Influence of cardioprotective cyclooxygenase and lipoxygenase inhibitors on peroxidative injury to myocardial-membrane phospholipid.
Oxygenase-catalyzed and non-enzymatic polyunsaturated fatty acid peroxidations have potential pathogenic roles in ischemic-reperfusion damage to the myocardium. Certain oxygenase inhibitors protect heart muscle from irreversible ischemic injury, and some antiperoxidants can inhibit oxygenase enzymes. We investigated the antiperoxidative abilities of eight anti-ischemic, cardioprotective oxygenase inhibitors to prevent myocardial-membrane phospholipid peroxidation through superoxide-driven, iron-promoted reactions with xanthine oxidase as the source of superoxide. Flurbiprofen, ibuprofen, and REV-5901-5 did not affect peroxidation at concentrations up to 1000 microM. BW755C, AA-861, nafazatrom, dipyridamole, and propyl gallate did protect and cardiac lipids against oxidative injury in a concentration-dependent manner with respective and antiperoxidant IC50 values (concentrations at which peroxidation was inhibited by 50%) of 0.22, 1.25, 3.0, 3.6 and 50 microM. Catechin and phenidone, known oxygenase inhibitors not yet evaluated as anti-ischemic agents, were also found to be antiperoxidants at low micromolar concentrations. Four cyclooxygenase inhibitors ineffective against myocardial infarction (aspirin, indomethacin, naproxen, and sulfinpyrazone) evidenced no antiperoxidant properties at concentrations up to 500 microM. The oxygenase inhibitor-antiperoxidants identified could neither quench superoxide radical nor inhibit xanthine oxidase. However, they were able to interrupt the propagation of an on-going peroxidation reaction. Their antiperoxidant profiles resembled those of known antioxidants, such as alpha-tocopherol, which inhibit peroxidation by intercepting lipid free-radical intermediates. These data raise the possibility that at least some oxygenase inhibitors could exert cardioprotective effects by directly influencing the sensitivity of myocardial-membrane phospholipid to peroxidative injury. Consequently, recognition of the antiperoxidant properties of these agents may aid dissection of their physiological and pharmacological actions.
Janero
D R
DR
Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, NJ 07110.
Burghardt
B
B
Lopez
R
R
Cardell
M
M
D001241:Aspirin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008563:Membrane Lipids / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009288:Naproxen / Q000494:pharmacology; D013442:Sulfinpyrazone / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014969:Xanthine Oxidase / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D008563:Membrane Lipids; D013481:Superoxides; D009288:Naproxen; D014969:Xanthine Oxidase; D001241:Aspirin; D013442:Sulfinpyrazone; D007213:Indomethacin