
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Ingår i: Journal of Sexual Medicine. - : Wiley-Blackwell. - 1743-6095 .- 1743-6109. ; 10:4, s. 939-950
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Cyclic adenosine 35 monophosphate (cAMP) is produced by adenylate cyclase after activation by, e.g., vasoactive intestinal polypeptide or prostaglandin E1 (PGE1). The cAMP-degrading phosphodiesterase 4 (PDE4) is expressed in the vagina and clitoris, but no information is available on the functional role for PDE4-related signals in the female neurovascular genital response. Aim. The aim of this study is to study the effect of inhibition of PDE4 with rolipram on nerve- and PGE1-induced vaginal and clitoral blood flow responses of rat. Methods. Measure of clitoral and vaginal blood flow and blood pressure in anesthetized rats during activation of the dorsal clitoral nerve (DCN) before and after intraperitoneal administration of rolipram or sildenafil (phosphodiesterase type 5 inhibitors [PDE5]) and nitro-L-arginine (L-NNA) (nitric oxide synthase inhibitor). Effect by topical administration of PGE1 on genital blood flow was also evaluated. Main Outcome Measure. Blood flow was recorded as tissue perfusion units (TPU) by a Laser Doppler Flowmeter. Mean arterial blood pressure (MAP) was recorded (cmH2O) in the carotid artery. Blood flow responses are expressed as TPU/MAP. Unpaired t-test and an analysis of variance were used. Results. Compared with control stimulations, rolipram (0.3mg/kg) caused a twofold increase in peak blood flow (Pandlt;0.05) and fourfold increase of the rate of clitoral blood flow during activation of the DCN (Pandlt;0.05). Simultaneously, a twofold increase in peak blood flow and threefold increase in rate of blood flow were noted in the vagina (Pandlt;0.05). Similar effects were noted for sildenafil (0.2mg/kg) (Pandlt;0.05). Inhibitory effects by L-NNA (60mg/kg) on blood flow responses to DCN activation were significantly lower for rats treated with rolipram than with sildenafil (Pandlt;0.05). PGE1-induced (10g) blood flow responses were significantly higher (Pandlt;0.05) in rats treated with rolipram than with sildenafil. Conclusions. These findings suggest that the cAMP/PDE4 system may be of similar functional importance as the nitric oxide/cyclic guanosine monophosphate/PDE5 pathway for neurovascular genital responses of the female rat. Castiglione F, Bergamini A, Russo A, La Croce G, Castagna G, Colciago G, Salonia A, Rigatti P, Montorsi F, and Hedlund P. Inhibition of phosphodiesterase 4 enhances clitoral and vaginal blood flow responses to dorsal clitoral nerve stimulation or PGE1 in anesthetized female rats. J Sex Med 2013; 10: 939-950.
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| 10. |
- Castiglione, Fabio, et al.
(författare)
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Intratunical Injection of Human Adipose Tissue-derived Stem Cells Prevents Fibrosis and Is Associated with Improved Erectile Function in a Rat Model of Peyronies Disease
- 2013
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Ingår i: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 63:3, s. 551-560
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peyronies disease (PD) is a connective tissue disorder of the tunica albuginea (TA). Currently, no gold standard has been developed for the treatment of the disease in its active phase. less thanbrgreater than less thanbrgreater thanObjective: To test the effects of a local injection of adipose tissue-derived stem cells (ADSCs) in the active phase of a rat model of PD on the subsequent development of fibrosis and elastosis of the TA and underlying erectile tissue. less thanbrgreater than less thanbrgreater thanDesign, setting, and participants: A total of 27 male 12-wk-old Sprague-Dawley rats were divided in three equal groups and underwent injection of vehicle (sham), 50-mu g transforming growth factor (TGF)-beta 1 in a 50-mu l vehicle in either a PD or a PD plus ADSC group in the dorsal aspect of the TA. less thanbrgreater than less thanbrgreater thanIntervention: The sham and PD groups were treated 1 d after TGF-beta 1 injection with intralesional treatment of vehicle, and the PD plus ADSC group received 1 million human-labeled ADSCs in the 50-mu l vehicle. Five weeks after treatment, six rats per group underwent erectile function measurement. Following euthanasia, penises were harvested for histology and Western blot. less thanbrgreater than less thanbrgreater thanOutcome measurements and statistical analysis: The ratio of intracavernous pressure to mean arterial pressure (ICP/MAP) upon cavernous nerve stimulation, elastin, and collagen III protein expression and histomorphometric analysis of the penis. Statistical analysis was performed by analysis of variance followed by the Tukey-Kramer test for post hoc comparisons or the Mann-Whitney test when applicable. less thanbrgreater than less thanbrgreater thanResults and limitations: Erectile function significantly improved after ADSC treatment (ICP/MAP 0.37 in PD vs 0.59 in PD plus ADSC at 5-V stimulation; p = 0.03). PD animals developed areas of fibrosis and elastosis with a significant upregulation of collagen III and elastin protein expression. These fibrotic changes were prevented by ADSC treatment. less thanbrgreater than less thanbrgreater thanConclusions: This study is the first to test stem cell therapy in an animal model of PD. Injection of ADSCs into the TA during the active phase of PD prevents the formation of fibrosis and elastosis in the TA and corpus cavernosum.
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| 11. |
- Castiglione, Fabio, et al.
(författare)
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Intratunical Injection of Human Adipose Tissue–Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease
- 2019
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Ingår i: Sexual Medicine. - : Oxford University Press (OUP). - 2050-1161. ; 7:1, s. 94-103
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Previous studies have shown that the injection of adipose tissue–derived stem cells (ADSCs) into the tunica albuginea (TA) during the active phase of Peyronie's disease (PD) prevents the development of fibrosis. Aim: To investigate, using an animal model, whether local injection of human ADSCs (hADSCs) can alter the degree of fibrosis in the chronic phase of PD. Methods: 27 male, 12-week-old rats were divided into 3 equal groups: sham, PD without treatment, and PD treated with hADSCs 1 month after disease induction. Sham rats underwent 2 injections of vehicle into the TA 1 month apart. PD rats underwent transforming growth factor β1 (TGFβ1) injection and injection of vehicle 1 month later. PD-hADSC rats underwent TGFβ1 injection followed by 1 million hADSCs 1 month later. 1 week after treatment, n = 3 animals/group were euthanized, and the penises were harvested for quantitative polymerase chain reaction. 1 month after treatment, the other animals, n = 6 per group, underwent measurement of intracavernous pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of the cavernous nerve. After euthanasia, penises were again harvested for histology and Western blot. Main Outcome Measure: The primary outcome measures included (a) gene expression at one week post-injection; (b) measurement of ICP/MAP upon cavernous nerve stimulation as a measure of erectile function; (c) elastin, collagen I and III protein expression; and (d) Histomorphometric analysis of the penis. Means where compared by analysis of variance (ANOVA) followed by a Student-Newman-Keuls test for post hoc comparisons or Mann-Whitney test when applicable. Results: No significant difference was noted in ICP or ICP/MAP in response to cavernous nerve electrostimulation between the 3 groups at 2.5, 5, and 7.5 V (P > .05 for all voltages). PD animals developed tunical and subtunical areas of fibrosis with a significant upregulation of collagen III protein. The collagen III/I ratio was higher in the PD (4.6 ± 0.92) group compared with sham (0.66 ± 0.18) and PD-hADSC (0.86 ± 0.06) groups (P < .05) These fibrotic changes were prevented when treated with hADSCs. Compared with PD rats, PD-hADSC rats demonstrated a decreased expression of several fibrosis-related genes. Conclusion: Injection of hADSCs reduces collagen III expression in a rat model of chronic PD. Castiglione F, Hedlund P, Weyne E, et al. Intratunical Injection of Human Adipose Tissue–Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease. Sex Med 2018;XX:XX–XX.
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| 12. |
- Castiglione, Fabio, et al.
(författare)
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Intratunical injection of stromal vascular fraction prevents fibrosis in a rat model of Peyronies disease
- 2019
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Ingår i: BJU International. - : WILEY. - 1464-4096 .- 1464-410X. ; 124:2, s. 342-348
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Tidskriftsartikel (refereegranskat)abstract
- Objective To investigate whether local injection of autologous adipose stromal vascular fraction (SVF) can prevent the development of fibrosis and elastosis in the tunica albuginea (TA) using a rat model of the acute phase of Peyronies disease (PD). Methods A total of 24 male 12-week-old Sprague-Dawley rats were divided into three equal groups: sham; PD without treatment (transforming growth factor-beta [TGF -beta]); and PD treated with SVF 1 day after disease induction. Sham rats received two injections of vehicle into the TA 1 day apart. TGF -beta rats received TGF- beta 1 injection and injection of vehicle 1 day later. SVF rats received TGF-beta 1 injection, followed by SVF 1 day later. One month after treatment, all rats underwent measurement of intracavernosal pressure and mean arterial pressure during electrostimulation of the cavernous nerve. The rats were then killed and penises were harvested for histology and Western blot analysis. Results Erectile function was moderately reduced in the TGF-beta group and was significantly improved after SVF treatment (P amp;lt; 0.05). PD rats developed areas of fibrosis with a significant upregulation of collagen III, collagen I and elastin protein expression. These fibrotic changes were prevented when treated with SVF. Conclusions Local injection of SVF may represent treatment for the acute phase of PD.
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| 13. |
- Castiglione, Fabio, et al.
(författare)
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Long-term consequences of bilateral cavernous crush injury in normal and diabetic rats : a functional study
- 2022
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Ingår i: International Journal of Impotence Research. - : Springer Science and Business Media LLC. - 0955-9930 .- 1476-5489. ; 34:8, s. 781-785
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Tidskriftsartikel (refereegranskat)abstract
- A recent statement from the European-Society-for-Sexual-Medicine has highlighted the limitations of using the rat model for nerve-sparing prostatectomy. The use of young rats with no comorbidities and the early evaluation of the erectile function (EF) are deemed a source of bias. Our aim was to evaluate the long-term consequences in EF of bilateral nerve cavernous crush- injury (BNCI) in type 1 diabetic (DM) rats 30-male/12-week-old rats were divided into four groups: Sham, BNCI, DM, and BNCI + DM. Sham group underwent an intraperitoneal injection (IP) of saline solution and after 1 month underwent a sham laparotomy. BNCI underwent an IP of saline solution and after 1 month to BNCI. DM underwent an IP of 60 mg/kg-1-streptozotocin (STZ) and after 1 month to a sham laparotomy. BNCI + DM underwent an IP of 60 mg/kg-1-STZ and after 1 month to BNCI. After 5 months from the induction of diabetes, all rats underwent measurement of intracorporeal pressure (ICP) and mean arterial pressure (MAP) during CN-electrostimulation. Multiple groups were compared using Kruskal–Wallis one-way analysis of variance followed by Mann–Whitney U test for post hoc comparisons. Blood glucose-level was higher (p < 0.05) in the groups with DM and BNCI + DM. After 5-months, DM and BNCI + DM also showed a lower weight compared to other groups (p < 0.05). No differences were noted in ICP/MAP between the sham and BNCI. BNCI + DM showed lower ICP/MAP compared to all the groups (p < 0.05). DM Showed lower ICP/MAP compared to Sham and BNCI (p < 0.05). BNCI in rats without comorbidities did not induce long-term erectile dysfunction (ED) suggesting a spontaneous EF recovery. BNCI in DM induced long-term ED. The results of previous short-term studies can only provide evidence on the time to recovery of spontaneous EF as to the actual EF recovery rate.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Fuellhase, Claudius, et al.
(författare)
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Spinal neuronal cannabinoid receptors mediate urodynamic effects of systemic fatty acid amide hydrolase (FAAH) inhibition in rats
- 2016
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Ingår i: Neurourology and Urodynamics. - : WILEY-BLACKWELL. - 0733-2467 .- 1520-6777. ; 35:4, s. 464-470
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Tidskriftsartikel (refereegranskat)abstract
- AimsTo test if urodynamic effects from systemic Fatty Acid Amide Hydrolase (FAAH) inhibition involve sacral spinal cannabinoid type 1 (CB1) or type 2 (CB2) receptors. MethodsMale rats with or without partial urethral obstruction were used for cystometry or immunohistochemistry. Urodynamic effects of intravenous (IV) 0.3mg/kg Oleoyl Ethyl Amide (OEtA; FAAH inhibitor), and intrathecal (IT) 5g rimonabant (CB1 antagonist) or 5g SR144528 (CB2 antagonist) were studied in awake rats. ResultsAfter administration of rimonabant or SR144528, non-obstructed rats with normal bladder function developed bladder overactivity (BO), which was counteracted by OEtA. OEtA also counteracted BO in obstructed rats. SR144528 did not affect bladder function in obstructed rats but counteracted the urodynamic effects of OEtA. Surprisingly, rimonabant (and AM251, another CB1 antagonist) reduced BO in obstructed rats, whereafter OEtA produced no additional urodynamic effects. CB1 expression increased in the sacral spinal cord of obstructed rats whereas no changes were observed for CB2 or FAAH. ConclusionsUrodynamic effects of systemic FAAH inhibition involve activities at spinal neuronal CB1 and CB2 receptors in normal and obstructed rats. Endogenous spinal CB receptor ligands seem to regulate normal micturition and BO. Altered spinal CB receptor functions may be involved in the pathogenesis of obstruction-induced BO. Neurourol. Urodynam. 35:464-470, 2016. (c) 2015 Wiley Periodicals, Inc.
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| 18. |
- Hakim, Lukman, et al.
(författare)
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Intratunical injection of autologous adipose stromal vascular fraction reduces collagen III expression in a rat model of chronic penile fibrosis
- 2019
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Ingår i: International Journal of Impotence Research. - : Springer Science and Business Media LLC. - 0955-9930 .- 1476-5489.
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronie’s disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-β1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-β1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD.
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| 19. |
- Hannan, Johanna L., et al.
(författare)
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Impaired contraction and decreased detrusor innervation in a female rat model of pelvic neuropraxia
- 2017
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Ingår i: International Urogynecology Journal. - : Springer Science and Business Media LLC. - 0937-3462 .- 1433-3023. ; 28:7, s. 1049-1056
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Tidskriftsartikel (refereegranskat)abstract
- Introduction and hypothesis: Bilateral pelvic nerve injury (BPNI) is a model of post-radical hysterectomy neuropraxia, a common sequela. This study assessed the time course of changes to detrusor autonomic innervation, smooth muscle (SM) content and cholinergic-mediated contraction post-BPNI. Methods: Female Sprague–Dawley rats underwent BPNI or sham surgery and were evaluated 3, 7, 14, and 30 days post-BPNI (n = 8/group). Electrical field-stimulated (EFS) and carbachol-induced contractions were measured. Gene expression was assessed by qPCR for muscarinic receptor types 2 (M2) and 3 (M3), collagen type 1α1 and 3α1, and SM actin. Western blots measured M2 and M3 protein expression. Bladder sections were stained with Masson’s trichrome for SM content and immunofluorescence staining for nerve terminals expressing vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), and neuronal nitric oxide synthase (nNOS). Results: Bilateral pelvic nerve injury caused larger bladders with less SM content and increased collagen type 1α1 and 3α1 gene expression. At early time points, cholinergic-mediated contraction increased, whereas EFS-mediated contraction decreased and returned to baseline by 30 days. Protein and gene expression of M3 was decreased 3 and 7 days post-BPNI, whereas M2 was unchanged. TH nerve terminals surrounding the detrusor decreased in all BPNI groups, whereas VAChT and nNOS terminals decreased 14 and 30 days post-BPNI. Conclusions: Bilateral pelvic nerve injury increased bladder size, impaired contractility, and decreased SM and autonomic innervation. Therapeutic strategies preventing nerve injury-mediated decline in neuronal input and SM content may prevent the development of a neurogenic bladder and improve quality of life after invasive pelvic surgery.
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| 20. |
- Hannan, Johanna L., et al.
(författare)
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Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats
- 2014
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Ingår i: Journal of Sexual Medicine. - : Wiley-Blackwell. - 1743-6095 .- 1743-6109. ; 11:6, s. 1442-1451
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims This study will characterize the molecular changes in penile HDAC after BCNI and determine if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods Five groups of rats (8-10 weeks, n=10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to determine intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-1 (TGF-1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were determined in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (-SMA) antibodies. Main Outcome Measures We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-1 protein expression; penile fibrosis; penile -SMA content. Results There was a voltage-dependent decline (Pless than0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (Pless than0.05) 14 days after BCNI. There was a slight increase in TGF-1 protein expression after BCNI. Histological analysis showed increased (Pless than0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (Pless than0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile -SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (Pless than0.05). Conclusion HDAC-induced pathological signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacological inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy.
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| 21. |
- Matsui, Hotaka, et al.
(författare)
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M1 Macrophages Are Predominantly Recruited to the Major Pelvic Ganglion of the Rat Following Cavernous Nerve Injury
- 2017
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Ingår i: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095 .- 1743-6109. ; 14:2, s. 187-195
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurogenic erectile dysfunction is a common sequela of radical prostatectomy. The etiology involves injury to the autonomic cavernous nerves, which arise from the major pelvic ganglion (MPG), and subsequent neuroinflammation, which leads to recruitment of macrophages to the injury site. Currently, two macrophage phenotypes are known: neurotoxic M1 macrophages and neuroprotective M2 macrophages. Aim To examine whether bilateral cavernous nerve injury (BCNI) in a rat model of erectile dysfunction would increase recruitment of neurotoxic M1 macrophages to the MPG. Methods Male Sprague-Dawley rats underwent BCNI and the MPG was harvested at various time points after injury. The corpora cavernosa was used to evaluate tissue myographic responses to electrical field stimulation ex vivo. Quantitative real-time polymerase chain reaction was used to examine the gene expression of global macrophage markers, M1 macrophage markers, M2 macrophage markers, and cytokines and chemokines in the MPG. Mathematical calculation of the M1/M2 index was used to quantify macrophage changes temporally. Western blot of MPG tissues was used to evaluate the protein amount of M1 and M2 macrophage markers quantitatively. Immunohistochemistry staining of MPGs for CD68, CD86, and CD206 was used to characterize M1 and M2 macrophage infiltration. Main Outcome Measures Corpora cavernosa responsiveness ex vivo; gene (quantitative real-time polymerase chain reaction) and protein (western blot) expressions of M1 and M2 markers, cytokines, and chemokines; and immunohistochemical localization of M1 and M2 macrophages. Results BCNI impaired the corporal parasympathetic-mediated relaxation response to electrical field stimulation and enhanced the contraction response to electrical field stimulation. Gene expression of proinflammatory (Il1b, Il16, Tnfa, Tgfb, Ccl2, Ccr2) and anti-inflammatory (Il10) cytokines was upregulated in the MPG 48 hours after injury. M1 markers (CD86, inducible nitric oxide synthase, interleukin-1β) and M2 markers (CD206, arginase-1, interleukin-10) were increased after BCNI in the MPG, with the M1/M2 index above 1.0 indicating that more M1 than M2 macrophages were recruited to the MPG. Protein expression of the M1 macrophage marker (inducible nitric oxide synthase) was increased in MPGs after BCNI. However, the protein amount of M2 macrophage markers (arginase-1) remained unchanged. Immunohistochemical characterization demonstrated predominant increases in M1 (CD68+CD86+) macrophages in the MPG after BCNI. Conclusion These results suggest that an increase in M1 macrophage infiltration of the MPG after BCNI is associated with impaired neurogenically mediated erectile tissue physiology ex vivo and thus has significant implications for cavernous nerve axonal repair. Future studies are needed to demonstrate that inhibition of M1 macrophage recruitment prevents erectile dysfunction after CNI.
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| 22. |
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| 23. |
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| 24. |
- Villa, Luca, et al.
(författare)
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The Rho-kinase inhibitor Y27632 promotes ureteral relaxation in an in vivo rat model for partial ureteral obstruction
- 2023
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Ingår i: World Journal of Urology. - : SPRINGER. - 0724-4983 .- 1433-8726. ; 41:9, s. 2541-2547
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Aim of this study was to evaluate the effect of intravenous Y27632 (a ROK inhibitor) on intra-ureteral pressures and on blood pressure in an in vivo rat model for unilateral partial ureteral obstruction (PUO). Methods: 15 Male Sprague Dawley rats were used. Under isofluran anesthesia, saline was continuously infused via polyethylene (PE)-10 catheters inserted in the ureters beneath the kidney pelvis. Left psoas muscle was sutured around the distal left ureter to create a partial obstruction. Carotid artery and femoral vein were cannulated with PE catheters for registration of mean arterial blood pressure (MAP) and for administration of drugs. Left and right ureter pressures and MAP were simultaneously recorded. Y27632 (0.03 and 0.1 mg/kg each n = 6–7) was given intravenously. T-test was used for comparisons. Results: Spontaneous peristaltic pressure waves were recorded at baseline for both ureters. After the obstruction, Y27632 reduced maximum pressure (MaxP) by 10.5 ± 1.9% (0.03 mg/kg; p = 0.004) and 29.1 ± 4.8% (0.1 mg/kg; p < 0.001), minimum pressure (MinP) by 5.2 ± 2.3% (0.03 mg/kg; p = 0.02) and 12.2 ± 3.4% (0.1 mg/kg; p = 0.009), the area under the curve (AUC) by 7.8 ± 2.4% (0.03 mg/kg; p = 0.008) and 16.5 ± 3.7% (0.1 mg/kg;p = 0.007), the waves amplitude by 23.4 ± 11.3% (0.03 mg/kg; p = 0.098) and 38.7 ± 7.5% (0.1 mg/kg; p < 0.001), with no effect on contraction frequency. During simultaneous recordings from the normal ureter at the investigated doses, Y27632 reduced MaxP, MinP, AUC and waves amplitude by 1–7%. The MAP was reduced by 12.5 ± 5.3% (0.03 mg/kg; p = 0.07) and 15.8 ± 1.8% (0.1 mg/kg; p < 0.001). Conclusions: Y27632 decreased intra-ureteral pressures of a partially obstructed ureter with limited effect on blood pressure in an animal model of unilateral PUO.
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| 25. |
- Weinhold, Philipp, et al.
(författare)
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The transient receptor potential A1 ion channel (TRPA1) modifies in vivo autonomous ureter peristalsis in rats
- 2021
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 40:1, s. 147-157
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Tidskriftsartikel (refereegranskat)abstract
- Aims: The current study aimed to explore the expression of transient receptor potential A1 ion channels (TRPA1) in the rat ureter and to assess if TRPA1-active compounds modulate ureter function. Methods: The expression of TRPA1 in rat ureter tissue was studied by immunofluorescence. The TRPA1 distribution was compared to calcitonin gene-related peptide (CGRP), α-actin (SMA1), anoctamin-1 (ANO1), and c-kit. For in vivo analyses, a catheter was implanted in the right ureter of 50 rats. Ureter peristalsis and pressures were continuously recorded by a data acquisition set-up during intraluminal infusion of saline (baseline), saline plus protamine sulfate (PS; to disrupt the urothelium), saline plus PS with hydrogen sulfide (NaHS) or cinnamaldehyde (CA). Comparisons were made between rats treated systemically with vehicle or a TRPA1-antagonist (HC030031). Results: TRPA1-immunoreactive nerves co-expressed CGRP and were mainly located in the suburothelial region of the ureter. Immunoreactivity for TRPA1 was also encountered in c-kit-positive but ANO1-negative cells of the ureter suburothelium and wall. In vivo, HC030031-treated rats had elevated baseline peristaltic frequency (p < 0.05) and higher intraluminal pressures (p < 0.01). PS increased the frequency of ureter peristalsis versus baseline in vehicle-treated rats (p < 0.001) but not in HC030031-treated rats. CA (p < 0.001) and NaHS (p < 0.001) decreased ureter peristalsis. This was counteracted by HC030031 (p < 0.05 and p < 0.01). Conclusions: In rats, TRPA1 is expressed on cellular structures considered of importance for peristaltic and mechanoafferent functions of the ureter. Functional data indicate that TRPA1-mediated signals regulate ureter peristalsis. This effect was pronounced after mucosal disruption and suggests a role for TRPA1 in ureter pathologies involving urothelial damage.
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