Effects of 4'-O-tetrahydropyranyl-doxorubicin on isolated perfused rat heart and cardiac mitochondrial cytochrome C oxidase activity.
The acute cardiac effects of the antitumour anthracycline 4'-O-tetrahydropyranyl-doxorubicin (THP) were studied on isolated, perfused, spontaneously beating rat hearts and on cardiac mitochondrial cytochrome c oxidase activity. Perfusion for 1 hour with 2.5 or 5.0 micrograms/ml of THP was associated with a marked widening of the QRS complex and the S alpha T segment, as well as with a reduction of the R- and T-wave amplitude, the heart rate, the isometric systolic tension and the coronary flow. Heart perfusion with equimolar doses of doxorubicin (2.2 or 4.4 micrograms/ml) induced a significant enlargement of the SaT segment and a reduction in the heart rate and the coronary flow. Both anthracyclines inhibited the cytochrome c oxidase activity in a dose-dependent manner; however, THP exerted a significant inhibition at concentrations higher than doxorubicin (20 microM). Results demonstrate that THP induces a higher degree of acute cardiotoxicity on isolated rat hearts compared with doxorubicin. The reduced inhibitory effect of THP on the cytochrome c oxidase activity of isolated heart mitochondria is consistent with the lower degree of chronic cardiotoxicity displayed by THP in animals and humans.
Del Tacca
M
M
Institute of Medical Pharmacology, University of Pisa, Italy.
Danesi
R
R
Solaini
G
G
Bernardini
M
M
Bertelli
A
A
D000818:Animals; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000633:toxicity; D004562:Electrocardiography; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects*; D051381:Rats
D004317:Doxorubicin; C027260:pirarubicin; D003576:Electron Transport Complex IV