: BASIC PHARMACOLOGY Dexrazoxane Prevents Myocardial Ischemia/ Reperfusion-induced Oxidative Stress in the Rat Heart Eyal Ramu & Amit Korach & Esther Houminer & Aviva Schneider & Amir Elami & Herzl Schwalb # Springer Science + Business Media, LLC 2006 Abstract Introduction Dexrazoxane (Dex), used clinically to protect against anthracycline-induced cardiotoxicity, possesses iron-chelating properties. The present study was designed to examine whether Dex could inhibit the ischemia/reperfusion (I/R) induced damage to the rat heart. Materials and methods Isolated perfused rat hearts were exposed to global ischemia (37-C) and 60 min reperfu- sion. Dex was perfused for 10 min prior to the ischemia, or administered intraperitoneally (150 mg) 30 min prior to anesthesia of the rats. I/R caused a significant hemo- dynamic function decline in control hearts during the reperfusion (e.g., the work index LVDP X HR declined to 42.7T10%). Dex (200 mM) applied during the pre- ischemia significantly increased the hemodynamic recov- ery following reperfusion (LVDP X HR recovered to 55.7T8.8%, p<0.05 vs. control). Intraperitoneal Dex, too, significantly increased the hemodynamic recovery of the reperfused hearts. I/R caused an increase in oxidation of cytosolic proteins, while Dex decreased this oxidation. Discussion The decrease in proteins carbonylation and correlative hemodynamic improvement suggests that Dex decreases I/R free radical formation and reperfu- sion injury. Key words adriamycin . chelation . radical . transition metals . carbonyl . heart . oxidative stress Introduction Hearts subjected to prolonged ischemia lose a consid- erable fraction of their function due to ischemia/reper- fusion (I/R) injury. A critical role in this injury is attributed to the formation of reactive oxygen species [1]. The formation of reactive oxygen species from relatively less reactive species seems to be mediated, at least in part, by redox-active metal ions [1, 2]. A burst of transition metals leakage correlates well with the degree of loss of cardiac function and with the redox activity of the metals during early reperfusion [3]. Oxidant-induced cell damage may be initiated by peroxidative injury to lysosomal membranes, catalyzed by intralysosomal low mass iron that appears to comprise a major part of cellular redox-active iron. Resulting relocation of lytic enzymes and low mass iron would result in secondary harm to various cellular constituents. [4]. Iron chelation has been shown to protect against tissue injury following ischemia [5], while addition of transition metal ions to the perfusate increased damage in hearts subjected to ischemia/ reperfusion [6, 7]. Shortly after the introduction of anthracyclines– anticancer drugs into clinical practice, it was realized that their use is associated with the appearance of cardiac damage in a dose-dependent manner. In further studies it was revealed that in addition to their ability to interact with DNA, anthracyclines induce formation of free radicals directly or through the formation of complexes with metal ions [8, 9]. Redox reactions transfer electrons to oxygen molecules through the Haber–Weiss and Fenton reactions, there- by facilitating the formation of deleterious hydroxyl radicals. The anthracycline-metal ion complex causes Cardiovasc Drugs Ther DOI 10.1007/s10557-006-0497-4 Eyal Ramu and Amit Korach contributed equally to this study. E. Ramu : A. Korach : E. Houminer : A. Schneider : A. Elami : H. Schwalb (*) The Joseph Lunenfeld Cardiac Surgery Research Center, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel e-mail: schwalb@hadassah.org.il