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, daunorubicinol, to stimulate and inhibit Ca2+ release from canine sarcoplasmic reticulum (SR) vesicles was investigated. It was observed that both daunorubicin and daunorubicinol were several fold more potent at inhibiting than they were at stimulating SR Ca2+ release. Respective IC50 inhibition of daunorubicin 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 daunorubicin- and daunorubicinol-induced calcium release were 30 and 15 muM, respectively. Inhibition of either spontaneous or caffeine-induced SR Ca2+ release was inversely related to the amount of Ca2+ loaded into the SR before exposure to daunorubicin or daunorubicinol. The free-radical scavenger dithiothreitol did not attenuate the ability of anthracyclines to inhibit SR Ca2+ 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 cardiotoxicity through free-radical independent, concentration-dependent effects on SR Ca2+ release. These effects involve either inhibition or stimulation of SR Ca2+ release and are partly dependent upon the presence of the quinone moiety. (C) 2000 Academic Press.