Adriamycin stimulates low-affinity Ca2+ binding and lipid peroxidation but depresses myocardial function.
Studies have been performed to examine the effects of different concentrations of adriamycin (10(-9)-10(-3) M) on sarcolemmal ATP-independent Ca2+ binding, contractility, ultrastructure, energy [ATP and creatine phosphate (CrP)] stores, and lipid peroxide activity in the rat myocardium. Low-affinity Ca2+ binding was stimulated, whereas high-affinity Ca2+ binding was inhibited by adriamycin in sarcolemmal vesicles isolated from ventricles. These alterations were accompanied by changes in the number of Ca2+ binding sites without affecting the membrane affinity for Ca2+. Peak developed force as well as positive and negative dF/dt in the isolated papillary muscle were depressed. The percent changes in contractility due to adriamycin were not affected by extracellular Ca2+ concentration. Ultrastructural changes in the papillary muscles due to adriamycin included mitochondrial swelling, presence of intramitochondrial granules, increased lysosomes, and disruption of myofibrils. ATP and CrP content of the papillary muscles was significantly reduced by the drug. Lipid peroxides, estimated by quantitating malondialdehyde content, were elevated by adriamycin. Most of these changes due to adriamycin became apparent at 10 microM or higher concentrations of the drug, and the maximum effect was seen at 1 mM of adriamycin. The in vitro depressant effect of adriamycin may not be related to changes in the low-affinity Ca2+ binding sites, but instead it appears to be associated with a lower energy state and myocardial cell damage.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009994:Osmolar Concentration; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012508:Sarcolemma / Q000378:metabolism; D013268:Stimulation, Chemical
D008054:Lipid Peroxides; D010725:Phosphocreatine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D002118:Calcium