Anthracycline-induced tension in permeabilized cardiac fibers: evidence for the activation of the calcium release channel of sarcoplasmic reticulum

J Mol Cell Cardiol. 1993 Mar;25(3):249-59. doi: 10.1006/jmcc.1993.1032.


Anthracyclines, such as doxorubicin (DOX), are important cancer chemotherapeutic agents that are cardiotoxic. The mechanism for the cardiotoxicity is not well-defined. Recent studies have concluded that anthracyclines release calcium (Ca2+) from membrane fractions containing sarcoplasmic reticulum (SR). To determine whether anthracyclines release Ca2+ in situ from cardiac SR, the effects of DOX on Ca(2+)-activated contractions were analyzed in membrane-permeabilized and membrane-intact fibers from rabbit heart. DOX (10-120 microM) induced tension development in calcium-preloaded permeabilized fibers. DOX-induced tension required submicromolar Ca2+, and was blocked by ruthenium red (20 microM) and Triton X-100 treatment, characteristics shared by caffeine-induced tension referable to SR Ca(2+)-release. DOX (50 microM) did not alter the maximum Ca(2+)-activated tension or shift the Ca2+ concentration-tension relationship of permeabilized fibers, indicating no effect of DOX on the myofilaments. DOX (44-350 microM) depressed post-rest isometric contractility of membrane-intact fibers but did not inhibit steady-state contractility (at 1 Hz; 2.5 Mm Ca2+), similar to effects of caffeine and submicromolar ryanodine. The specific effects of DOX on post-rest contractility of membrane-intact fibers are consistent with DOX-induced Ca2+ release from the SR of membrane-permeabilized fibers. Thus, DOX alters SR Ca2+ release in situ which may contribute to the inotropic and lusitropic dysfunction observed with anthracyclines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / drug effects*
  • Calcium Channels / metabolism
  • Cardiotonic Agents / toxicity*
  • Doxorubicin / toxicity*
  • In Vitro Techniques
  • Myocardial Contraction / drug effects*
  • Permeability
  • Purkinje Fibers / drug effects*
  • Rabbits
  • Sarcoplasmic Reticulum / drug effects*
  • Sarcoplasmic Reticulum / metabolism


  • Calcium Channels
  • Cardiotonic Agents
  • Doxorubicin
  • Calcium