Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure.
To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.
Kusuoka
H
H
First Department of Medicine, Osaka University Medical School, Japan.
Futaki
S
S
Koretsune
Y
Y
Kitabatake
A
A
Suga
H
H
Kamada
T
T
Inoue
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives; D004734:Energy Metabolism / Q000502:physiology*; D005289:Ferrets; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D006706:Homeostasis / Q000502:physiology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism
D010710:Phosphates; D010725:Phosphocreatine; D004533:Egtazic Acid; D004317:Doxorubicin; C039877:5,5'-difluoro-1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D000255:Adenosine Triphosphate; D002118:Calcium