AJP - Heart and Circulatory Physiology, Vol 250, Issue 3 419-H425, Copyright © 1986 by American Physiological Society
Adriamycin stimulates low-affinity Ca2+ binding and lipid peroxidation but depresses myocardial function
P. K. Singal and G. N. Pierce
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.
