Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.

Department of Bioanalysis, TNO Pharma, 3700 AJ Zeist, The Netherlands. izeboud@pharma.tno.nl
To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats.Standard male Wistar rats.A disease-model of lipopolysaccharide (LPS)-induced acute systemic inflammation was used. The beta(2)-selective AR agonist clenbuterol was administered before, during, and after LPS-challenge to investigate its effects on the acute inflammatory response and associated liver-failure.The following parameters have been measured in plasma: TNF alpha, IL-1 beta, IL-6, IL-10, AST, ALT, and Bilirubin. Liver histological examination was performed to look for changes in tissue morphology.Administration of clenbuterol (p.o.) one hour before, or intravenous at the same time as LPS-challenge resulted in a marked reduction of plasma levels of TNF alpha, IL-1 beta, and IL-6. A change both in plasma-level and in time-concentration profile of the anti-inflammatory cytokine IL-10 was found. Clenbuterol minimized LPS-induced liver damage, as represented by significantly lowered concentrations of several parameters for liver-failure (AST, ALT, Bilirubin), and improved hepatic tissue morphology. Clenbuterol administration after LPS challenge failed to inhibit TNF alpha-release but reduced liver-damage. Simultaneous use of the beta(2)-AR antagonist propranolol augmented LPS-induced liver failure, suggesting a role of endogenous adrenoceptor-agonists in prevention of organ-failure during systemic inflammation.The results indicate that a selective beta(2)-AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of (acute) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure.
Mesh Terms:
Adrenergic beta-Agonists, Adrenergic beta-Antagonists, Alanine Transaminase, Animals, Aspartate Aminotransferases, Clenbuterol, Endotoxins, Inflammation, Interleukin-1, Interleukin-10, Interleukin-6, Lipopolysaccharides, Liver, Liver Failure, Male, Osmolar Concentration, Propranolol, Rats, Rats, Wistar, Tumor Necrosis Factor-alpha
Inflamm. Res. Mar. 01, 2004; 53(3);93-9 [PUBMED:15021963]
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