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Inhibitory effects of the β2-adrenergic receptor agonist zilpaterol on the LPS-induced production of TNF-α in vitro and in vivo

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Author: Verhoeckx, K.C.M. · Doornbos, R.P. · Greef, J. van der · Witkamp, R.F. · Rodenburg, R.J.T.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Journal of Veterinary Pharmacology and Therapeutics, 6, 28, 531-537
Identifier: 238830
doi: doi:10.1111/j.1365-2885.2005.00691.x
Keywords: Biology Pharmacology · Analytical research · 3 isopropylamino 1 (7 methyl 4 indanyloxy) 2 butanol · alprenolol · atenolol · bacterium lipopolysaccharide · beta 1 adrenergic receptor blocking agent · beta 2 adrenergic receptor blocking agent · beta 2 adrenergic receptor stimulating agent · clenbuterol · cyclic AMP · formoterol · isoprenaline · propranolol · salbutamol · tumor necrosis factor alpha · unclassified drug · zilpaterol · animal experiment · antiinflammatory activity · article · cattle · cell strain U937 · controlled study · cytokine production · dose response · drug effect · drug receptor binding · drug structure · human · human cell · inflammation · macrophage · male · nonhuman · priority journal · rat · rat strain · Adrenergic beta-Agonists · Animals · Cattle · Cyclic AMP · Dose-Response Relationship, Drug · Escherichia coli · Humans · Immunologic Factors · Lipopolysaccharides · Macrophage Activation · Male · Rats · Rats, Wistar · Trimethylsilyl Compounds · Tumor Necrosis Factor-alpha · U937 Cells · Animalia · Bacteria (microorganisms) · Bos taurus · Rattus norvegicus

Abstract

In this study the anti-inflammatory properties of zilpaterol, a β2-adrenergic receptor (AR) agonist specifically developed as a growth promoter in cattle were investigated. Although zilpaterol has a different structure compared with the β2-AR agonists known to date, it was noted that it was able to bind to both the β2-AR (K i = 1.1 × 10-6) and the β1-AR (Ki = 1.0 × 10-5). Using lipopolysaccharide (LPS)-exposed U937 macrophages, the production of cyclic adenosine-3′, 5′-cyclic monophosphate (cAMP) and tumor necrosis factor alpha (TNF-α) were investigated. Zilpaterol inhibited TNF-α release and induced intracellular cAMP levels in a dose-dependent manner. The inhibition of TNF-α release and induction of cAMP production was mainly mediated via the β2-AR, as indicated by addition of β1- and β2-specific antagonists. The effects of zilpaterol were investigated in LPS-treated male Wistar rats after pretreatment with zilpaterol. Zilpaterol dosed at 500 μg/kg body weight reduced the TNF-α plasma levels. In conclusion, zilpaterol is a β2-adrenergic agonist and an inhibitor of TNF-α production induced by LPS both in vivo and in vitro. © 2005 Blackwell Publishing Ltd.