Doxorubicin cardiotoxicity is associated with alterations of plasma levels of atrial natriuretic factor

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Abstract
In order to determine the involvement of the atrial natriuretic factor (ANF) in a model of drug-induced cardiomyopathy, the effects of a single or repeated doses of doxorubicin on plasma ANF levels were examined. Female Wistar rats were treated with doxorubicin at two different schedules: a single 10 mg/kg iv dose or multiple 3 mg/kg iv doses once a week for 3 weeks; control groups were given vehicle (isotonic saline, 0.9% NaCI) intravenously. ANF was assayed in plasma by a specific and sensitive radioimmunoassay method and cardiac function was evaluated by monitoring of ECG and hemodynamic parameters. In the doxorubicin single-dose study plasma ANF values were measured during a period of 6 hours after dosing and were found to be significantly decreased at the 180th (12.5 ± 2.9 pg/ml) and 360th minute (19.4 ± 1.2 pg/ml) after dosing, compared to vehicle-treated animals (35.1 ± 5.7 and 37.9 ± 4.1 pg/ml, 180 and 360th minute, respectively). Rats treated with multiple doses of doxorubicin showed a significant increase in plasma ANF levels at the 21st (88.3 ± 7.7 pg/ml) and 31st day (61.0 ± 14.3 pg/ml) of the study compared to vehicle-treated animals at the same time points (41.8 ± 8.0 and 26.5 ± 7.2 pg/ml, respectively). At the 42nd day plasma ANF concentration in doxorubicin-treated rats was not significantly different from vehicle-treated rats. In both studies ANF level changes occurred in the setting of acute or chronic doxorubicin-induced cardiac damage, as evidenced by alterations of hemodynamic and ECG parameters. These results suggest that the significant alterations in plasma ANF levels during doxorubicin treatment represent a new aspect of cardiac toxicity of the drug and might contribute to doxorubicin-induced heart damage.