| 1. |
- Andersson, Karl-Erik, et al.
(författare)
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Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS
- 2007
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 26:6, s. 928-933
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Tidskriftsartikel (refereegranskat)abstract
- Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.
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| 2. |
- 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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| 3. |
- Gandaglia, G., et al.
(författare)
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The fatty acid amide hydrolase inhibitor oleoyl ethyl amide counteracts bladder overactivity in female rats
- 2014
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Ingår i: Neurourology and Urodynamics. - : John Wiley & Sons. - 0733-2467 .- 1520-6777. ; 33:8, s. 1251-1258
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Tidskriftsartikel (refereegranskat)abstract
- AIMS:To study micturition and bladder overactivity in female rats after chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor oleoyl ethyl amide (OEtA).METHODS:Sprague-Dawley rats received daily subcutaneous injections of OEtA (0.3 mg/kg), or vehicle for 2 weeks. Cystometries, organ bath studies, Western blot, and immunofluorescence were then used. Expressions of FAAH, cannabinoid 1 and 2 receptors (CB1 and CB2), mitogen-activated protein kinase (MAPK), vesicular acetyl choline-transporter protein (VAChT), and calcitonin gene-related peptide (CGRP) were evaluated.RESULTS:At baseline, OEtA-treated rats had higher values (P < 0.05) of micturition intervals (MI) and volumes (MV), bladder capacity (BC), threshold pressure, and flow pressure than vehicle controls. Intravesical PGE2 reduced MI, MV, and BC, and increased basal pressure and the area under the curve in all rats. However, these urodynamic parameters were altered less by intravesical PGE2 in OEtA-treated rats (P < 0.05 vs. vehicle controls). Compared to vehicle controls, detrusor from OEtA-treated rats had larger contractions to carbachol at 10-0.1 µM, but no difference in Emax was recorded. FAAH, CB1, CB2, VAChT, or CGRP was similarly expressed in bladders from all rats. In separate experiments, intravesical OEtA increased mucosal expression of phosphorylated MAPK.CONCLUSIONS:Chronic FAAH inhibition altered sensory urodynamic parameters and reduced bladder overactivity. Even if it cannot be excluded that OEtA may act on central nervous sensory pathways to contribute to these effects, the presence of FAAH and CB receptors in the bladder and activation of intracellular signals for CB receptors by intravesical OEtA suggest a local role for FAAH in micturition control. Neurourol. Urodynam
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| 4. |
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| 5. |
- Hedlund, Petter
(författare)
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Cannabinoids and the Endocannabinoid System in Lower Urinary Tract Function and Dysfunction
- 2014
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Ingår i: Neurourology and Urodynamics. - : Wiley-Blackwell. - 0733-2467 .- 1520-6777. ; 33:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- AimsTo review knowledge on cannabinoids and the endocannabinoid system in lower urinary tract function and dysfunction. MethodsReview of MEDLINE using defined search terms, and manual analysis. Articles published in English were included. Results and DiscussionComponents of the endocannabinoid systemcannabinoid (CB) receptor types 1 and 2, anandamide, and fatty acid amide hydrolase (FAAH), which degrades anandamide and related fatty-acid amideshave been located to lower urinary tract tissues of mice, rats, monkeys, and humans. Studies have located CB receptors in urothelium and sensory nerves and FAAH in the urothelium. CB receptor- and FAAH-related activities have also been reported in the lumbosacral spinal cord. Data on supraspinal CB functions in relation to micturition are lacking. Cannabinoids are reported to reduce sensory activity of isolated tissues, cause antihyperalgesia in animal studies of bladder inflammation, affect urodynamics parameters reflecting sensory functions in animals models, and appear to have effects on storage symptoms in humans. FAAH inhibitors have affected sensory bladder functions and reduced bladder overactivity in rat models. Cannabinoids may modify nerve-mediated functions of isolated lower urinary tract tissues. ConclusionsEvidence suggests components of the endocannabinoid system are involved in regulation of bladder function, possibly at several levels of the micturition pathway. It is unclear if either CB receptor has a dominant role in modification of sensory signals or if differences exist at peripheral and central nervous sites. Amplification of endocannabinoid activity by FAAH inhibitors may be an attractive drug target in specific pathways involved in LUTS.
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| 6. |
- Lee, Tack, et al.
(författare)
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Simultaneous registration of intraabdominal and intravesical pressures during cystometry in conscious rats-effects of bladder outlet obstruction and intravesical PGE(2)
- 2008
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Ingår i: Neurourology and Urodynamics. - : John Wiley and Sons, Ltd. - 0733-2467 .- 1520-6777. ; 27:1, s. 88-95
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: A method was developed and evaluated to simultaneously register intraabdominal pressure (IAP) and intravesical pressure (IVP) during cystometry in conscious rats. In addition, IAP and IVP were recorded in rats with experimental detrusor overactivity (DO).METHODS: Sprague Dawley rats (n = 24) were used. Six female rats were subjected to partial bladder outlet obstruction for 2 weeks. A catheter was implanted into the bladder to record the IVP, and a balloon-fitted catheter was positioned in the abdominal cavity to record the IAP. PGE(2) was given intravesically to induce DO. Detrusor pressure (DP) was defined as the IVP corrected for IAP.RESULTS: Recorded as increases in IAP, all rats of both sexes exhibited abdominal straining during every void. In controls, a maximal IAP of 6.0 +/- 1.4 cmH(2)O (range 3-15 cmH(2)O) was registered (n = 12) at the time of the flow pressure (FP). Intravesical administration of PGE(2) or BOO did not affect the IAP at basal pressure, FP or micturition pressure. Changes in IAP due to movement or non-voiding-related straining were subtracted from IVP to generate DP and to visualize DO after BOO or intravesical PGE(2).CONCLUSIONS: The conscious rat uses abdominal straining during voiding, and maximal IAP is recorded at the onset of urinary flow. Simultaneous registration of IAP and IVP during the micturition cycle in conscious rats is a convenient method for accurate quantification of pressures inside the bladder and for studying "true" DO without interference from movement artifacts
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| 7. |
- Semerdzhiev, Y, et al.
(författare)
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Cystometric and in vitro muscle studies of cystoplastic appendiceal segments in the rat
- 2006
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Ingår i: Neurourology and Urodynamics. - : John Wiley and Sons, Ltd. - 0733-2467 .- 1520-6777. ; 25:3, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The functional integration of the smooth muscle of enterocystoplasties into the detrusor muscle was investigated in an awake-rat cystometry model and in vitro.METHODS: The upper fourth of the bladder was removed, and a detubularized appendiceal segment (7 x 7 mm), with preserved vasculature, was incorporated into the bladder. After 1 or 3 months, a catheter was fixed to the top of the bladders. After a 3-day recovery, cystometries were performed. In separate experiments, agonist and nerve-induced responses were evaluated on isolated bladder strips.RESULTS: Cystometries revealed reduced basal pressure and micturition pressure in enterocystoplasty (ECP) bladders. Bladder capacity and micturition volume were increased. Threshold pressure (pressure immediately before micturition) was significantly lower at 1 month, but not at 3 months. Bladder compliance was significantly higher in the operated at 1 month but not at 3 months. Threshold tension did not differ between control and corresponding operated groups. Residual urine was significantly higher in the operated groups. ECP strips showed increased maximal contractions to nerve stimulation, to levels similar to those of detrusor strips. Maximal responses to carbachol increased to levels between those of intestine and detrusor. The inhibitory effect of scopolamine on nerve induced contractions increased to levels similar to those for detrusor. Purinergic activation had no effect on intestinal or ECP strips, but contracted detrusor muscle.CONCLUSIONS: The smooth muscle of the bowel segment in rat ECP bladders underwent a partial change in the response to nerve stimulation from that of intestine towards that of detrusor. The cystometry experiments suggested a partial functional integration of the ECP segment into the detrusor.
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| 8. |
- 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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| 9. |
- Weinhold, Philipp, et al.
(författare)
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Transient receptor potential a1 (TRPA1) agonists inhibit contractions of the isolated human ureter
- 2018
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Ingår i: Neurourology and Urodynamics. - : Wiley. - 0733-2467 .- 1520-6777. ; 37:2, s. 600-608
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Mechanoafferent and peristaltic mechanisms of the human ureter involve transient receptor potential V1 (TRPV1)- and purinoceptor-mediated functions. Hydrogen sulphide, an endogenous TRPA1 ligand, is linked to inhibitory neurotransmission of the pig ureter. No information is available on TRPA1 activity in the human ureter. We therefore examined the distribution and function of TRPA1 in the human ureter. Methods: Expression of TRPA1 in human ureter tissue was studied by Western blot and immunofluorescence. The TRPA1 distribution was compared to TRPV1, calcitonin gene related peptide (CGRP), tyrosine hydroxylase (TH), and vimentin. Effects of the TRPA1 agonists allyl isothiocyanate (AI), cinnamaldehyde (CA), sodium hydrogen sulfide (NaHS), and capsaicin (TRPV1 agonist) on human ureter preparations were studied in organ baths. Results: By Western blot, bands were detected at the expected molecular weight for TRPA1. TRPA1- and TRPV1-immunoreactivities were located on CGRP-positive nerves, but not on TH-positive nerves. TRPA1 was also located in vimentin-positive interstitial cells. In functional experiments, neither of the TRPA1-agonists (1-100 μM) had any direct effects on ureter tension (baseline/potassium-induced contractions). However, CA, AI, NaHS, and capsaicin (10 μM) decreased (P < 0.01-0.05) tetrodotoxin-sensitive electrically induced (2,4,8,16,32 Hz) contractions. Inhibitory activities were 50-61% (CA), 30-56% (AI), 30-40% (NaHS), and 37-67% (Capsaicin). Conclusions: In the human ureter, TRPA1 is located to sensory nerves and interstitial cells. TRPA1 agonists inhibited electrically induced contractions but had no direct effect on smooth muscle tension of the human ureter. A role for TRPA1 in modulating neurotransmission and possibly peristalsis of the human ureter is proposed.
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