Prevention of doxorubicin-induced cardiomyopathy by reduced glutathione.
The aim of the present investigation was to evaluate the potential cardioprotective effect of reduced glutathione (GSH) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a well-documented rat model. DXR was administered i.v. at a weekly dose of 3 mg/kg for a total of 4 doses; 250 or 500 mg/kg of GSH was given i.v. 10 min before and 2 h after each DXR injection, resulting in a total weekly dose of 500 or 1000 mg/kg, respectively. The development of cardiotoxicity was monitored in vivo by means of electrocardiography (QaT duration), and was evaluated by measuring the contractile performance of isolated atria and by light and electron microscopy of left ventricular samples excised 5 weeks after the last DXR administration. DXR was found to impair body weight gain and to produce an irreversible and time-dependent prolongation of QaT, a decrease in myocardial contractility of isolated atria and typical morphologic alterations, including myocyte vacuolization and myofibrillar loss. Pretreatment with GSH at a dose of 500 mg/kg x 2, but not at 250 mg/kg x 2, partially prevented the impairment of body weight gain, QaT prolongation in ECG and the decrease in myocardial contractility of isolated atria induced by DXR. Alterations of the morphologic pattern were also significantly reduced in animals receiving the higher dose of GSH. Determinations of the cardiac non-protein sulfhydryl group content showed that GSH, at doses higher than or equal to 500 mg/kg, significantly increased this parameter, irrespective of the presence of DXR. In conclusion, the present data indirectly support the hypothesis that oxidative damage is involved in DXR cardiotoxicity and indicate that maintenance of the reduced thiol pool could be an important issue in myocardial protection.
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
F
F
Villani
M
M
Galimberti
F
F
Zunino
E
E
Monti
A
A
Rozza
E
E
Lanza
L
L
Favalli
P
P
Poggi
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism / Q000627:therapeutic use*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000032:analysis / Q000378:metabolism; D013997:Time Factors
D013438:Sulfhydryl Compounds; D004317:Doxorubicin; D005978:Glutathione