Adriamycin-induced myocardial dysfunction in vitro is mediated by free radicals.
The role of free radicals in adriamycin (Adr)-induced acute myocardial changes was examined by using different antioxidants. Exposure of papillary muscles to Adr (100 microM) in a tissue bath for 60 min reduced developed force by 42%, increased lipid peroxidation by 200%, and resulted in characteristic ultrastructural changes. Catalase (4 x 10(4) U/l), an enzyme effective in the hydrolysis of hydrogen peroxide (H2O2), was more effective in maintaining the developed force than mannitol (20 mM), a hydroxyl radical scavenger. A small protection of developed force seen with superoxide dismutase (1.2 x 10(5) U/l), a quencher of superoxide radical, was evident for the first 15 min only. Only catalase and mannitol showed significant protection against Adr-induced increase in lipid peroxidation. Ultrastructural changes due to Adr alone included mitochondrial swelling, intramitochondrial granules, vacuolization, and disruption of sarcomeres. All of these changes were reduced in the presence of both catalase and mannitol, whereas superoxide dismutase was without any effect. Complete structural or functional protection was not seen with any of the antioxidants used in the study. Although both H2O2 and hydroxyl radical appear to be involved in Adr-induced deleterious effects, data on developed force also indicate that H2O2 may have a major role in mediating the acute effects of Adr in vitro.
Cardiovascular Sciences Division, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
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Lee
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Randhawa
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Singal
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced*; D002374:Catalase / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000648:ultrastructure; D004317:Doxorubicin / Q000494:pharmacology; D016166:Free Radical Scavengers; D005609:Free Radicals; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D008353:Mannitol / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000648:ultrastructure; D010100:Oxygen / Q000494:pharmacology*; D010210:Papillary Muscles / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D013482:Superoxide Dismutase / Q000494:pharmacology
D016166:Free Radical Scavengers; D005609:Free Radicals; D008353:Mannitol; D008315:Malondialdehyde; D004317:Doxorubicin; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen