Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage

Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13683-8. doi: 10.1073/pnas.0402927101. Epub 2004 Sep 3.


Nitric oxide (NO.) is thought to protect against the damaging effects of myocardial ischemia-reperfusion injury, whereas xanthine oxidoreductase (XOR) normally causes damage through the generation of reactive oxygen species. In the heart, inorganic nitrite (NO(2)(-)) has the potential to act as an endogenous store of NO., liberated specifically during ischemia. Using a detection method that we developed, we report that under ischemic conditions both rat and human homogenized myocardium and the isolated perfused rat heart (Langendorff preparation) generate NO. from NO(2)(-) in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 microM) reduced infarct size from 47.3 +/- 2.8% (mean percent of control +/- SEM) to 17.9 +/- 4.2% and 17.4 +/- 1.0%, respectively (P < 0.001), and was associated with comparable improvements in recovery of left ventricular function. This protective effect was completely blocked by the NO. scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO). In summary, the generation of NO. from NO(2)(-), by XOR, protects the myocardium from ischemia-reperfusion injury. Hence, if XOR is presented with NO(2)(-) as an alternative substrate, the resultant effects of its activity may be protective, by means of its production of NO. , rather than damaging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Myocardial Ischemia / enzymology
  • Myocardial Ischemia / metabolism*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Nitric Oxide / metabolism*
  • Nitrites / metabolism*
  • Oxidation-Reduction
  • Rats
  • Rats, Wistar
  • Xanthine / metabolism
  • Xanthine Oxidase / antagonists & inhibitors
  • Xanthine Oxidase / metabolism


  • Cardiotonic Agents
  • Nitrites
  • Xanthine
  • Nitric Oxide
  • Xanthine Oxidase