Shun-suke Takahashi (1), Martin A. Denvir (2), Lisbet Harder (3), David
J. Miller (4), Stuart M. Cobbe (2), Midori Kawakami (1), Niall G. MacFarlane
(4) and Eiichiro Okabe (1,*)
(1) Department of Pharmacology and ESR Laboratory, Kanagawa Dental College, 82 Inaoka-cho, Yokosuka, Kanagawa 238-8580, Japan
(2) Department of Medical Cardiology, Glasgow Royal Infirmary, Glasgow, United Kingdom
(3) Department of Pharmacology, Arhus University, Arhus, Denmark
(4) Institute of Biomedical and Life Sciences, Glasgow University, Glasgow, United Kingdom
(*) To whom correspondence should be addressed.
Abstract: Doxorubicin is an anthracycline antibiotic that is used widely as a chemotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this cardiotoxicity remain essentially unknown, despite numerous studies describing a range of structural and functional abnormalities. The purpose of the present study was to determine the in vivo and in vitro effects of doxorubicin exposure on sarcoplasmic reticulum (SR) Ca22+-content and contractile protein function. The Ca22+-content of SR is shown to have a biphasic response to in vivo and in vitro doxorubicin exposure that is time- and dose-dependent. In vitro doxorubicin exposure initially reduces the SR Ca22+-content, but the predominant action to block the SR Ca22+-release channel increases SR Ca22+-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca22+-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca22+-overload.
Keywords: Doxorubicin, Sarcoplasmic reticulum, Myofilament, Calcium sensitivity, Ventricular trabeculae (rabbit)