Physiological studies on the protective effect of melatonin against doxorubicin cardiotoxicity

ABSTRACT

This study was designed to investigate the effect of melatonin pretreatment on doxorubicin-induced cardiotoxicity, using Langendorff model of isolated perfused rat hearts. Male Wistar rats were divided into 2 groups, the first was untreated served as the control group and the second was melatonin pretreated test group. Rats of the test group received melatonin in a dose of 5mg/kg body weight, one hour before heart isolation. Hearts isolated, from both groups, were perfused with 30 micro M doxorubicin [DXO] for 60 minutes. The cardiac functions were assessed at 10, 30 and 60 minutes by heart rate [HR], peak tension [PT], time to peak tension [TPT], half relaxation time [HRT], and myocardial flow rate [MFR]. Cardiac muscle samples were ultrastructurally examined by electron microscope. DXO perfusion induced marked deterioration in cardiac functions of the control rats. At 60 minutes of DXO perfusion, there were significant bradycardia, significant increase in PT and significant prolongation in all cardiac times. Moreover, MFR was significantly compromised during the whole period of DXO perfusion. Ultrastructural examination revealed myofilament disarray with areas of focal loss and necrosis, hyper-contracted fibers and rarefied mitochondrial matrix, signifying its degeneration. Melatonin pretreated hearts, at 60 minutes of DXO perfusion, had significantly less bradycardiac response, significantly enhanced TPT and HRT, as well as a significantly higher MFR compared to the untreated control group. Therefore, the observed DXO-induced deterioration in cardiac chronotropy, inotropy, lusitropy and myocardial flow, was greatly attenuated by melatonin pretreatment. Moreover, melatonin could protect the myofilaments from degeneration and preserve mitochondrial integrity. Single injection of melatonin greatly attenuated both structural and functional insults of doxorubicin on the heart. Therefore, melatonin could be recommended as a protective measure against the high risks of doxorubicin-induced cardiotoxicity