Prevention of doxorubicin-induced damage to rat heart myocytes by arginine analog nitric oxide synthase inhibitors and their enantiomers

Norman Barnabé, Rosemary A. Marusak, Brian B. Hasinoff

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The clinical use of the widely used anticancer drug doxorubicin is limited by a dose-dependent cardiotoxicity. Doxorubicin can be reduced to its semiquinone free radical form by nitric oxide synthases (NOS). The release of lactate dehydrogenase (LDH) from doxorubicin-treated neonatal cardiac rat myocytes was used as a model of doxorubicin-induced cardiotoxicity. The NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and N G-monomethyl-L-arginine (L-NMMA) protected myocytes from doxorubicin as did their non-inhibitory enantiomers D-NAME and D-NMMA. Thus, these agents did not protect by inhibiting NOS. L-NAME, which does not act at the reductase domain of NOS, also had no effect on the production of the doxorubicin semiquinone by myocytes. Nitric oxide (NO) EPR spin trapping experiments showed that L-NAME reacted with various biological reducing agents to produce NO. Ascorbic acid was highly effective in reacting with L-NAME to produce NO, while glutathione, NADPH, and NADH were much less effective. Thus, these guanadino-substituted analogs of L-arginine likely protected through their ability to slowly produce NO by reaction with intracellular ascorbic acid. Thus, some caution must be exercised in their use. NO may exert its protective effects either by directly acting as an antioxidant or through some other NO-dependent pathway.

Original languageEnglish (US)
Pages (from-to)211-216
Number of pages6
JournalNitric Oxide - Biology and Chemistry
Volume9
Issue number4
DOIs
StatePublished - Dec 2003
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Canadian Institutes of Health Research, the Canada Research Chairs Program, and a Canada Research Chair in Drug Development for Brian Hasinoff. Rosemary Marusak was supported by a NSF-FY2000 POWRE Award.

Keywords

  • Antioxidant
  • Cardiotoxicity
  • Doxorubicin
  • EPR
  • Iron
  • L-NAME
  • Myocyte
  • Nitric oxide

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