Hypoxia as a risk factor for doxorubicin-induced cardiotoxicity: A NMR evaluation

• Published in: Biochemical and biophysical research communications Vol. 163; no. 2; pp. 682 - 688
• Main Authors: Bradamante, S., Monti, E., Paracchini, L., Perletti, G.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.09.1989; Elsevier
• Subjects: Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Cardiomyopathies - chemically induced; Cardiomyopathies - metabolism; Cardiomyopathies - physiopathology; Doxorubicin - toxicity; Fundamental and applied biological sciences. Psychology; Heart; Heart - drug effects; Heart - physiopathology; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Contraction - drug effects; Myocardium - metabolism; Oxygen - metabolism; Phosphocreatine - metabolism; Rats; Rats, Inbred Strains; Risk Factors; Vertebrates: cardiovascular system; Heart; Vertebrata; Energy metabolism; Mammalia; Rat; Perfusion; Toxicity; Rodentia; Hypoxia; NMR spectrometry; Isolated organ; Dose activity relation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/0006-291X(89)92277-8

Previous studies suggested that one possible mechanism of doxorubicin (DXR)-induced cardiomyopathy involves the depletion of high-energy phosphate stores. In this study, we used 31P nuclear magnetic resonance to assess the high-energy phosphate content in Langendorff perfused rat hearts. Hearts were perfused in normoxic conditions (spontaneous flow) or in partially hypoxic conditions obtained by perfusing at 50% of the spontaneous flow. DXR was used at the subtoxic conditions of 50 mg/l for 15 min and at the cardiotoxic concentration of 100 mg/l for 60 min. Left ventricular pressure (dP/dt), heart rate, myocardial ATP and PCr levels andPCr/ATP ratio were measured. We found that, in normoxic conditons, DXR (50 mg/l, 15 min) does not impair cellular high-energy phosphate metabolism. However, in mild hypoxic conditions, DXR induces a significant decrease inPCr/ATP ratio, due to a decrease in PCr and to a simultaneous increase in ATP. Similar results are obtained after 60 min perfusion with the cardiotoxic dose of DXR. This study suggests that hypoxia may represent a risk factor for the development of DXR-induced acute cardiotoxicity.