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- Abrams, P, et al.
(författare)
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Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder
- 2006
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 148:5, s. 565-578
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Forskningsöversikt (refereegranskat)abstract
- 1 The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures. 2 Muscarinic M-3 receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M-2 receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents. 3 Although the role of muscarinic receptors in the bladder, other than M3 receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected. 4 This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M-3 selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.
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| 3. |
- Andersson, Michael, 1980, et al.
(författare)
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Cholinergic nitric oxide release from the urinary bladder mucosa in cyclophosphamide-induced cystitis of the anaesthetized rat.
- 2008
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Ingår i: British journal of pharmacology. - : Wiley. - 0007-1188. ; 153:7, s. 1438-44
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Previous reports have suggested that nitric oxide (NO) may be released by cholinergic stimuli in the rat bladder in cyclophosphamide-induced cystitis, affecting bladder function. In the current study, we evaluated the effects of cyclophosphamide-induced cystitis on muscarinic whole bladder contractile responses in vivo, and further, if NO might be released from the mucosa by cholinergic stimuli.Experimental approach: Male rats were pre-treated either with cyclophosphamide (100 mg kg(-1); to induce cystitis) or saline (serving as controls). 60 h later, rats were anaesthetized and bladder pressure monitored.Key results: The muscarinic receptor agonist methacholine (MeCh; 0.5-5 mug kg(-1) i.v.) induced similar contractions (i.e. bladder pressure increases) in inflamed bladders as in controls, which were attenuated dose-dependently by the muscarinic M(1)/M(3)/M(5) antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP; 0.1-1000 mug kg(-1) i.v.). In inflamed bladders, the cholinergic bladder contractions were enhanced after removing the mucosa, while cholinergic contractions were similar in intact and urothelium-denuded inflamed bladders in the presence of the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 30 mg kg(-1) i.v.). L-NAME attenuated the antagonistic effect of 4-DAMP on MeCh-induced contractions in intact inflamed bladders. However L-NAME did not affect the antagonism by 4-DAMP of MeCh-induced contractions of urothelium-denuded bladders, under control conditions or with cyclophosphamide-induced cystitis.Conclusions and implications: In cyclophosphamide-induced cystitis, the cholinergic function of the bladder is altered. In the inflamed bladder, NO seems to be released via cholinergic stimuli through mucosal muscarinic M(3)/M(5) receptors, presumably on urothelial cells, affecting bladder function.British Journal of Pharmacology (2008) 153, 1438-1444; doi:10.1038/bjp.2008.6; published online 4 February 2008.
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- Bassil, A K, et al.
(författare)
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Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract.
- 2007
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 150:1, s. 58-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated.EXPERIMENTAL APPROACH: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPgammaS assay and transfected cells.KEY RESULTS: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01-1000 nM, respectively (P>0.05 each; n=4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 microM to facilitate EFS-evoked contractions of the stomach (increases were 42.7+/-7.8% and 21.2+/-5.0 % in the absence and presence of obestatin 1 nM; P<0.05; n=12); higher concentrations (10-1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT(4) receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3+/-14.0% and 42.6+/-8.7% in the absence and presence of 1000 nM obestatin; n=10). Obestatin (up to 10 microM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg(-1) min(-1)) had no effects. Obestatin (2500 pmol kg(-1) min(-1), starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg(-1) min(-1)) to shorten MMC cycle time.CONCLUSIONS AND IMPLICATIONS: Obestatin has little ability to modulate rat GI motility.
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- Bengtsson, Jörgen, et al.
(författare)
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The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 157:6, s. 1085-1096
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied. Experimental approach Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg.kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated. Key results Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups. Conclusions and implications The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.
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- Dold, Stefan, et al.
(författare)
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Simvastatin protects against cholestasis-induced liver injury.
- 2009
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 156, s. 466-474
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg.kg(-1)) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg.kg(-1) simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg.kg(-1) simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications: These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.
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