Propranolol as xanthine oxidase inhibitor: implications for antioxidant activity.
Propranolol is the beta-blocker most widely used in the management of cardiovascular disorders. It has been proposed that propranolol may act as a "chain-breaking" antioxidant. We have directly examined the ability of propranolol to inhibit superoxide-dependent, iron-promoted cardiac membrane phospholipid peroxidation, with xanthine oxidase (XOD) as a physiologically-recognized, enzymatic superoxide generator. Our results demonstrate that propranolol not only protects cardiac-membrane lipid from peroxidative damage, but also acts as a simple, reversible XOD inhibitor, noncompetitive with xanthine substrate. Propranolol, at effective antiperoxidant and XOD-inhibitory concentrations, cannot scavenge superoxide radical. The antiperoxidative profile of propranolol resembles that of the known XOD inhibitor allopurinol, although allopurinol, a tight-binding substrate-analog competitive with xanthine, inhibits XOD in a manner mechanistically very different from that of propranolol. Furthermore, the antiperoxidative profiles of both propranolol and allopurinol do not resemble those of chain-breaking antioxidants such as alpha-tocopherol. These data, along with the tendency of propranolol to concentrate in myocardial membranes and cytosol, suggest that the observed antioxidant action of propranolol, as a consequence of XOD inhibition, could play a pharmacologic role in propranolol's cardioprotective effects.
Janero
D R
DR
Department of Pharmacology and Chemotherapy, Hoffman-La Roche Inc., Nutley, New Jersey 07110.
Lopez
R
R
Pittman
J
J
Burghardt
B
B
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000032:analysis; D005609:Free Radicals; D007501:Iron / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects*; D008081:Liposomes / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D009206:Myocardium / Q000032:analysis; D010084:Oxidation-Reduction; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism; D019820:Xanthine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000378:metabolism
D005609:Free Radicals; D008081:Liposomes; D008563:Membrane Lipids; D014970:Xanthines; D013481:Superoxides; D019820:Xanthine; D000493:Allopurinol; D011433:Propranolol; D007501:Iron; D014969:Xanthine Oxidase