Hypoxia as a risk factor for doxorubicin-induced cardiotoxicity: a NMR evaluation.
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 and PCr/ATP ratio were measured. We found that, in normoxic conditions, DXR (50 mg/l, 15 min) does not impair cellular high-energy phosphate metabolism. However, in mild hypoxic conditions, DXR induces a significant decrease in PCr/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.
Bradamante
S
S
Centro CNR Studio Sintesi e Stereochimica Speciali Sistemi Organici, Univesità di Milano, Italy.
Monti
E
E
Paracchini
L
L
Perletti
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012307:Risk Factors
D010725:Phosphocreatine; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D010100:Oxygen