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

Christian J. Hunter, André Dejam, Arlin B. Blood, Howard Shields, Daniel B. Kim-Shapiro, Roberto Machado, Selamawit Tarekegn, Neda Mulla, Andrew O. Hopper, Alan N. Schechter, Gordon G. Power, Mark T. Gladwin

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins. 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 hypoxemia. 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.

Original languageEnglish (US)
Pages (from-to)1122-1127
Number of pages6
JournalNature Medicine
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

Fingerprint

Nitrites
Vasodilator Agents
Nitric Oxide
Pulmonary Hypertension
Lung
Vasodilation
Blood
Gases
Sodium Nitrite
Hemeproteins
Methemoglobin
Protonation
Vasoconstriction
Aerosols
Heme
Inhalation
Anions
Hemoglobins
Hypoxia
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hunter, C. J., Dejam, A., Blood, A. B., Shields, H., Kim-Shapiro, D. B., Machado, R., ... Gladwin, M. T. (2004). Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nature Medicine, 10(10), 1122-1127. https://doi.org/10.1038/nm1109

Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. / Hunter, Christian J.; Dejam, André; Blood, Arlin B.; Shields, Howard; Kim-Shapiro, Daniel B.; Machado, Roberto; Tarekegn, Selamawit; Mulla, Neda; Hopper, Andrew O.; Schechter, Alan N.; Power, Gordon G.; Gladwin, Mark T.

In: Nature Medicine, Vol. 10, No. 10, 01.10.2004, p. 1122-1127.

Research output: Contribution to journalArticle

Hunter, CJ, Dejam, A, Blood, AB, Shields, H, Kim-Shapiro, DB, Machado, R, Tarekegn, S, Mulla, N, Hopper, AO, Schechter, AN, Power, GG & Gladwin, MT 2004, 'Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator', Nature Medicine, vol. 10, no. 10, pp. 1122-1127. https://doi.org/10.1038/nm1109
Hunter, Christian J. ; Dejam, André ; Blood, Arlin B. ; Shields, Howard ; Kim-Shapiro, Daniel B. ; Machado, Roberto ; Tarekegn, Selamawit ; Mulla, Neda ; Hopper, Andrew O. ; Schechter, Alan N. ; Power, Gordon G. ; Gladwin, Mark T. / Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. In: Nature Medicine. 2004 ; Vol. 10, No. 10. pp. 1122-1127.
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