Chronic doxorubicin induced cardiomyopathy in rabbits: mechanical, intracellular action potential, and   adrenergic characteristics of the failing myocardium

Histological studies showed widespread myocardial damage that became more severe as the cumulative doses increased. Right ventricular papillary muscles of doxorubicin treated rabbits had lower total tension (1.5 v 3.3 g.mm-2 for controls, p less than 0.05) and dT/dt, shorter contraction duration, and lower velocity of shortening than the control muscles under all loading conditions. The changes progressed as the cumulative doxorubicin dose increased. Action potential duration was shorter in the doxorubicin treated groups (APD50 = 76 v 62 ms for controls, p less than 0.01), although resting action potential amplitude was normal. Tension-frequency response (6-36 stimuli.min-1) and response to increasing calcium concentrations (2.54-6.32 mM) were attenuated in the doxorubicin group. Percent change in tension and dT/dt in response to noradrenaline (50 microM), isoprenaline (20 microM), or dibutyryl cyclic AMP (40 mM), was increased in the doxorubicin group v controls (300-600% v 100-200% respectively), despite chronic increase in circulating catecholamines, depletion of myocardial catecholamines, and no change in beta adrenergic receptor number or affinity. The apparent increase in beta adrenergic responsiveness in the doxorubicin group may have been partly due to decreased basal cyclic AMP production (13 v 31 pMol.mg-1 protein.min-1, p less than 0.01), although maximum catecholamine stimulated cyclic AMP production was only mildly decreased (251 v 315 pMol.mg-1 protein.min-1, p less than 0.05). CONCLUSIONS - The subacute effects of chronic doxorubicin become progressively more marked as the cumulative dose increases, and there are significant differences in the myocardial characteristics between this chronic model and other models of heart failure. These differences may be related to the cytotoxic effects of doxorubicin on membranes and membrane bound enzymes.