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on June 2, 2008

A more recent version of this article appeared on June 10, 2008

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Submitted on October 27, 2007
Accepted on March 12, 2008

Nitrite Anion Provides Potent Cytoprotective and Antiapoptotic Effects as Adjunctive Therapy to Reperfusion for Acute Myocardial Infarction

Felix M. Gonzalez BS, Sruti Shiva PhD, Pamela S. Vincent RT, Lorna A. Ringwood BS, Li-Yueh Hsu DSc, Yuen Yi Hon PharmD, Anthony H. Aletras PhD, Richard O. Cannon III MD, Mark T. Gladwin MD, and Andrew E. Arai MD^*

From the Translational Medicine Branch (F.M.G., P.S.V., L.H., A.H.A., R.O.C., A.E.A.) and Pulmonary-Vascular Medicine Branch (S.S., L.A.R., M.T.G.), National Heart, Lung, and Blood Institute; Critical Care Medicine Department (S.S., L.A.R., M.T.G.) and Pharmacy Department (Y.Y.H.), Clinical Center, National Institutes of Health; and Howard Hughes Medical Institute, National Institutes of Health Research Scholars Program (F.M.G.), Bethesda, Md.

^* To whom correspondence should be addressed. E-mail: araia{at}nih.gov.

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.

Methods and 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.

Key words: apoptosis • ischemia • magnetic resonance imaging • myocardial infarction • nitric oxide

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