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Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator

Nature Medicine volume 10, pages 1122–1127 (2004)Cite this article

Abstract

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)–generating reaction with deoxyhemoglobin and potentially other heme proteins1. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia2. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction (∼65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.

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Figure 1: Vasodilatory effects of nitrite during hypoxia-induced pulmonary hypertension.
Figure 2: Hypoxic potentiation of nitrite-dependent vasodilation.
Figure 3: Nitric oxide formation from nitrite is potentiated by hypoxia and physiological acidosis.
Figure 4: Comparison of the physiological effects of nitrite versus inhaled NO gas.

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Acknowledgements

The authors thank S. Bragg for expert technical assistance. This work was supported in part by the Clinical Center intramural funds (M.T.G.), and National Institutes of Health grants HL654941 (G.G.P.) and HL58091 (D.B.K.-S.). C.J.H. is a fellow in the Clinical Research Training Program at the National Institutes of Health supported through a grant from Pfizer Pharmaceuticals Group administered by the Foundation for the National Institutes of Health.

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Author notes

  1. Gordon G Power and Mark T Gladwin: These two authors contributed equally to this work.

Authors and Affiliations

  1. Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, 20892-1662, Maryland, USA

    Christian J Hunter, Roberto F Machado, Selamawit Tarekegn & Mark T Gladwin

  2. Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, 20892-1662, Maryland, USA

    Christian J Hunter, Roberto F Machado & Mark T Gladwin

  3. Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, 20892-1662, Maryland, USA

    Christian J Hunter, André Dejam, Roberto F Machado, Alan N Schechter & Mark T Gladwin

  4. Department of Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, 11234 Anderson Drive, Loma Linda, 92350, California, USA

    Christian J Hunter, Arlin B Blood & Gordon G Power

  5. Department of Physics, Wake Forest University, 1834 Gulley Drive, Winston-Salem, 27109-7507, North Carolina, USA

    Howard Shields & Daniel B Kim-Shapiro

  6. Department of Pediatrics, Loma Linda University School of Medicine, 11234 Anderson Drive, Loma Linda, 92350, California, USA

    Neda Mulla & Andrew O Hopper

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Correspondence to Gordon G Power or Mark T Gladwin.

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Hunter, C., Dejam, A., Blood, A. et al. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 10, 1122–1127 (2004). https://doi.org/10.1038/nm1109

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