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Time‐related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function
Author(s) -
Mushlin Phillip S.,
Cusack Barry J.,
Boucek Robert J.,
Andrejuk Tomasz,
Li Xuande,
Olson Richard D.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13909.x
Subject(s) - doxorubicin , cardiac function curve , medicine , pharmacology , function (biology) , cardiology , chemistry , biology , heart failure , chemotherapy , microbiology and biotechnology
1 The present study evaluated the time‐dependency of acute anthracycline cardiotoxicity by varying the duration of exposure of rabbit isolated atria to doxorubicin and determing changes (1) in contraction and relaxation and (2) in atrial concentrations of doxorubicin and its C‐13 hydroxy metabolite, doxorubicinol. 2 Following addition of doxorubicin (175 μ m ) to atria, contractility ( d F/ d t), muscle stiffness (resting force, RF) and relaxation (90% relaxation time, 90% RT) were monitored for a 3.5 h period. 3 Doxorubicin (175 μ m ) progressively diminished mechanical function (decreased d F/ d t, increased RF and prolonged 90% RT) over 3 h. Doxorubicinol (1.8 μ m ), however, failed to produce time‐related cardiac dysfunction; it depressed contractile function and increased muscle stiffness during the first 30 min without causing additional cardiac dysfunction during the remaining 3 h of observation. Doxorubicinol had no effect on 90% RT. 4 During treatment with doxorubicin, atria contained considerably more doxorubicin than doxorubicinol (ratio of doxorubicin to doxorubicinol ranged from 778 to 74 at 0.5 and 3 h, respectively). Elevations of doxorubicin and doxorubicinol in atria paralleled the degree of dysfunction of both contraction and relaxation; increases in muscle stiffness, however, were more closely associated with increases of doxorubicinol than doxorubicin. 5 To probe the relation between cardiac doxorubicinol and myocardial dysfunction further, without confounding effects of cardiac doxorubicin, concentration‐response experiments with doxorubicinol (0.9–7.2 μ m ) were conducted. 6 Plots of doxorubicinol concentrations in atria vs contractility indicated that the cardiac concentration of doxorubicinol, at which contractility is reduced by 50%, is five fold lower in doxorubicin‐treated than in doxorubicinol‐treated preparations. Thus, doxorubicin and doxorubicinol appear to interact to depress contractile function. 7 Cardiac concentrations of both doxorubicin and doxorubicinol, as observed in these studies, were found to stimulate markedly Ca 2+ release from isolated SR vesicles, but 3 μ m doxorubicinol promoted a 15 fold greater release rate than 3 μ m doxorubicin. 8 Our observations coupled with the previously reported finding that doxorubicinol inhibits Ca 2+ loading of SR, suggests that doxorubicinol accumulation in heart contributes to the time‐dependent component of doxorubicin cardiotoxicity, through a mechanism that could involve perturbations of Ca 2+ homeostasis.