| 1. |
- 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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| 2. |
- 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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| 3. |
- Ekman, Mari, et al.
(författare)
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Receptor-induced phasic activity of newborn mouse bladders is inhibited by protein kinase C and involves T-type Ca channels.
- 2009
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 104:5, s. 690-697
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the mechanisms involved in the phasic contractile activity after muscarinic receptor activation of newborn urinary bladders and to compare neonatal and adult bladders. MATERIALS AND METHODS Detrusor muscle strips were isolated from newborn mice (aged 0-2 days) and compared with preparations from adult mice (aged 10-12 weeks). The effects of an activator (phorbol 12,13-dibutyrate, PDBu) and an inhibitor (GF109203X) of protein kinase C (PKC) on contractions were investigated. T-type Ca(2+) channels were blocked with NiCl(2). RESULTS The newborn urinary bladders responded with prominent phasic contractile activity in response to carbachol (1 microm). GF109203X (3 microm) reduced carbachol-induced force by approximately 60% in the newborn, compared with 30% in the adult. PDBu (1 microm) enhanced the muscarinic receptor-mediated contraction in adult bladder muscle, whereas it completely abolished the responses in the newborn. There was no inhibition after activation with depolarization (high-K(+)) or purinergic agonists (ATP, alpha,beta-methylene ATP). NiCl(2) (>30 microm) inhibited the peak responses to carbachol in the newborn and at 300 microm it completely abolished the phasic contractile response. The responses of the adult bladder muscle were only marginally affected by NiCl(2). CONCLUSIONS Muscarinic receptor stimulation recruits the PKC signalling pathway in both the adult and neonatal urinary bladder. Potent PKC activation is inhibitory on carbachol-induced activation in the newborn and stimulatory in the adult bladder. Furthermore, muscarinic receptor stimulation activates T-type Ca(2+) channels in the newborn, but not the adult bladder.
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| 4. |
- Ekman, Mari, et al.
(författare)
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Signal transduction pathways of muscarinic receptor mediated activation in the newborn and adult mouse urinary bladder.
- 2009
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Ingår i: BJU International. - 1464-4096. ; 103:1, s. 90-97
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To study the role of M(2) and M(3) muscarinic receptor subtypes, sources of activator Ca(2+), and mechanisms involved in increased force oscillations in muscarinic contractions in the bladders of newborn and adult mice, as in the adult bladder muscarinic M(3) receptors are considered to mediate the main part of bladder contraction, and this has not been established in the newborn bladder. MATERIALS AND METHODS Bladder preparations from newborn (0-2 days) and adult (10-12 weeks) mice were mounted for in vitro force registration and activated with carbachol and high-K(+) solution in the presence of M(3) (4-DAMP 30 nm) or M(2) (methoctramine, 100 nm) receptor antagonists. Thapsigargin (1 microm) or ryanodine (10 microm) were used to inhibit sarcoplasmic reticulum Ca(2+) release. L-NAME (300 microm) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microm) were used to inhibit nitric oxide synthase and guanylyl cyclase, respectively. Gap-junction function was inhibited with by 18-beta-glycyrrhetinic acid (18-beta-GA; 0.1-100 microm). Big-conductance (BK) and small-conductance (SK) K(+) channels were inhibited by apamine and charybdotoxin (0.3 microm), respectively. RESULTS Concentration-response relations for carbachol in the presence of 4-DAMP and methoctramine showed that M(3) receptors are the main activating pathway also in the newborn bladder. Neither thapsigargin nor ryanodine influenced the muscarinic responses of the newborn and adult bladders. Carbachol-induced contractions were not influenced by L-NAME or ODQ. The 18-beta-GA inhibited carbachol-induced contractions in both newborn and adult tissue in a similar manner. Apamine and charybdotoxin slightly increased the amplitude of the contractile responses. CONCLUSION These results suggest that in the newborn mouse bladder, as in adult bladders, the M(3) muscarinic receptor subtype is mainly responsible for carbachol-induced contractile responses. The main mechanism for muscarinic receptor-induced activation is influx of Ca(2+) from the extracellular medium, and there seems to be no major contribution of Ca(2+) release from intracellular stores. The phasic contractile activity induced by carbachol in the newborn bladder is not influenced by gap junction inhibition and does not involve SK and BK channels.
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| 5. |
- Lagou, M, et al.
(författare)
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Location of interstitial cells and neurotransmitters in the mouse bladder
- 2006
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 97:6, s. 1332-1337
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether interstitial cells (ICs) are present in the adult mouse bladder, and what transmitters characterize adjacent nerve fibres, as ICs in human and guinea-pig bladder lie close to nerve fibres but transmitters present in these nerves have not yet been reported. Sections of the bladder wall from 12 adult male mice (six each, aged 3-4 or 18-24 months) were incubated in carboxygenated Krebs' solution containing isobutyl-methyl-xanthene (1 mM), followed by the nitric oxide (NO) donor diethylamino-NONOate; control tissues remained in Krebs' solution. Samples were fixed in 4% paraformaldehyde and processed for immunofluorescence histochemistry for cGMP, neuronal NO synthase (nNOS), vesicular acetylcholine transferase (VAChT), calcitonin gene-related polypeptide (CGRP) and protein gene product (PGP) 9.5. ICs were identified as non-neuronal cells of appropriate morphology manifesting an increase in cGMP after exposure to the NO donor. ICs were apparent in the outer muscle, but not the inner muscle or suburothelial region. nNOS- and CGRP-immunoreactive fibres were close to and alongside IC processes. In contrast, nerve fibres containing VAChT were only occasionally found close to ICs and rarely running alongside them. ICs showed no immunoreactivity to c-kit. There was no overt difference in IC cell distribution between young and aged adult specimens. Older mice showed patchy denervation of the detrusor, but ICs were not specifically affected. ICs are confined to the outer part of the bladder wall in the mouse and may receive peptidergic and nitrergic innervation, which might serve to modulate their putative functional role. Alterations in the overall IC population do not appear to underlie ageing-related changes in lower urinary tract function.
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| 6. |
- Streng, Tomi, et al.
(författare)
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Phasic non-micturition contractions in the bladder of the anaesthetized and awake rat
- 2006
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 97:5, s. 1094-1101
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To characterize the contractile activity that occurs in the bladder during the filling phase of the micturition cycle (non-micturition contractions, NMCs), which generate transient rises in intravesical pressure not associated with urine flow.MATERIALS AND METHODS: The experiments were conducted using anaesthetized (chloral hydrate) and un-anaesthetized rats. In un-anaesthetized rats bladder contractile activity was measured using an intravesical cannula implanted under full surgical anaesthesia 3 days previously. In the anaesthetized rats the bladder was exteriorized and a cannula inserted through the dome. In these experiments electrical activity within the detrusor was also measured with a suction electrode on the bladder surface. For each rat, the experimental protocol involved filling the bladder at a constant rate (10 mL/h) to evoke micturition cycles, or infusion of a fixed volume and recording made under effective isovolumetric conditions.RESULTS: In both anaesthetized and un-anaesthetized rats there were transient rises in bladder pressure (0.5-3 cmH2O). In the anaesthetized rats the amplitude of the transients increased throughout the filling phase, with little change in frequency. The phasic NMCs generating these pressure transients were accompanied by electrical changes in the detrusor. In the middle phase of bladder filling the slow pressure changes were accompanied by slow waves of electrical activity which changed in the pressure cycles immediately before micturition to high-frequency low-amplitude signals. In the un-anaesthetized rats there was a period immediately after voiding where there was no activity. As filling proceeded, low-amplitude low-frequency NMCs appeared that gradually increased in frequency and amplitude during the filling phase. However, the frequency of the transients decreased immediately before micturition despite an increase in amplitude. Similar responses were seen during isovolumetric recording.CONCLUSION: The present results show the presence of NMCs in the rat bladder, identify volume-dependent changes in the pattern of this activity during the micturition cycle, and show that NMCs are accompanied by electrical changes in the detrusor. The physiological significance of NMCs is not known but it might be linked to the generation of afferent discharge from mechanoreceptors in the wall, so contributing to sensations related to bladder volume.
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| 7. |
- Vande Walle, Johan GJ, et al.
(författare)
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A new fast-melting oral formulation of desmopressin : A pharmacodynamic study in children with primary nocturnal enuresis
- 2006
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 97:3, s. 603-609
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the pharmacodynamic properties of a new oral lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 μg) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE, additional objectives were to determine the safety and tolerability of desmopressin in this population. PATIENTS AND METHODS: Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was >0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. RESULTS: All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose, for the highest threshold, the values were 1.3-8.6 h. CONCLUSION: Desmopressin, as the oral lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 μg) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night. © 2006 BJU International.
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| 8. |
- Waldkirch, Eginhard, et al.
(författare)
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Non-genomic effects of androgens on isolated human vascular and nonvascular penile erectile tissue
- 2008
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 101:1, s. 71-74
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To evaluate non-genomic effects of testosterone and dihydrotestosterone (DHT) on isolated human cavernosal arteries (HCA) and corpus cavernosum (HCC) using organ-bath studies and radio-immunoassays (RIA), as non-genomic effects of androgens are reported for vascular smooth musculature and there is evidence that the relaxant response involves a modulation of cyclic nucleotide tissue levels. MATERIALS AND METHODS The relaxation induced by the cumulative addition of testosterone and DHT (0.01-10 mu M) was studied using circular segments of HCA and strip preparations of HCC. To evaluate the effects of testosterone and DHT on tissue levels of cAMP and cGMP, specimens were exposed to increasing concentrations of the hormones. Forskolin and sodium nitroprusside (SNP) served as reference compounds. RESULTS Testosterone and DHT dose-dependently reversed the noradrenaline-induced tension of vascular segments and HCC strips. At the maximum concentration, testosterone and DHT reduced the mean (SD) tension to 79.8 (4.43)% and 83.9 (10.94)%, respectively. SNP and forskolin significantly stimulated the production of cGMP and cAMP. No effects of testosterone and DHT on cGMP and cAMP levels were detected. CONCLUSION Rapid androgen-induced relaxation of HCA and HCC occurs via non-genomic mechanisms. In penile erectile tissue, non-genomic relaxant effects of testosterone and DHT are not mediated via modulation of cyclic nucleotide tissue levels. Additional studies are required to establish if non-genomic relaxant effects are important in ensuring a basal level of perfusion to maintain overall penile function.
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| 9. |
- Werkström, Viktoria, et al.
(författare)
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Phosphodiesterase 5 in the female pig and human urethra : morphological and functional aspects
- 2006
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Ingår i: BJU International. - : Blackwell Publishing Ltd. - 1464-4096 .- 1464-410X. ; 98:2, s. 414-423
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To characterize the distribution of phosphodiesterase 5 (PDE-5), cGMP and cGMP-dependent protein kinase I (PKG1), and to evaluate the effect of pharmacological inhibition of PDE-5 in isolated preparations of pig and human urethra, as the nitric oxide (NO)/cGMP pathway generates the main inhibitory signals to reduce resistance in the bladder outlet and urethra during emptying of the bladder.MATERIALS AND METHODS: After obtaining ethics committee approval, urethral specimens were obtained from three female patients during cystectomy, and from young female pigs. The specimens were prepared for immunohistochemical investigations and for functional studies in organ baths. Effects of sildenafil, vardenafil and tadalafil (1 nm to 30 microm) were studied in l-noradrenaline (1 microm)-activated or spontaneously contracted preparations, and on relaxations induced by electrical-field stimulation (EFS). Levels of cGMP were determined by radioimmunoassay.RESULTS: After stimulation with the NO donor, DETA NONO-ate (1 mm), there was greater cGMP-immunoreactivity (IR) in urethral and vascular smooth muscles. There was a wide distribution of cGMP- and vimentin-positive interstitial cells between pig urethral smooth muscle bundles. There was also cGMP-IR within NO-synthase-IR endothelium. There was PDE-5 IR within the urethral and vascular smooth muscle cells, but also in vascular endothelial cells that expressed cGMP-IR. In pig and human sections, there was strong PKG1-IR in alpha-actin-IR urethral smooth muscle cells that also contained IR for cGMP. Sildenafil, vardenafil and tadalafil caused mean (sem) concentration-dependent relaxations of the pig urethra which, at 30 microm, were 80 (3)% (11 samples), 81 (5)% (12 samples) and 64 (4)% (10 samples) of the spontaneous tone. The relaxation of L-noradrenaline-contracted female human urethra was 100% in response to 10 microm sildenafil, and 85 (15)% and 47 (13)% for 30 microm of vardenafil and tadalafil, respectively (three samples). Vardenafil or sildenafil (30 microm) doubled cGMP levels in pig specimens. There were no effects on cGMP levels with tadalafil. EFS (1-32 Hz) caused l-NG-nitroarginine-sensitive relaxations of pig urethral muscle that were increased in amplitude and duration by PDE-5 inhibition. At 0.1 microm, sildenafil, vardenafil or tadalafil significantly prolonged the mean (sem) duration of the relaxation at 4 Hz by 55 (19)%, 45 (14)% and 51 (12)%, respectively.CONCLUSIONS: PDE-5-, cGMP- and PKG1-IR is widely distributed in human and pig urethral tissues. Nerve-induced relaxations of urethral preparations were enhanced at low concentrations of sildenafil, vardenafil and tadalafil, whereas there were direct smooth muscle-relaxant actions of the PDE-5 inhibitors at high concentrations. Inhibition of PDE-5 might be an interesting option to facilitate cGMP-mediated relaxation of the outflow region.
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| 10. |
- Asplund, Ragnar, et al.
(författare)
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Nocturia in relation to somatic health, mental health and pain in adult men and women
- 2005
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 95:6, s. 816-819
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the relationship of nocturia to somatic health, mental health and bodily pain. SUBJECTS AND METHODS: A randomly selected group of men and women aged 20-64 years, living in three small municipalities in northern Sweden, or in the city of Ostersund or in Stockholm, were sent a postal questionnaire containing questions on somatic and mental health, satisfaction with life, pain, nocturnal voiding, work and sick-listing from work. RESULTS: Reports (from 1948 respondents) on poor somatic and mental health and on pain all increased in parallel with increasing frequency of nocturnal voids. In a multiple logistic regression analysis with sex, age, somatic health, mental health and bodily pain as the independent variables, significant independent correlates (odds ratios, confidence intervals) of nocturnal micturition (two or more episodes vs none or one) were: age 45-59 vs 20-44 years, 1.9 (1.3-2.7), > or =60 vs 20-44 years, 3.8 (2.4-6.0); somatic health, poor vs good, 2.3 (1.4-3.7); mental health, poor vs good, 1.9 (1.2-3.0); pain, rather mild vs very mild or none, 1.5 (1.0-2.3); rather severe vs very mild or none, 1.9 (1.1-3.2); and very severe vs very mild or none, 6.0 (2.5-14.0). Gender was deleted by the logistic model. Sick-listing for > or = 60 days during the past year was reported by 4.9%, 10.6%, 5.6% and 38.9% of the men with none, one, two or > or = three nocturnal voids, respectively, and by 10%, 12.4%, 23% and 46.7% (both P < 0.001) of the corresponding women, respectively. Life satisfaction decreased in parallel with increased nocturia. CONCLUSION: The impairment of both somatic and mental health was associated with increased nocturnal voiding. Pain was associated with a substantial increase in nocturia after adjusting for age and somatic and mental health. Sick-leave was more common in association with more nocturnal voids.
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