Increased cardiac endothelin-1 and nitric oxide in adriamycin-induced acute cardiotoxicity: protective effect of Ginkgo biloba extract.
Cardiotoxicity and congestive heart failure are the major factors that limit the use of anti-neoplastic drug adriamycin (ADR). There is increasing experimental evidence that endothelin-1 (ET-1) and nitric oxide (NO) are vasoactive mediators that regulate cardiac performance. The present study was undertaken to investigate the role of ET-1 and NO in ADR-induced acute cardiotoxicity and to evaluate the protective effect of Ginkgo biloba extract (EGb761) in rats. A single dose of ADR (20 mg/kg i.p.) caused a significant increase in the cardiac enzyme activities of aspartate transaminases (AST), lactate dehydrogenase (LDH) and creatine phosphokinase isoenzyme (CK-MB) in the serum of animals. This was accompanied by significant increase in cardiac malondialdehyde (MDA), total antioxidant capacity (TAC), tumor necrosis factor-alpha (TNF-alpha), ET-1 and nitrite/nitrate (NOx) levels. On the other hand, reduced glutathione (GSH) was significantly depressed. Histopathological examination of heart tissues showed hyalinization of the myocardium, with interstitial edema and inflammatory exudates. Pre-treatment of the animals with EGb761 (100 mg/kg, orally) 10 days before and 5 days after ADR treatment reversed the cardiac enzyme levels to normal value, decreased cardiac MDA, TAC, TNF-alpha. ET-1 and NO(x), increased GSH and reversed the histopathological damage induced by ADR. In conclusion, the cardioprotective effects of EGb761 on markers of ADR-induced acute cardiotoxicity appeared to have been mediated by the regulation of inflammatory and vasoactive mediators, as well as the inhibition of membrane lipid peroxidation. Thus, EGb761 may find use as promising adjuvant therapy to ameliorate cardiotoxicity of ADR.