Anthraquinone-sensitized Ca2+ release channel from rat cardiac sarcoplasmic reticulum: Possible receptor-mediated mechanism of doxorubicin cardiomyopathy

Isaac N Pessah, Emily L. Durie, Mary J. Schiedt, Ildiko Zimanyi

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110 Citations (Scopus)

Abstract

Rat cardiac membrane vesicles enriched in biochemical markers of the junctional region of sarcoplasmic reticulum (SR) and exhibiting ruthenium red-sensitive rapid Ca2+ release have been prepared. Doxorubicin and seven congeners are shown to enhance the binding of [3H]ryanodine to the ryanodine receptor with a strong structural requirement. Doxorubicin enhances the binding of [3H]ryanodine to SR membranes and soluble receptor preparations and induces Ca2+ release from SR vesicles in a highly Ca2+-dependent manner, suggesting that anthraquinones promote the open state of the junctional Ca2+ release channel by increasing the affinity of the Ca2+ activator site for Ca2+. Doxorubicin reduces the Kd of [3H]ryanodine binding solely by enhancing the rate of association. Caffeine competes for the same site with anthraquinones, because the caffeine-activated binding of [3H]ryanodine is inhibited by doxorubicin and vice versa. The acute effect of doxorubicin on the cardiac Ca2+ release channel is fully reversible; however, long term treatment (up to 24 hr) with doxorubicin increases the sensitivity of the preparation to subsequent acute challenge with doxorubicin. The thiol-reductive agent dithiothreitol enhances, whereas the reactive disulfide 4,4′-dithiodipyridine reduces, the doxorubicin-enhanced binding of [3H]ryanodine. These results demonstrate that the acute and chronic cardiotoxicity of anthraquinones may be accounted for by a receptor-mediated mechanism. Our findings suggest that the chronic effects observed with the clinical use of anthraquinones may be the result of a receptor-mediated shift in the redox equilibrium of allosteric thiols at the ryanodine receptor complex, which in turn leads to long term sensitization of the Ca2+ release channel.

Original languageEnglish (US)
Pages (from-to)503-514
Number of pages12
JournalMolecular Pharmacology
Volume37
Issue number4
StatePublished - Apr 1990

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Anthraquinones
Sarcoplasmic Reticulum
Cardiomyopathies
Doxorubicin
Ryanodine
Ryanodine Receptor Calcium Release Channel
Caffeine
Sulfhydryl Compounds
Ruthenium Red
Membranes
Dithiothreitol
Disulfides
Oxidation-Reduction
Biomarkers

ASJC Scopus subject areas

  • Pharmacology

Cite this

Anthraquinone-sensitized Ca2+ release channel from rat cardiac sarcoplasmic reticulum : Possible receptor-mediated mechanism of doxorubicin cardiomyopathy. / Pessah, Isaac N; Durie, Emily L.; Schiedt, Mary J.; Zimanyi, Ildiko.

In: Molecular Pharmacology, Vol. 37, No. 4, 04.1990, p. 503-514.

Research output: Contribution to journalArticle

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