Trends in Cardiovascular Medicine
Volume 18, Issue 5 , Pages 163-172, July 2008

Myocardial Protection by Nitrite: Evidence That This Reperfusion Therapeutic Will Not Be Lost in Translation☆

  • Shashank S. Sinha

      Affiliations

    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
    • Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814, USA
    • ,
  • Sruti Shiva

      Affiliations

    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
    • ,
  • Mark T. Gladwin

      Affiliations

    • Pulmonary and Vascular Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
    • Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892, USA
    • Corresponding Author InformationAddress correspondence to: Mark T. Gladwin, National Institutes of Health Building 10-CRC, Room 5-5140 10 Center Dr, MSC 1454 Bethesda, MD 20892, USA. Tel.: (+1) 301 435 2310

The circulating anion nitrite (NO2−), previously thought to be an inert product of nitric oxide (NO) oxidation, has now been identified as an important storage reservoir of bioavailable NO in the blood and tissues. Reduction of NO2− to NO over the physiologic pH and oxygen gradient by deoxyhemoglobin, myoglobin, xanthine oxidoreductase, and by nonenzymatic acidic disproportionation has been demonstrated to confer cytoprotection against ischemia-reperfusion injury in the heart, liver, brain, and kidney. Here, we review the mechanisms that have been established to regulate hypoxic NO2− reduction to NO, analyze the preclinical and clinical evidence supporting NO2−-mediated cytoprotection after ischemia-reperfusion injury, and examine the therapeutic potential of NO2− for cardiovascular disease. Evidence is accumulating that suggests NO2− has surmounted many of the direct challenges to reperfusion therapeutics summarized by the National Heart, Lung, and Blood Institute Working Group in “Myocardial protection at a crossroads: the need for translation into clinical therapy.” In this context, we discuss important considerations in designing human clinical trials to test the efficacy of NO2− in the setting of ischemia-reperfusion injury, with particular attention to the study of ST-segment elevation myocardial infarction.

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☆ Dr Gladwin is listed as a coinventor on a National Institutes of Health government patent application for the use of NaNO2 for cardiovascular indications..

PII: S1050-1738(08)00099-6

doi:10.1016/j.tcm.2008.05.001

Trends in Cardiovascular Medicine
Volume 18, Issue 5 , Pages 163-172, July 2008

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