Cardiovascular effects of doxorubicin-induced toxicity in the intact Lou/M Wsl rat and in isolated heart preparations.

Hemodynamic effects were followed for 25 days in conscious nontumor bearing Lou/M Wsl rats during i.v. administration of doxorubicin (DXR) (1 mg/kg) on 5 consecutive days and then weekly. At day 24 cardiac output was significantly reduced in the DXR-treated group (cumulative dose of 7 mg/kg) in comparison with a saline-treated group, suggesting a reduction in myocardial performance. Urethane anesthesia at day 25 depressed cardiac output in control rats whereas this variable was not influenced in DXR-treated rats. Furthermore, blood pressure was significantly higher within DXR-treated rats, suggesting the presence of compensatory mechanisms. Separate experiments 25 days after the first DXR administration (cumulative dose of 7 mg/kg) demonstrated that the inotropic response toward dobutamine or norepinephrine as well as the vasoconstrictor response toward norepinephrine were impaired profoundly, suggesting compensatory mechanisms were functioning within the DXR-treated rats around day 25. In the isolated and perfused rat heart no changes in myocardial contraction under either basal or inotropic stimulatory conditions were observed 24 days after DXR treatment, indicating extracardiac phenomena have to contribute to a reduction in cardiac output and the occurrence of counter regulation mechanisms as observed in the in vivo experiments. However, after a cumulative dose of 11 mg/kg (at day 52), contraction function appeared to be disturbed upon contractility demand by dobutamine in the isolated heart. This observation supports the histological evidence of cardiomyopathy occurring at that time.(ABSTRACT TRUNCATED AT 250 WORDS)