Doxorubicin cardiotoxicity: contractile changes after long-term treatment in the rat

Doxorubicin (DXR; Adriamycin) was administered i.v. to 20 Sprague-Dawley rats at 2.5 mg/kg once a week for 8 weeks. The rats were then observed for 2 to 5 weeks post treatment until they developed signs of general and cardiotoxicity (lassitude, ascites, marked ECG changes), at which time 11 of these animals and 11 age-matched controls were killed for evaluation of isometric contractile activity changes in isolated right ventricular papillary muscles. At necropsy the animals were examined for evidence of congestive heart failure (enlarged liver, s.c. edema). Baseline contractile changes in preparations from DXR-treated rats, compared with controls, were a decrease in maximum rate of tension development and prolongation in time to peak tension, time to half-relaxation from peak tension and duration of tension. Both developed tension and tension duration in the DXR-exposed muscles were reduced less than those in controls by a decrease in the stimulus interval, and some DXR preparations exhibited a positive staircase rather than the negative staircase normally observed in rats. Increasing extracellular Ca++ produced substantially greater changes in peak tension and maximum rate of tension development, as well as time to half-relaxation and tension duration in the DXR muscles; however, the effects of isoproterenol on these four parameters were blunted in the DXR muscles (although decreased isoproterenol sensitivity was borderline in the case of tension duration and time to half-relaxation). The results suggest that long-term DXR treatment leads to a loss of adrenergic support in the rat heart, and that calcium deficiency, rather than overload, occurs in cells that are still functionally active.(ABSTRACT TRUNCATED AT 250 WORDS)