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 effica cy of a variety of antiasthma drugs to reduce oxidant-mediated cytotox icity and to inhibit superoxide anion generated by human polymorphonuc lear leukocytes. We quantified in vitro the prevention of H2O2-mediate d cytotoxicity (lactate dehydrogenase release assay) using the antiast hma drugs as follows: ipratropium bromide, salbulamol (salbutamol base ), fenoterol (fenoterol hydrobromide), terbutaline (terbutaline sulfat e), isoproterenol, prednisolone (prednisolone hydrogensuccinate), becl omethasone (17,21-beclomethasone dipropionate) and reduced glutathione . Furthermore, fenoterol and isoproterenol were evaluated ex vivo to r educe superoxide anion (O-2(-)) generated by freshly isolated polymorp honuclear cells (PMN) from smokers with chronic obstructive lung disea se (n = 10). Using a concentration of 10(-4)M reduction of cytotoxicit y was quite different among beta(2)-agonists: fenoterol (97.8%) > isop roterenol (67.6%) > salbulamol (41.8%) > terbutaline (30.5%) > ipratro pium bromide (18.1%). Corticosteroids and theophylline had no antioxid ant effect. The cellular O-2(-) production of freshly isolated PMN was significantly (p < 0.05, comparisons O vs. greater than or equal to 1 0(-7) M) reduced with fenoterol and isoproterenol at concentrations gr eater than or equal to 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 molecul ar structure. These results demonstrate that beta(2)-agonists have in part a good intrinsic scavenger function on reactive oxygen species wh en 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.