Doxorubicin: mechanism of cardiodepressant actions in guinea pigs.
The clinical use of doxorubicin is frequently limited by its depressant effects on cardiac muscle, presumably resulting from alterations of Ca2+ movements. Therefore, the modification of various Ca2+ pools that contribute to cardiac contraction was assessed from developed tension observed in isolated atrial muscle preparations incubated at 31 degrees C and stimulated at 0.5 Hz. Doxorubicin (100 or 200 microM) caused a transient positive inotropic effect followed by a sustained and marked negative effect, prolonged the time to peak twitch tension and decreased the rate of relaxation. Potentiated posttest contraction was depressed to a greater extent compared with contractions observed at 0.5-Hz stimulation. After a 3-hr exposure to doxorubicin, effects of ryanodine to depress developed tension observed in preparations stimulated at 0.5 Hz were markedly smaller, indicating a reduced contribution of the ryanodine-sensitive Ca2+ pool to contractile activation. In atrial muscle preparations obtained from guinea pigs treated for 10 days with doxorubicin (total dose 5 mg/kg iv), similar results as above were observed. Moreover, a longer quiescent period was required to attain the maximal posttest contraction. These results indicate that an acute or subacute exposure to doxorubicin impairs the function of the cardiac sarcoplasmic reticulum.
Hagane
K
K
Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
Akera
T
T
Berlin
J R
JR
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology
D012433:Ryanodine; D004317:Doxorubicin; D002118:Calcium