title: Methylxanthine bronchodilators potentiate multiple human neutrophil functions.
abstract: Methylxanthines, including the bronchodilators theophylline and aminophylline, in high concentrations (greater than 10(-4) M) inhibit cyclic nucleotide phosphodiesterase activity and in low, clinically relevant concentrations (10(-5) to 10(-4) M) are antagonists of extracellular adenosine receptors. The effect of therapeutic concentrations of methylxanthines on human neutrophil functions stimulated by N-formyl-methionyl-leucyl-phenylalanine (FMLP) was examined. Preincubation of cytochalasin B-treated neutrophils with 10(-5) M to 3 X 10(-3) M methylxanthine resulted in a biphasic, concentration-dependent effect on neutrophil aggregation, lysosomal enzyme release, and superoxide anion formation. At 10(-5) to 10(-4) M, theophylline and aminophylline potentiated neutrophil aggregation, lysosomal enzyme release (30 to 50%, p less than 0.005), and superoxide anion formation (30 to 60%, p less than 0.005). 1-Methyl-3-isobutylxanthine at these same concentrations potentiated only neutrophil aggregation and lysosomal enzyme release (30 to 40%, p less than 0.005). The three methylxanthines inhibited each response up to 90% at concentrations greater than 10(-4) M. 8-Phenyltheophylline, which does not inhibit phosphodiesterase activity, produced only potentiation. Preincubation of neutrophils with adenosine deaminase mimicked the methylxanthine potentiation, whereas addition of adenosine (3 X 10(-8) to 3 X 10(-7) M) reversed the methylxanthine-induced potentiation in a concentration-dependent manner. These results indicate that therapeutic concentrations of methylxanthines may potentiate neutrophil activation in vivo by competing with circulating adenosine for neutrophil adenosine receptors.
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000241:Adenosine / Q000502:physiology*; D000243:Adenosine Deaminase / Q000494:pharmacology; D000628:Aminophylline / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002449:Cell Aggregation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors; D011983:Receptors, Purinergic / Q000187:drug effects*; D013481:Superoxides / Q000096:biosynthesis; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D011983:Receptors, Purinergic; D014970:Xanthines; D013481:Superoxides; D000628:Aminophylline; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013806:Theophylline; D000243:Adenosine Deaminase; D000241:Adenosine; D015056:1-Methyl-3-isobutylxanthine