Nitrite anion provides potent cytoprotective and antiapoptotic effects as adjunctive therapy to reperfusion for acute myocardial infarction.
BACKGROUND
Accumulating evidence suggests that the ubiquitous anion nitrite (NO2-) is a physiological signaling molecule, with roles in intravascular endocrine nitric oxide transport, hypoxic vasodilation, signaling, and cytoprotection. Thus, nitrite could enhance the efficacy of reperfusion therapy for acute myocardial infarction. The specific aims of this study were (1) to assess the efficacy of nitrite in reducing necrosis and apoptosis in canine myocardial infarction and (2) to determine the relative role of nitrite versus chemical intermediates, such as S-nitrosothiols.


RESULTS
We evaluated infarct size, microvascular perfusion, and left ventricular function by histopathology, microspheres, and magnetic resonance imaging in 27 canines subjected to 120 minutes of coronary artery occlusion. This was a blinded, prospective study comparing a saline control group (n=9) with intravenous nitrite during the last 60 minutes of ischemia (n=9) and during the last 5 minutes of ischemia (n=9). In saline-treated control animals, 70+/-10% of the area at risk was infarcted compared with 23+/-5% in animals treated with a 60-minute nitrite infusion. Remarkably, a nitrite infusion in the last 5 minutes of ischemia also limited the extent of infarction (36+/-8% of area at risk). Nitrite improved microvascular perfusion, reduced apoptosis, and improved contractile function. S-Nitrosothiol and iron-nitrosyl-protein adducts did not accumulate in the 5-minute nitrite infusion, suggesting that nitrite is the bioactive intravascular nitric oxide species accounting for cardioprotection.


CONCLUSIONS
Nitrite has significant potential as adjunctive therapy to enhance the efficacy of reperfusion therapy for acute myocardial infarction.
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1061, USA.
Felix M
FM
Gonzalez
Sruti
S
Shiva
Pamela S
PS
Vincent
Lorna A
LA
Ringwood
Li-Yueh
LY
Hsu
Yuen Yi
YY
Hon
Anthony H
AH
Aletras
Richard O
RO
Cannon
Mark T
MT
Gladwin
Andrew E
AE
Arai
D000818:Animals; D000838:Anions / Q000097:blood / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D006454:Hemoglobins / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015425:Myocardial Reperfusion; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D009336:Necrosis; D009569:Nitric Oxide / Q000097:blood; D009573:Nitrites / Q000097:blood / Q000494:pharmacology*; D026403:S-Nitrosothiols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D000838:Anions; D002316:Cardiotonic Agents; D006454:Hemoglobins; D009573:Nitrites; D026403:S-Nitrosothiols; D009569:Nitric Oxide