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.
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.
Takahashi
S
S
Department of Pharmacology and ESR Laboratory, Kanagawa Dental College, Yokosuka, Japan.
Denvir
M A
MA
Harder
L
L
Miller
D J
DJ
Cobbe
S M
SM
Kawakami
M
M
MacFarlane
N G
NG
Okabe
E
E
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D002110:Caffeine; D004317:Doxorubicin; D002118:Calcium