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

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 [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}({NO}₂⁻){equation*}{document} 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 [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{NO}₂⁻{equation*}{document} in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 μM) 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 [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{NO}₂⁻{equation*}{document} , by XOR, protects the myocardium from ischemia–reperfusion injury. Hence, if XOR is presented with [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{NO}₂⁻{equation*}{document} as an alternative substrate, the resultant effects of its activity may be protective, by means of its production of NO • , rather than damaging.