title: Inhibition of superoxide generation and myeloperoxidase release by carvedilol after receptor and nonreceptor stimulation of human neutrophils.
abstract: OBJECTIVE
  To compare three stimuli which activate human neutrophils with different signal transduction mechanisms, in order to better localize the effect of the beta-adrenoceptor antagonist carvedilol (CARV) on superoxide generation (O2*-) and myeloperoxidase release (MPO). The effect of CARV [0.1-100 micromol/l] on O2*- generation and MPO release from isolated human neutrophils was studied after specific receptor activator N-formyl-methionyl-leucyl-phenylalanine (fMLP) and nonreceptor phorbol-12-myristate-13-acetate (PMA) and calcium ionophor (A23187) stimuli.
  
  
  METHODS
  O2*- generation was measured as superoxide dismutase inhibitable reduction of cytochrome c and MPO release as the oxidation of o-dianisidine in the presence of hydrogen peroxide in a spectrophotometer Hewlet Packard 8452 A at respective 550 and 463 nm.
  
  
  RESULTS
  CARV had no effect on O2*- generation and MPO release in nonstimulated cells. In the concentration 10 and 100 micromol/l, it significantly decreased fMLP and PMA stimulated O2*- generation and MPO release. Incubation of neutrophils with CARV [100 micromol/l] caused significant inhibition of O2*- generation and MPO release induced by A23187. Wortmannin, a specific inhibitor of 1-phosphatidylinositol-3-kinase, inhibited significantly only fMLP stimulated O2*- generation. CARV [100 micromol/l] with wortmannin [50 nmol/l] further decreased O2*- generation after the same stimulus.
  
  
  CONCLUSIONS
  CARV decreased O2*- generation and MPO release from isolated human neutrophils both by membrane-operating stimulus - fMLP and membrane bypassing activators - PMA and A 23187. This fact, together with effect the of wortmannin, indicates that the inhibition may be attributed to the non-specific action of CARV and its interference with phospholipase D signaling pathway, which plays only a minor role in proteinkinase C stimulated O2*- generation.
authors.affiliation: Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia. exfatama@savba.sk
authors.forename: Tatiana
authors.initials: T
authors.lastname: Macickova
authors.forename: Jana
authors.initials: J
authors.lastname: Pecivova
authors.forename: Radomir
authors.initials: R
authors.lastname: Nosal
authors.forename: Antonin
authors.initials: A
authors.lastname: Lojek
authors.forename: Michaela
authors.initials: M
authors.lastname: Pekarova
authors.forename: Daniela
authors.initials: D
authors.lastname: Cupanikova
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D016877:Oxidants / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000319:Adrenergic beta-Antagonists; D000730:Androstadienes; D002227:Carbazoles; D016877:Oxidants; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D013481:Superoxides; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin