The efficacy of selenium, WR-2721, and their combination in the prevention of adriamycin-induced cardiotoxicity in rats.
It is known that the antineoplastic drug adriamycin (ADR) can cause cardiotoxic effects. Some data imply that pretreatment with selenium (Se) and the radio- and chemoprotector, amifostine (WR-2721), may confer a protective effect. The aim of this study was to evaluate the efficacy of single doses of Se and WR-2721, alone or in combination, in the prevention of acute ADR-induced cardiotoxicity in male Wistar rats. Se, in the form of sodium selenite (1.6 mg/kg i.p.), and WR-2721 (300 mg/kg i.p.) were given 24 hours and 20 minutes, respectively, before ADR (6 mg/kg i.v.). The cardiotoxicity of ADR was recorded 48 hours after its administration because earlier studies revealed that structural damage of the myocardium occurs within this period. Evaluation of these toxic effects, as well as of the cardioprotective efficacy of the administered drugs, was performed using (1) ECG-records before and during the infusion of the proarrhythmogenic compound, aconitine (8 microg/kg/min i.v.) and (2) the serum activity of creatine kinase (CK), aspartate aminotransferase-(AST), lactate dehydrogenase (LDH), and its isoenzyme alpha-hydroxybutyrate dehydrogenase (alpha-HBDH). The results showed that the arrhythmogenic dose of aconitine was significantly reduced in ADR-treated rats (57.22 vs. 99.65 microg/kg in control; p < 0.05) and that this proarrhythmogenic compound caused a significant increase in heart rate in such animals compared to controls. Pretreatment with Se, WR-2721, and their combination partly reversed the arrhythmogenic dose of aconitine to control (72.09, 82.1, and 88.99 microg/kg, respectively). Se failed to prevent an aconitine-induced increase in heart rate, whereas WR-2721 and their combination successfully counteracted this effect. In addition, ADR produced a significant increase in the serum activity of all monitored enzymes. Pretreatment with Se failed to prevent this increase, whereas pretreatment with WR-2721 did. The best result was obtained with their combination. We conclude that the radio- and chemoprotector, WR-2721, particularly in combination with Se, may provide a significant protective effect against acute ADR-induced cardiotoxicity in rats.
Dobrić
S
S
National Poison Control Center, Military Medical Academy, Belgrade, Yugoslavia.
Dragojević-Simić
V
V
Bokonjić
D
D
Milovanović
S
S
Marincić
D
D
Jović
P
P
D000157:Aconitine / Q000633:toxicity; D004999:Amifostine / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D001219:Aspartate Aminotransferases / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000633:toxicity*; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D006884:Hydroxybutyrate Dehydrogenase / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D011837:Radiation-Protective Agents; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D006884:Hydroxybutyrate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase; D012643:Selenium; D004999:Amifostine; D000157:Aconitine