Patterns of interaction between anthraquinone drugs and the calcium-release channel from cardiac sarcoplasmic reticulum.
We have studied the effects of clinically useful anthraquinones on the cardiac sarcoplasmic reticulum calcium-release channel. Micromolar concentrations of doxorubicin and other anthracyclines at the cytosolic face of the channel significantly and reversibly increase the open probability of single channels in artificial phospholipid bilayers. Lifetime analysis shows that anthracyclines and calcium are synergistic activators of the calcium-release channel. Radiolabeled ryanodine binding suggests that all the anthracyclines studied are equally potent as channel activators in vitro. Mitoxantrone, an anthracenedione derivative, variably increases channel open probability at low (1-10 microM) concentrations. Higher concentrations are associated with the appearance of channel currents with lower amplitudes than the fully open state, and normal openings are reduced in frequency. At these concentrations, the interaction of mitoxantrone with the channel reduces the level of ryanodine binding. Abnormal function of the cardiac calcium-release channel will alter calcium handling within the myocyte and may be the basis for anthraquinone-related cardiotoxicity.
Holmberg
S R
SR
Department of Cardiac Medicine, National Heart & Lung Institute, London, UK.
Williams
A J
AJ
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D007700:Kinetics; D008051:Lipid Bilayers; D008942:Mitoxantrone / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology*; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D012756:Sheep
D015220:Calcium Channels; D008051:Lipid Bilayers; D011950:Receptors, Cholinergic; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D004317:Doxorubicin; D008942:Mitoxantrone; D002118:Calcium