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)