Effects of in vitro and in vivo exposure to doxorubicin (Adriamycin) on caffeine-induced Ca2+ release from sarcoplasmic reticulum and contractile protein function in 'chemically-skinned' rabbit ventricular trabeculae

Takahashi, S.-s., Denvir, M. A., Harder, L., Miller, D. J., Cobbe, S., Kawakami, M., MacFarlane, N. G. and Okabe, E. (1998) Effects of in vitro and in vivo exposure to doxorubicin (Adriamycin) on caffeine-induced Ca2+ release from sarcoplasmic reticulum and contractile protein function in 'chemically-skinned' rabbit ventricular trabeculae. Japanese Journal of Pharmacology, 76(4), pp. 405-413. (doi: 10.1254/jjp.76.405) (PMID:9623719)

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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) Ca2+-content and contractile protein function. The Ca2+-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 Ca2+-content, but the predominant action to block the SR Ca2+-release channel increases SR Ca2+-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca2+-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca2+-overload.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Dr David and Harder, Miss Lisbeth and MacFarlane, Professor Niall and Cobbe, Professor Stuart
Authors: Takahashi, S.-s., Denvir, M. A., Harder, L., Miller, D. J., Cobbe, S., Kawakami, M., MacFarlane, N. G., and Okabe, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Japanese Journal of Pharmacology
Publisher:Japanese Pharmacological Society
ISSN:0021-5198
ISSN (Online):1347-8648

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