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(Circulation. 2008;117:2986-2994.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Andrew Arai, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10, Room B1D416, MSC 1061, 10 Center Dr, Bethesda, MD 20892-1061. E-mail araia{at}nih.gov

Received October 27, 2007; accepted March 12, 2008.

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.

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