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Adenosine and selective A(2A) receptor agonists reduce ischemia/reperfusion injury of rat liver mainly by inhibiting leukocyte activation.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2000 Sep; Vol. 294 (3), pp. 1034-42. - Publication Year :
- 2000
-
Abstract
- To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A(2) receptor (A(2)R) stimulation, we investigated the effects of adenosine and selective A(2A) receptor (A(2A)R) agonists (YT-146 and CGS21680C) on I/R-induced liver injury in rats. Adenosine, YT-146, and CGS21680C, in the concentration of 10(-7) to 10(-5) M, significantly inhibited neutrophil elastase release by about 30 to 40% and increased intracellular Ca(2+) concentrations in isolated neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. Adenosine, YT-146, and CGS21680C, in the concentration of 10(-7) to 10(-5) M, significantly inhibited tumor necrosis factor (TNF)-alpha production by monocytes stimulated with endotoxin by about 50%. Although ZM241385, a selective A(2A)R antagonist, significantly enhanced the increase in neutrophil elastase release and intracellular Ca(2+) concentrations in neutrophils stimulated with fMLP, this agent did not affect the endotoxin-induced TNF-alpha production by monocytes. Rats were subjected to liver ischemia for 60 min. Serum levels of transaminases increased after hepatic I/R, peaking at 12 h after reperfusion. The i.v. infusion of adenosine (1 and 10 mg/kg/h), YT-146 (0.1 and 1 mg/kg/h), and CGS21680C (0.1 and 1 mg/kg/h) significantly inhibited the I/R-induced increase in serum transaminase levels 12 h after reperfusion. The I/R-induced decrease in hepatic tissue blood flow was significantly prevented by adenosine and YT-146. Hepatic levels of TNF-alpha, cytokine-induced neutrophil chemoattractant (equivalent to human interleukin-8), and myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by the administration of adenosine, YT-146, and CGS21680C. Although the histological neutrophil accumulation in the liver was significantly increased after I/R as evaluated by the naphthol AS-D chloroacetate technique, the administration of adenosine, YT-146, and CGS21680C significantly inhibited this increase. These findings suggest that adenosine reduces I/R-induced liver injury both by inhibiting the synthesis of inflammatory mediators and by inhibiting neutrophil degranulation directly, probably through A(2A)R stimulation.
- Subjects :
- Adenosine pharmacology
Animals
Calcium metabolism
Cells, Cultured
Chemokine CXCL1
Chemotactic Factors metabolism
Growth Substances metabolism
Humans
Ischemia metabolism
Ischemia pathology
Leukocyte Elastase metabolism
Lipopolysaccharides
Liver metabolism
Liver pathology
Male
Monocytes drug effects
Monocytes enzymology
Monocytes pathology
Peroxidase metabolism
Phenethylamines pharmacology
Purinergic P1 Receptor Antagonists
Rats
Rats, Wistar
Receptor, Adenosine A2A
Reperfusion Injury metabolism
Reperfusion Injury pathology
Triazines pharmacology
Triazoles pharmacology
Tumor Necrosis Factor-alpha biosynthesis
Adenosine analogs & derivatives
Alkynes pharmacology
Chemokines, CXC
Intercellular Signaling Peptides and Proteins
Ischemia drug therapy
Liver blood supply
Neutrophil Activation drug effects
Purinergic P1 Receptor Agonists
Reperfusion Injury drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 294
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 10945856