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ORIGINAL RESEARCH ARTICLE

The Cobalamin Precursor Cobinamide Detoxifies Nitroprusside-Generated Cyanide

Kate E. Broderick^*, Maheswari Balasubramanian^*, Adriano Chan^*, Prasanth Potluri, Jake Feala, Darrell D. Belke^*, Andrew McCulloch, Vijay S. Sharma^*, Renate B. Pilz^*, Timothy D. Bigby^*, and Gerry R. Boss^*,1

^* Department of Medicine, University of California, San Diego, La Jolla, California 92093; Department of Biochemistry, University of California, Irvine, Irvine, California 92697; Department of Bioengineering, University of California, San Diego, La Jolla, California 92093; and Veterans Administration San Diego Healthcare System, San Diego, California 92161

To whom requests for reprints should be addressed at ¹ University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0652. E-mail: gboss{at}ucsd.edu

Sodium nitroprusside is used to treat hypertensive emergencies and acute heart failure. It acts by releasing nitric oxide (NO), a highly potent vasodilator, but unfortunately, for each NO molecule released, five cyanide ions are released. Thus, nitroprusside therapy is limited by cyanide toxicity. Therefore, a cyanide scavenger could be beneficial when administering nitroprusside. Hydroxocobalamin, which has a relatively high binding affinity for cyanide, has been shown to reduce cyanide levels in nitroprusside-treated patients. Cobinamide, the penultimate precursor in hydroxocobalamin biosynthesis, has a much greater affinity for cyanide than cobalamin, and binds two cyanide ions. We now show that cobinamide is highly effective in neutralizing cyanide ions released by nitroprusside in cultured mammalian cells, Drosophila melanogaster, and mice. Cobinamide also binds NO, but at molar concentrations 2.5–5 times that of nitroprusside, it did not decrease NO concentrations or the physiological effectiveness of nitroprusside. We conclude that cobinamide could be a valuable adjunct to nitroprusside therapy.

Key Words: acute hypertension • nitroprusside • nitric oxide • cyanide • cobinamide