| 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. |
- Benigni, F, et al.
(författare)
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Oral treatment with a vitamin D3 analogue (BXL628) has anti-inflammatory effects in rodent model of interstitial cystitis
- 2006
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 97:3, s. 617-624
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the effects of a vitamin D3 analogue (BXL628) in a model of chronic cystitis, as calcitriol analogues might be an interesting new therapeutic option for interstitial cystitis, for although the cause of the disease remains unclear, the increase in mast cells in the mucosa and detrusor muscle are significant. We devised a mouse model of allergen-induced allergic cystitis that is associated with the up-regulation of genes for interleukin-13, Fc epsilon RI alpha and mast cells-derived proteases, a massive inflammatory reaction in the bladder tissue, and augmented levels of mast cell-derived protease 1 (MMCP1) detected in mouse sera. Oral administration of BXL628 significantly reduced the expression of interleukin-13, Fc epsilon RI alpha and MMCP1 in the bladder. Furthermore, histological analysis showed a decrease in oedema and leukocyte infiltration in the bladder wall. BXL628 treatment reduced serum MMCP1 levels, indicating an effect on mast cell degranulation in vivo. Vitamin D3 analogues may successfully be used as anti-inflammatory agents in allergen-mediated inflammatory reactions. Moreover, the modulatory effect shown on mast cell activation by the BXL628 analogue strongly supports its potential therapeutic use in a possibly mast cell-dependent disease such as human interstitial cystitis.
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| 3. |
- Bivalacqua, Trinity J., et al.
(författare)
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Dysregulation of cGMP-dependent protein kinase 1 (PKG-1) impairs erectile function in diabetic rats: influence of in vivo gene therapy of PKG1 alpha
- 2007
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 99:6, s. 1488-1494
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the expression of cGMP-dependent protein kinase 1 (PKG1)alpha and PKG1 beta in the corpus cavernosum, and to evaluate the effect of adenoviral gene transfer of PKG1 alpha to the erectile compartment on erectile function in a rat model of diabetes. Diabetic (DM; induced by streptozotocin) male Sprague Dawley rats were transfected with adenoviruses (AdCMV beta gal or AdCMVPKG1 alpha, in 10 rats each) 2 months after the induction of DM. Intracavernosal pressure (ICP) during stimulation of the cavernosal nerve (CN) was assessed, and compared with mean arterial pressure (MAP). Erectile tissue was harvested for Western blot analysis, immunohistochemistry and total PKG activity. Ten age-matched rats without DM served as the control. Compared to controls, AdCMV beta gal-transfected DM rats had significantly lower peak ICP responses, ICP/MAP ratios, and filling rates during CN stimulation. In DM rats transfected with AdCMVPKG1 alpha, peak ICP, ICP/MAP ratios and filling rates were significantly better than in DM rats transfected with the reporter gene. As assessed by Western blot and immunohistochemistry, expression of PKG1 alpha and PKG1 beta was lower in corporal tissue from DM AdCMV beta gal-transfected rats than in controls. PKG1 alpha expression was improved after AdCMVPKG1 alpha gene therapy. Total PKG activity was lower in DM rat corporal tissue than in controls, and PKG1 alpha gene transfer significantly improved DM corporal PKG activity to a value greater than in the control. PKG1 alpha and PKG1 beta activities are reduced in the erectile tissue of the diabetic rat, and gene transfer of PKG1 alpha to the penis restored PKG activity and erectile function in vivo in diabetic rats. Gene therapy procedures targeting PKG1 alpha might be an interesting future therapeutic approach to overcome diabetic erectile dysfunction resistant to oral pharmacotherapy.
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| 4. |
- Dizeyi, Nishtman, et al.
(författare)
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Expression of serotonin receptors 2B and 4 in human prostate cancer tissue and effects of their antagonists on prostate cancer cell lines.
- 2005
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 47:6, s. 895-900
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Overexpression of receptors to neuroendocrine (NE) cell products has been suggested to contribute to development of hormone-refractory prostate cancer (HRPC). In this study, we evaluated the expression of 5-HTR2B and 5-HTR4 in HRPC, and the effects of their antagonist on PC cell line growth. METHODS: Proteins and mRNA expression was determined by immunohistochemistry, western blot and RT-PCR. Growth inhibition of PC cell lines was determined in vitro using ELISA-BrdU proliferation assay and cell cycle was evaluated by flow cytometry. RESULTS: Immunostaining of 5-HTR2B was observed in low-grade and high-grade tumours, PIN and BPH cells, and in vascular endothelial cells, whereas 5-HTR4 was found predominantly in high-grade tumours. This result was confirmed by western blot analysis. At the mRNA level, 5-HTR4 mRNA was expressed in DU145 and LNCaP cells. Antagonists to both receptor subtypes inhibited proliferation of PC cells in a dose-dependent manner. CONCLUSIONS: The present result indicate that 5-HTRs are present at various tumour stages and that antagonists to these receptors can inhibit the proliferative activity of androgen-independent PC cell lines.
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| 5. |
- Gomez-Pinilla, Pedro J., et al.
(författare)
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Effect of melatonin on age associated changes in guinea pig bladder function
- 2007
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 177:4, s. 1558-1561
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The incidence of urinary incontinence increases with age but the cause and effect relationship between aging and altered bladder function is poorly understood. It was suggested that melatonin can ameliorate negative effects induced by aging by its free radical scavenging activity and its ability to decrease oxidative stress. We investigated the changes in bladder function evoked by aging and the possible benefits of melatonin treatment on age related bladder disturbances. Materials and Methods: Bladder function was assessed using cystometry in conscious, freely moving female guinea pigs. Animals were grouped according to age as young adults (4 months old) and senescents (18 to 20 months old). A group of senescent animals were treated with 2.5 mg kg(-1) day(-1) melatonin for 21 days. Results: Aging led to increased detrusor activity, as demonstrated by short micturition intervals, decreased bladder capacity and spontaneous contractions during the filling phase. During the voiding phase aged animals showed lower micturition pressures than young adults. Melatonin counteracted the cystometric changes in senescent animals and restored micturition parameters to those of young adults. Conclusions: These results show that in guinea pigs aging induces detrusor overactivity. Melatonin treatment improved age induced changes in bladder function. If similar effects can be demonstrated in humans, melatonin treatment may be a new approach to decrease the impact of age related bladder disorders.
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| 6. |
- Gomez-Pinilla, Pedro J, et al.
(författare)
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Melatonin restores impaired contractility in aged guinea pig urinary bladder
- 2008
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Ingår i: Journal of Pineal Research. - : Blackwell Publishing Ltd. - 1600-079X .- 0742-3098. ; 44:4, s. 416-425
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Tidskriftsartikel (refereegranskat)abstract
- Urinary bladder disturbances are frequent in the elderly population but the responsible mechanisms are poorly understood. This study evaluates the effects of aging on detrusor myogenic contractile responses and the impact of melatonin treatment. The contractility of bladder strips from adult, aged and melatonin-treated guinea pigs was evaluated by isometric tension recordings. Cytoplasmatic calcium concentration ([Ca2+](i)) was estimated by epifluorescence microscopy of fura-2-loaded isolated detrusor smooth muscle cells, and the levels of protein expression and phosphorylation were quantitated by Western blotting. Aging impairs the contractile response of detrusor strips to cholinergic and purinergic agonists and to membrane depolarization. The impaired contractility correlates with increased [Ca2+](i) in response to the stimuli, suggesting a reduced Ca(2+)sensitivity. Indeed, the agonist-induced contractions in adult strips were sensitive to blockade with Y27362, an inhibitor of Rho kinase (ROCK) and GF109203X, an inhibitor of protein kinase C (PKC), but these inhibitors had negligible effects in aged strips. The reduced Ca2+ sensitivity in aged tissues correlated with lower levels of RhoA, ROCK, PKC and the two effectors CPI-17 and MYPT1, and with the absence of CPI-17 and MYPT1 phosphorylation in response to agonists. Interestingly, melatonin treatment restored impaired contractility via normalization of Ca2+ handling and Ca2+ sensitizations pathways. Moreover, the indoleamine restored age-induced changes in oxidative stress and mitochondrial polarity. These results suggest that melatonin might be a novel therapeutic tool to palliate aging-related urinary bladder contractile impairment.
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| 7. |
- Gratzke, Christian, et al.
(författare)
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Distribution and Function of Cannabinoid Receptors 1 and 2 in the Rat, Monkey and Human Bladder
- 2009
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Ingår i: JOURNAL OF UROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 181:4, s. 1939-1948
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We investigated the distribution of cannabinoid receptor subtypes 1 and 2 in the detrusor of different species and studied the effects of cannabinoid receptor 1 and 2 agonists on bladder function. Materials and Methods: Cannabinoid receptor 1 and 2 expression was studied with Western blot and immunohistochemistry in rat, monkey and human detrusors. Co-staining was done for markers of sensory nerves using calcitonin gene-related peptide (Euro-Diagnostica, Malmo, Sweden) and transient receptor potential vanilloid 1, and for cholinergic nerves using VAChT (Santa Cruz Biotechnology, Santa Cruz, California). Actions of the endogenous cannabinoid receptor-1 and 2 agonist anandamide (Sigma (R)), and the cannabinoid receptor 1 and 2 agonist CP55,940 (Sigma) on isolated detrusor and during cystometry in conscious rats were recorded. Results: Higher expression of cannabinoid receptor 2 but not cannabinoid receptor 1 was noted in the mucosa than in the detrusor. Compared to the detrusor larger amounts of cannabinoid receptor 2 containing nerves that also expressed transient receptor potential vanilloid 1 or calcitonin gene-related peptide were observed in the suburothelium. Nerve fibers containing cannabinoid receptor 2 and VAChT were located in the detrusor. Neither anandamide nor CP55,940 affected isolated detrusor carbachol (Sigma) contractions. Nerve contractions were enhanced by 10 mu M anandamide and decreased by 10 AM CP55,940 (P<0.05). In vivo CP55,940 increased the micturition interval by 46% and threshold pressure by 124% (p <0.05). Anandamide increased threshold pressure by 26% and decreased the micturition interval by 19% (p <0.05 and <0.01, respectively). Conclusions: The distribution of cannabinoid receptor 2 on sensory nerves and in the urothelium, and effects by CP55940 on the micturition interval and threshold pressure suggest a role for cannabinoid receptor 2 in bladder afferent signals. Co-expression of VAChT and cannabinoid receptor 2, and effects by CP55940 on nerve contractions suggest a cannabinoid receptor 2 mediated modulatory effect on cholinergic nerve activity. Anandamide may not be a good tool for cannabinoid receptor studies due to its activity at other receptors.
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| 8. |
- Gratzke, Christian, et al.
(författare)
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Transient Receptor Potential A1 (TRPA1) Activity in the Human Urethra-Evidence for a Functional Role for TRPA1 in the Outflow Region
- 2009
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Ingår i: EUROPEAN UROLOGY. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 55:3, s. 696-704
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Tidskriftsartikel (refereegranskat)abstract
- Background: A role for the transient receptor potential (TRP) A1 ion channel in rat lower urinary tract (LUT) sensation and disease has been proposed, but in the human LUT no information on TRPA1 activity is available. Objectives: To investigate the distribution of TRPA1 in the human urethra and to study the effect of TRPA1 agonists on isolated urethral strip preparations. Design, settings, and participants: Urethral specimens were obtained preoperatively from 10 patients and were freshly prepared for Western blot, immunohistochemistry, and functional in vitro investigations. Measurements: The expression patterns of TRPA1 were studied with Western blot and immunohistochemistry. The effects of allyl isothiocyanate (A1), cinnamaldehyde (CA), and NaHS (donor of H2S) on tension of urethral strips were investigated in tissue baths. Results and limitations: TRPA1 immunoreactivity (-IR) was found in nerve fibres in the suburothelial space and was also located to nerve fibres of the muscle layer. Single TRPA1-IR nerves extended into the urothelium. A majority, but not all TRPA1-IR nerves also expressed immunoreactivity for CGRP or TRPV1. In the urothelium, TRPV1 was located to the outer layers whereas TRPA1 was observed in basal urothelial cells. Interspersed between strands of smooth muscle cells of the urethral wall, TRPA1- and vimentin-IR cells containing central nuclei and slender cytoplasmatic extensions were observed. In functional experiments, TRPA1-agonists had no contractile effect in urethral preparations. After precontraction with phenylephrine, AI, CA, and NaHS caused concentration-dependent relaxations of urethral strip preparations.´ Conclusions: The localization of TRPA1 to nerves that also express TRPV1 and CGRP, and in urothelial cells and interstitial cells, as well as the findings that TRPA1 agonists can modify tone of urethral preparations, propose a role for TRPA1 in afferent and efferent sensory signaling of the human outflow region.
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| 9. |
- Hedlund, Petter, et al.
(författare)
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Effects of Tolterodine on Afferent Neutransmission in Normal and Resiniferatoxin Treated conscious Rats
- 2007
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 178, s. 326-331
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters. Materials and Methods The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine. Results In resiniferatoxin treated animals (0.3 mg kg−1 subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 μg kg−1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 μg kg−1 tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 μg kg−1 apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment. Conclusions Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding. Purpose The beneficial effects of antimuscarinics on detrusor overactivity and overactive bladder syndrome are exerted during bladder filling, when there is no parasympathetic outflow from the spinal cord. We tested the hypothesis that, if tolterodine exerts some of its effects on afferent nerves, the functional elimination of C-fiber afferents should affect the actions of the drug on urodynamic parameters. Materials and Methods The study was performed in normal female Sprague Dawley rats and rats treated with resiniferatoxin to eliminate vanilloid sensitive afferent nerves. Tolterodine was given intravenously to normal and resiniferatoxin treated animals. To test if tolterodine at the doses used affects efferent neurotransmission the drug was given to normal and resiniferatoxin treated animals in which detrusor activity was induced by apomorphine. Results In resiniferatoxin treated animals (0.3 mg kg−1 subcutaneously) the mean micturition interval and volume, and mean residual volume increased significantly compared to those in controls. Baseline and micturition pressures in control and resiniferatoxin treated animals were similar, whereas threshold pressures were higher in resiniferatoxin treated animals. In controls 10 μg kg−1 tolterodine administered intravenously increased the mean micturition interval, bladder capacity and micturition volume. In resiniferatoxin treated rats 1 and 10 μg kg−1 tolterodine increased the mean micturition interval, bladder capacity and micturition volume. Subcutaneous administration of 100 μg kg−1 apomorphine induced detrusor overactivity in all rats. The AUC of intravesical pressure during the initial 10 minutes from the start of detrusor overactivity showed no difference between normal and resiniferatoxin treated rats with or without tolterodine pretreatment. Conclusions Tolterodine increased the micturition interval and bladder capacity in controls and in resiniferatoxin treated animals, suggesting that these effects were exerted independently of resiniferatoxin sensitive afferents. Tolterodine did not decrease the contractile effects of apomorphine at the doses used, suggesting that the drug had no effect on efferent neurotransmission during voiding.
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| 10. |
- Hedlund, Petter
(författare)
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Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract-is there a basis for pharmacological targeting of cGMP?
- 2005
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Ingår i: World journal of urology. - : Springer Science Business Media. - 0724-4983 .- 1433-8726. ; 23:6, s. 362-367
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with alpha-adrenoceptor antagonists that reduce the tone of prostatic stromal and urethral smooth muscle has beneficial effects in patients with benign prostatic hyperplasia (BPH) and lower urinary tracts symptoms (LUTS) and has brought attention to regulatory mechanisms of smooth muscle contractility of the outflow region. The prostate, urethra and bladder neck are densely supplied by nitric oxide (NO)-synthase-containing nerves that cause relaxation upon activation. In various experimental models, altered function or activity of the NO/cGMP pathway of the bladder neck and urethra may be related to inappropriate or un-coordinated functions of the bladder outlet and detrusor, but causal connections between alterations in this signaling system, a dysfunctional bladder outlet, and the development of LUTS are not established for humans. The present review focuses on regulatory functions of smooth muscle contractility by the NO/cGMP-pathway in the bladder neck, urethra, and prostate. Disease-related alterations in the NO/cGMP-pathway, and putative options for pharmacological modification of this signaling pathway in the out-flow region are briefly discussed.
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