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 (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.
Webb
Andrew
A
Clinical Pharmacology, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, England.
Bond
Richard
R
McLean
Peter
P
Uppal
Rakesh
R
Benjamin
Nigel
N
Ahluwalia
Amrita
A
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D017202:Myocardial Ischemia / Q000201:enzymology / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D002316:Cardiotonic Agents; D009573:Nitrites; D019820:Xanthine; D009569:Nitric Oxide; D014969:Xanthine Oxidase