The reaction between nitrite and hemoglobin: the role of nitrite in hemoglobin-mediated hypoxic vasodilation Daniel B. Kim-Shapiro a , Mark T. Gladwin b , Rakesh P. Patel c , Neil Hogg d, * a Department of Physics, Wake Forest University, Winston-Salem, NC, USA b Department of Critical Care Medicine, Laboratory of Chemical Biology, NIDDK, National Institutes of Health, Bethesda, MD, USA c Department of Pathology and Center for Free Radical Biology, University of Alabama, Birmingham, AL, USA d Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA Received 22 April 2004; received in revised form 2 October 2004; accepted 28 October 2004 Abstract The reaction between nitrite and hemoglobin has been studied for over a century. However, recent evidence indicating nitrite is a latent vasodilatory agent that can be activated by its reaction with deoxyhemoglobin has led to renewed interest in this reaction. In this review we survey, in the context of our own recent studies, the chemical reactivity of nitrite with oxyhemoglobin, deoxyhemo- globin and methemoglobin, and place these reactions in both a physiological and pharmacological/therapeutic context. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Nitrite; Hemoglobin; Hypoxia; Vasodilation 1. Introduction Recent evidence suggests that plasma nitrite anion represents a latent substance that can be activated by hemoglobin in areas of hypoxia to elicit vasodilation [1]. The mechanisms by which activation and vasodila- tion occur are currently uncertain and are under intense study. Although the reaction between nitrite and hemo- globin has been appreciated since at least the middle 1800s, a definitive mechanistic understanding of these reactions is lacking. In this review, we survey published mechanisms in the context of our own recent studies, and highlight how such mechanisms either complement or are at odds with the recent physiological findings. In addition we place the nitrite/hemoglobin reaction in its physiological and pharmacological context. 2. The chemistry of the nitrite/hemoglobin reaction 2.1. The reaction between nitrite and oxyhemoglobin Ask most researchers in the nitric oxide or hemo- globin fields ‘‘what happens when you mix nitrite with oxyHb’’ and they will say the same thing: nitrite gets oxidized to nitrate and the hemoglobin gets oxidized to the ferric form (methemoglobin or metHb). Ask these same researchers for the mechanism and you will likely also get the same answer: ‘‘ItÕs complicated!’’ Neverthe- less there is often an underlying assumption that this reaction must be responsible for the oxidation of nitrite to nitrate in the blood stream, is perhaps the most important factor in determining why nitrate and not ni- trite is the predominant metabolite of nitric oxide in vivo, and is why plasma nitrite is maintained at low- to sub-micromolar levels. In this section we will de- tail what is known about this reaction and then contrast it to the reaction between nitrite and hemoglobin in the 0162-0134/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2004.10.034 * Corresponding author. Tel.: +1 414 456 4012; fax: +1 414 456 6512. E-mail address: nhogg2@mcw.edu (N. Hogg). www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 99 (2005) 237–246 JOURNAL OF Inorganic Biochemistry