Inhibitory effects of the beta-adrenergic receptor agonist zilpaterol on the LPS-induced production of TNF-alpha in vitro and in vivo.
In this study the anti-inflammatory properties of zilpaterol, a beta2-adrenergic receptor (AR) agonist specifically developed as a growth promoter in cattle were investigated. Although zilpaterol has a different structure compared with the beta2-AR agonists known to date, it was noted that it was able to bind to both the beta2-AR (Ki = 1.1 x 10(-6)) and the beta1-AR (Ki = 1.0 x 10(-5)). Using lipopolysaccharide (LPS)-exposed U937 macrophages, the production of cyclic adenosine-3',5'-cyclic monophosphate (cAMP) and tumor necrosis factor alpha (TNF-alpha) were investigated. Zilpaterol inhibited TNF-alpha release and induced intracellular cAMP levels in a dose-dependent manner. The inhibition of TNF-alpha release and induction of cAMP production was mainly mediated via the beta2-AR, as indicated by addition of beta1- and beta2-specific antagonists. The effects of zilpaterol were investigated in LPS-treated male Wistar rats after pretreatment with zilpaterol. Zilpaterol dosed at 500 microg/kg body weight reduced the TNF-alpha plasma levels. In conclusion, zilpaterol is a beta2-adrenergic agonist and an inhibitor of TNF-alpha production induced by LPS both in vivo and in vitro.
Verhoeckx
K C M
KC
TNO Pharma, Zeist, The Netherlands. Verhoeckx@pharma.tno.nl
Doornbos
R P
RP
van der Greef
J
J
Witkamp
R F
RF
Rodenburg
R J T
RJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014297:Trimethylsilyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects* / Q000378:metabolism; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D014297:Trimethylsilyl Compounds; D014409:Tumor Necrosis Factor-alpha; C475840:Zilpaterol; D000242:Cyclic AMP