Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive hea rt failure. Although several mechanisms have been suggested to explain the exact cause of doxorubicin-induced cardiomyopathy, the role of the vascular endothelium-derived vasoactive mediators in the pathophysiology of this to xic effect is still unknown. Accordingly, the present study has been initia ted to investigate whether the changes in plasma level of endothelin and ni tric oxide along with cardiac nitric oxide are associated with the developm ent of doxorubicin-induced cardiomyopathy. Doxorubicin was injected with a single dose of 5 mg/kg and every other day with a dose of 5 mg/kg, intraper itoneally, to have four cumulative doses of, 10, 15, 20 and 25 mg/kg in fiv e separate groups of male rats. An additional group receiving a single dose of 20 mg/kg and one receiving normal saline were also included in the stud y. Twenty-four hr after the last dose, the animals were sacrificed and the plasma levels of endothelin-1 and nitric oxide in addition to cardiac nitri c oxide were determined. The results show that doxorubicin caused a statist ically significant increase of 85%, 76% and 97% in plasma endothelin-1 at a cumulative dose levels of 10, 15 and 20 mg/kg, respectively. However, the level of plasma nitric oxide remained unchanged. Furthermore, doxorubicin t reatment resulted in a significant dose-dependent increase in serum lactate dehydrogenase and creatine phosphokinase. In contrast, the increase in nit ric oxide production in cardiac tissue by doxorubicin was not dose-dependen t with the maximum increase (81%) at a cumulative dose of 10 mg/kg. It is w orth mentioning that plasma endothelin-1 and cardiac nitric oxide were sign ificantly increased at 24 hr after the single dose of 20 mg/kg doxorubicin. The increase of plasma endothelin-1 and cardiac nitric oxide with the card iomyopathy enzymatic indices, may point to the conclusion that both endothe lin-1 and cardiac nitric oxide are increased during the development of doxo rubicin-induced cardiomyopathy.