Nitrate/nitrite therapy showed only limited cardioprotective potential in chronic ANT cardiotoxicity settings which is in contrast with previous data from myocardial I/R injury and acute high dose ANT cardiotoxicity. A relatively high nitrite dose was required for the positive modulation of some pathways participating in chronic ANT cardiotoxicity and was found to reduce incidence of end-stage cardiotoxicity and related premature deaths; however, this dose was not sufficient for the prevention of most of the other cardiotoxicity endpoints. This result contrasted with the remarkable efficacy of DEX in all of the studied parameters which suggests its rather upstream target. Although further studies are needed, the ability to affect the proximal target within the cardiomyocytes may be important for cardioprotection and may explain the differences in efficacy of DEX and nitrite in chronic ANT cardiotoxicity. The present data also suggest that effects of the possible cardioprotectants on TOP2b in chronic ANT cardiotoxicity merit further study.
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