The receptor channel transient receptor potential vanilloid 1 (TRPV1) functions as a sensor of noxious heat and various chemicals. There is increasing evidence for a crosstalk between TRPV1 and opioid receptors. Here we investigated the effect of the prototypical TRPV1 agonist capsaicin and selected opioid ligands on TRPV1 movement in the plasma membrane and intracellular calcium levels in HEK293 cells expressing TRPV1 tagged with cyan fluorescent protein (CFP). We observed that lateral mobility of TRPV1 increased after treatment of cells with capsaicin or naloxone (a nonselective opioid receptor antagonist) but not with DAMGO (a μ-opioid receptor agonist). Interestingly, both capsaicin and naloxone, unlike DAMGO, elicited intracellular calcium responses. The increased TRPV1 movement and calcium influx induced by capsaicin and naloxone were blocked by the TRPV1 antagonist capsazepine. The ability of naloxone to directly interact with TRPV1 was further corroborated by [3H]-naloxone binding. In conclusion, our data suggest that besides acting as an opioid receptor antagonist, naloxone may function as a potential TRPV1 agonist.
- Klíčová slova
- calcium, fluorescence recovery after photobleaching, naloxone, receptor lateral mobility, transient receptor potential vanilloid 1,
- MeSH
- buněčná membrána metabolismus MeSH
- HEK293 buňky MeSH
- kapsaicin analogy a deriváty farmakologie MeSH
- kationtové kanály TRPV agonisté genetika metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- naloxon farmakologie MeSH
- narkotika - antagonisté farmakologie MeSH
- vápník metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kapsaicin MeSH
- kationtové kanály TRPV MeSH
- ligandy MeSH
- naloxon MeSH
- narkotika - antagonisté MeSH
- TRPV1 protein, human MeSH Prohlížeč
- vápník MeSH
A rat model of early sepsis induced by lipopolysaccharide (LPS) combined with interleukin-2 (IL-2) was developed. The primary aim was to assess the pharmacokinetics of gentamicin and sepsis-induced pathophysiological changes. Moreover, the effects on the glomerular filtration rate and tubular function were studied in septic and control rats. First, an intravenous (i.v.) bolus of LPSIL-2 (1 mg/kg-Pseudomonas aeruginosa, 15 µg/kg IL-2) or saline (controls, C) was administred. The Wistar rats were treated 30 min after LPSIL-2 with gentamicin as a 3 mg/kg i.v. bolus followed 10 min later by an i.v. 170-min infusion (GE, 0.09 mg/kg·min(-1)). The monitoring of vital functions, biochemistry and GE concentrations was performed. Creatinine clearance was 2-3 times lower and fractional urea excretion was 3-4 times less in septic rats as compared to controls(p<0.05), although urine flow was comparable. Capillary leakage caused a 55% elevation in the volume of distribution (V(c)) in the LPSIL+GE group vs. C+GE (p<0.05). The renal CL(ge) was less (2.2±0.59 vs. 3.8±0.53 mL/min·kg(-1), p<0.05), while the total CL(ge) was comparable (5.9±1.5 vs. 6.7±1.1 mL/min·kg(-1); p=0.30). In the LPSIL+GE group relative to C+GE, the half-life (t(1/2)) was 79% higher (p<0.05) and GE concentrations detected at the end of the study in the plasma and kidney were elevated 2.5-fold (p=0.09) and 2.2-fold (p<0.05), respectively. The model reproduced several consequences of early sepsis like in patients such as capillary leak, a decreased glomerular filtration rate (GFR) and the changes in pharmacokinetics of GE (increased values of V(c) and t(1/2) and a drop in renal CL(ge) proportional to that of CL(cr)). Nonrenal routes which, for the most part, compensate the reduced renal CL(ge) in septic rats deserve further study.
- MeSH
- antibakteriální látky krev farmakokinetika moč MeSH
- gentamiciny krev farmakokinetika moč MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- interleukin-2 aplikace a dávkování MeSH
- kapilární permeabilita účinky léků MeSH
- krysa rodu Rattus MeSH
- ledviny účinky léků metabolismus patofyziologie MeSH
- lipopolysacharidy aplikace a dávkování MeSH
- modely nemocí na zvířatech * MeSH
- potkani Wistar MeSH
- sepse metabolismus patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antibakteriální látky MeSH
- gentamiciny MeSH
- interleukin-2 MeSH
- lipopolysacharidy MeSH
The ultraviolet (UV) region of solar radiation is a critical factor in the initiation and development of a number of skin diseases. However, it is not only skin which is directly exposed to solar light that is affected by UV radiation, through low molecular weight mediators, generated upon irradiation, "non-skin" tissues can also be affected. The aim of this study was to examine in detail, the acute effects of UVA and UVB wavebands on hairless mice. Female SKH-1 hairless mice were exposed to a single dose of UVB (200, 800 mJ/cm(2)) or UVA (10, 20 J/cm(2)) using a solar simulator. The effects on haematological parameters, activity and/or expression of antioxidant enzymes, level of glutathione (GSH), markers of oxidative damage (lipid peroxidation and carbonylated proteins) were analysed in erythrocytes, plasma, liver and whole skin homogenates. No macroscopic changes were observed either 4 or 24 h after UVA/UVB exposure. The blood count showed a significant increase in leukocyte number and reduction of platelets 4 h following UVA and UVB irradiation, which disappeared 24 h after irradiation except for the higher UVA dose. Changes in oxidative stress-related parameters, particularly activity of catalase (CAT) and superoxide dismutase (SOD) and level of GSH and lipid peroxidation products, were found in skin, erythrocytes and liver. The expression of several enzymes (CAT, SOD, glutathione transferase (GST), nicotinamide adenine dinucleotide (phosphate) quinone oxidoreductase (NQO1) and hem oxygenase-1 (HO-1)) in skin was affected following UVA and UVB radiation. Increase in carbonylated proteins was found in plasma and skin samples.
- MeSH
- antioxidancia metabolismus MeSH
- biologické markery metabolismus MeSH
- erytrocyty metabolismus účinky záření MeSH
- játra enzymologie účinky záření MeSH
- karbonylace proteinů účinky záření MeSH
- krev imunologie metabolismus účinky záření MeSH
- kůže enzymologie účinky záření MeSH
- leukocyty účinky záření MeSH
- myši bezsrsté MeSH
- myši MeSH
- oxidační stres účinky záření MeSH
- peroxidace lipidů účinky záření MeSH
- sluneční záření škodlivé účinky MeSH
- trombocyty metabolismus účinky záření MeSH
- ultrafialové záření škodlivé účinky MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antioxidancia MeSH
- biologické markery MeSH
Methotrexate (MTX), an important anticancer and immunosuppressive agent, has been suggested for the treatment of primary biliary cirrhosis. However, the drug's pharmacodynamics and toxicity is dependent on its concentrations in plasma which in turn are directly related to MTX's elimination in the liver and kidney. Therefore, the aim of this study was to evaluate changes in MTX biliary and renal excretion during either intrahepatic or obstructive cholestasis in rats. The steady state pharmacokinetic parameters of MTX were evaluated in rats one (BDO1) or seven (BDO7) days after bile duct obstruction (BDO) or 18 h after administration of lipopolysaccharide (LPS). In comparison to the respective control groups, biliary and total clearances of MTX were decreased to 12% and 49% in the BDO1 group, to 5% and 56% in the BDO7 animals, and to 42% and 43% in the LPS group, respectively. Renal clearance of MTX was unchanged in BDO groups, but decreased to 23% of controls in the LPS animals. The serum biochemistry and expression of main hepatic MTX transporters (Mrp2, Mrp3, Mrp4, Bcrp, Oatp1a1, Oatp1a4 and Oatp1b2) confirmed the pathological cholestatic changes in the liver and partly elucidated the cause of changes in MTX pharmacokinetic parameters. In conclusion, this study is the first describing marked alteration of MTX hepatic and renal elimination induced by cholestasis in rats. Moreover, the reported changes in MTX pharmacokinetics and respective transporter expression suggest important mechanistic differences between the two widely used cholestatic models.
- MeSH
- biologický transport MeSH
- extrahepatální cholestáza metabolismus MeSH
- intrahepatální cholestáza metabolismus MeSH
- játra metabolismus patologie MeSH
- krysa rodu Rattus MeSH
- ledviny metabolismus MeSH
- lipopolysacharidy MeSH
- membránové transportní proteiny metabolismus MeSH
- methotrexát farmakokinetika MeSH
- modely u zvířat MeSH
- potkani Wistar MeSH
- žlučové ústrojí metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- lipopolysacharidy MeSH
- membránové transportní proteiny MeSH
- methotrexát MeSH
