Sarcoplasmic reticulum calcium release is stimulated and inhibited by daunorubicin and daunorubicinol

Cardiac effects of anthracyclines or their metabolites may include both the stimulation and inhibition of Ca2+ release from sarcoplasmic reticulum. In this study, the ability of daunorubicin and its primary metabolite, daunor ubicinol, to stimulate and inhibit Ca2+ release from canine sarcoplasmic re ticulum (SR) vesicles was investigated. It was observed that both daunorubi cin and daunorubicinol were several fold more potent at inhibiting than the y were at stimulating SR Ca2+ release. Respective IC50 inhibition of daunor ubicin and daunorubicinol for caffeine-induced calcium release was 1.2 and 0.6 muM, and for spontaneous Ca2+ release was 3 and 1 muM. EC50's for dauno rubicin- and daunorubicinol-induced calcium release were 30 and 15 muM, res pectively. Inhibition of either spontaneous or caffeine-induced SR Ca2+ rel ease was inversely related to the amount of Ca2+ loaded into the SR before exposure to daunorubicin or daunorubicinol. The free-radical scavenger dith iothreitol did not attenuate the ability of anthracyclines to inhibit SR Ca 2+ release. A nonquinone daunorubicin derivative, 5-iminodaunorubicin, was less potent than daunorubicin at inhibiting caffeine-induced Ca2+ release. These data suggest anthracyclines and their metabolites may produce cardiot oxicity through free-radical independent, concentration-dependent effects o n SR Ca2+ release. These effects involve either inhibition or stimulation o f SR Ca2+ release and are partly dependent upon the presence of the quinone moiety. (C) 2000 Academic Press.