Bradamante S, Monti E, Paracchini L, Perletti G
Centro CNR Studio Sintesi e Stereochimica Speciali Sistemi Organici, Univesità di Milano, Italy.
Biochem Biophys Res Commun. 1989 Sep 15;163(2):682-8. 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 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.
先前的研究表明，阿霉素（DXR）诱发心肌病的一种可能机制涉及高能磷酸储存的消耗。在本研究中，我们使用31P核磁共振来评估Langendorff灌注大鼠心脏中的高能磷酸含量。心脏在常氧条件下（自然流量）或通过以自然流量的50%进行灌注获得的部分缺氧条件下进行灌注。DXR在50mg/l的亚毒性条件下使用15分钟，并在100mg/l的心脏毒性浓度下使用60分钟。测量左心室压力（dP/dt）、心率、心肌ATP和PCr水平以及PCr/ATP比值。我们发现，在常氧条件下，DXR（50mg/l，15分钟）不会损害细胞的高能磷酸代谢。然而，在轻度缺氧条件下，由于PCr的减少和ATP的同时增加，DXR会导致PCr/ATP比值显著降低。在用心脏毒性剂量的DXR灌注60分钟后也获得了类似的结果。本研究表明，缺氧可能是DXR诱发急性心脏毒性发生的一个危险因素。
