ANTHRACYCLINE-ASSOCIATED CARDIAC AND RENAL DAMAGE IN RABBITS - EVIDENCE FOR MEDIATION BY VASOACTIVE SUBSTANCES

Abstract

The hypothesis that anthracycline-induced cardiac and renal damage is mediated by vasoactive substances was tested. A 1 min exposure to 5 .mu.g/ml of doxorubicin (DXR, Adriamycin) produced cardiac histamine release in isolated rabbit hearts. Under conditions in which histamine uptake and metabolism were impaired, the administration of DXR, 2 mg/kg, over 1 min was associated with elevations in arterial histamine and catecholamines. The chronic weekly administration of DXR produced severe cardiac and renal damage. The administration of combined histaminic and adrenergic blockade with diphenhydramine, cimetidine, phentolamine and propranolol (DCPP) pre- and immediately post-DXR resulted in near total protection against DXR-mediated cardiac damage and prevented the majority of the renal lesions. The combined administration of DCPP did not appear to be acting by mechanisms other than blockade of vasoactive amine receptors as cardiac uptake of DXR and the DXR antitumor response were not altered by DCPP. Anthracycline-associated cardiac and renal toxicity may be mediated by vasoactive substances. Anthracycline cardiomyopathy is potentially preventable.