Nω-Nitro-L-Arginine Methylester Ameliorates Myocardial Toxicity Induced by Doxorubicin

Abstract

The effects of Nω-nitro-L-arginine methylester (L-NAME) and L-arginine on cardiotoxicity that is induced by doxorubicin (Dox) were investigated. A single dose of Dox 15 mg/kg i.p. induced cardiotoxicity, manifested biochemically by a significant elevation of serum creatine phosphokinase (CPK) activity [EC 2.7.3.2]. Moreover, cardiotoxicity was further confirmed by a significant increase in lipid peroxides, measured as malon-di-aldehyde (MDA) in cardiac tissue homogenates. The administration of L-NAME 4 mg/kg/d p.o. in drinking water 5 days before and 3 days after the Dox injection significantly ameliorated the cardiotoxic effects of Dox, judged by the improvement in both serum CPK activity and lipid peroxides in the cardiac tissue homogenates. On the other hand, the administration of L-arginine 70 mg/kg/d p.o. did not protect the cardiac tissues against the toxicity that was induced by the Dox treatment. The findings of this study suggest that L-NAME can attenuate the cardiac dysfunction that is produced by the Dox treatment via the mechanism(s), which may involve the inhibition of the nitric oxide (NO) formation. L-NAME may, therefore, be a beneficial remedy for cardiotoxicity that is induced by Dox and can then be used to improve the therapeutic index of Dox.

Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study

“…The two amino acids involved in the urea cycle exert multiple cardioprotective effects. They were particularly important during periods of acute myocardial injury, as these states tend to be characterized as increasing degrading enzyme arginase, resulting in a transient arginine deficiency [36, 37]. Further, arginine represents a by-product of nitric oxide formation.…”

The Redox Imbalance and the Reduction of Contractile Protein Content in Rat Hearts Administered with L-Thyroxine and Doxorubicin

“…However, in DOX-exposed group of the present study, where the organ samples were examined three weeks after the last dose of DOX, a lack of oxidative stress—tested on the basis of lipids and DNA oxidation products—was found. According to the literature, oxidative stress markers are elevated a short time after drug administration (hours or even days) because DOX is still present in the tested tissue [35, 44, 45]. In these cases, oxidative stress in the heart is the direct effect of DOX participating in the transfer of electrons from NADPH to O 2 , which results in superoxide overproduction.…”

Tirapazamine-Doxorubicin Interaction Referring to Heart Oxidative Stress and Ca2+Balance Protein Levels

“…The majority of prior researches indicated oxidative stress symptoms within short time after single-dose administration or last dose application of DOX. Knowing the red-ox metabolism of DOX, it is possible to assume that while the drug is still present in the tissue, there will be production of ROS and oxidative stress, which was evidenced in multiple studies [23, 42, 43]. Presence of oxidative stress one week after the last dose of DOX, therefore after the drug has been removed from the organism, is consistent with another study [44] and hypothesis explaining late cardiotoxicity of DOX based on oxidative stress [45, 46].…”