Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation

Abstract

Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 μmol/min into the forearm brachial artery resulted in supra- and near-physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron-nitrosylated hemoglobin and, to a lesser extent, S-nitroso-hemoglobin. NO-modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO-modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation.

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Figure 1: Hemodynamic and metabolic measurements at baseline and during exercise (protocol, part I).
Figure 2: Effects of nitrite infusion.
Figure 3: Effects of low-dose nitrite infusion.
Figure 4: Formation of iron-nitrosylated hemoglobin and S-nitroso-hemoglobin after nitrite infusion in vivo and in vitro.
Figure 5: Production of NO gas and vasodilation are augmented by nitrite reaction with deoxyhemoglobin.

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Acknowledgements

This work was supported by Clinical Center and National Heart, Lung and Blood Institute intramural funds (R.O.C. and M.T.G.), National Institutes of Health grant HL58091 (D.B.K.-S.), RO1HL70146 (R.P.P.) and Medical Scientist Training Program T32GM08361. We thank V. Annavajjhala for helpful laboratory assistance.

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Correspondence to Richard O Cannon III or Mark T Gladwin.

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Cosby, K., Partovi, K., Crawford, J. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9, 1498–1505 (2003). https://doi.org/10.1038/nm954

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