Acute effects of doxorubicin on skinned cardiac muscle fibres of guinea pigs.
OBJECTIVE
The aim was to examine the effect of doxorubicin on spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum of skinned fibres, as measured by isometric tension development in EGTA free, Ca2+ free solution.


METHODS
Experiments were done on fragments of papillary muscles from the right ventricles of guinea pigs. Skinned fibres were prepared by treatment with saponin. The effects of doxorubicin in concentrations of 2 x 10(-9) to 2 x 10(-5) M on cyclic contractions were evaluated in 20 muscles. The effects of doxorubicin in concentrations of 2 x 10(-7) and 2 x 10(-5) M on pCa-tension relation were examined in 14 muscles treated with Brij-58.


RESULTS
Doxorubicin (2 x 10(-9) to 2 x 10(-5) M) increased the frequency of cyclic contractions and induced an incomplete muscle relaxation in a dose dependent manner. Doxorubicin 2 x 10(-7) M had no effect on pCa-tension relation. Doxorubicin 2 x 10(-5) M shifted the pCa-tension curve slightly to the left.


CONCLUSIONS
An incomplete muscle relaxation is considered to be due to an increase in Ca2+ release from the sarcoplasmic reticulum and a slight increase in the sensitivity of the contractile proteins to Ca2+. These observations suggest that one cause of the intracellular Ca2+ overload induced by doxorubicin, a putative mechanism of the doxorubicin induced cardiomyopathy, is attributable to the direct effects of doxorubicin on the sarcoplasmic reticulum, impairing its ability to sequester Ca2+.
Asayama
J
J
Second Department of Medicine, Kyoto Prefectural University of Medicine, Japan.
Yamahara
Y
Y
Tatsumi
T
T
Miyazaki
H
H
Inoue
M
M
Omori
I
I
Inoue
D
D
Nakagawa
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*
D004317:Doxorubicin; D002118:Calcium