PT  - JOURNAL ARTICLE
AU  - K Hagane
AU  - T Akera
AU  - J R Berlin
TI  - Doxorubicin: mechanism of cardiodepressant actions in guinea pigs.
DP  - 1988 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 655--661
VI  - 246
IP  - 2
4099  - http://jpet.aspetjournals.org/content/246/2/655.short
4100  - http://jpet.aspetjournals.org/content/246/2/655.full
SO  - J Pharmacol Exp Ther1988 Aug 01; 246
AB  - 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.