Beta-2-agonists have antioxidant function in vitro. 2. The effect of beta-2-agonists on oxidant-mediated cytotoxicity and on superoxide anion generated by human polymorphonuclear leukocytes.
Therapeutic agents which may be able to enhance the antioxidant screen of the epithelial surface of the lung have the potential to influence the progression of lung inflammation. This study evaluates the efficacy of a variety of antiasthma drugs to reduce oxidant-mediated cytotoxicity and to inhibit superoxide anion generated by human polymorphonuclear leukocytes. We quantified in vitro the prevention of H2O2-mediated cytotoxicity (lactate dehydrogenase release assay) using the antiasthma drugs as follows: ipratropium bromide, salbutamol (salbutamol base), fenoterol (fenoterol hydrobromide), terbutaline terbutaline sulfate), isoproterenol, prednisolone (prednisolone hydrogensuccinate), beclomethasone (17,21-beclomethasone dipropionate) and reduced glutathione. Furthermore, fenoterol and isoproterenol were evaluated ex vivo to reduce superoxide anion (O2-) generated by freshly isolated polymorphonuclear cells (PMN) from smokers with chronic obstructive lung disease (n = 10). Using a concentration of 10(-4) M, reduction of cytotoxicity was quite different among beta(2)-agonists: fenoterol (97.8%) > isoproterenol (67.6% > salbutamol (41.8%) > terbutaline (30.5%) > ipratropium bromide (18.1%). Corticosteroids and theophylline had no antioxidant effect. The cellular O2- production of freshly isolated PMN was significantly (p < 0.05, comparisons 0 vs. > or = 10(-7) M) reduced with fenoterol and isoproterenol at concentrations > or = 10(-7) M. Propranolol had no inhibitory effect on antioxidant properties of beta(2)-agonists. We hypothesize that the antioxidant function of beta(2)-agonists is related to the number and formation of hydroxyl groups of the phenol rings within their molecular structure. These results demonstrate that beta(2)-agonists have in part a good intrinsic scavenger function on reactive oxygen species when used in micromolar concentrations. However, to achieve this effect supratherapeutic concentrations were necessary. Thus, the conceivable benefit of beta(2)-agonists in the treatment of high oxidant burden in vivo seems doubtful.
Gillissen
A
A
Department of Internal Medicine, University Hospital Bergmannsheil, Bochum, Germany.
Wickenburg
D
D
van Zwoll
D
D
Schultze-Werninghaus
G
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008173:Lung Diseases, Obstructive / Q000097:blood / Q000150:complications; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D005938:Glucocorticoids; D013481:Superoxides; D006861:Hydrogen Peroxide