title: Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator.
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 ( approximately 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.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1662, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hunter
authors.forename: André
authors.initials: A
authors.lastname: Dejam
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
authors.forename: Howard
authors.initials: H
authors.lastname: Shields
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Kim-Shapiro
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Selamawit
authors.initials: S
authors.lastname: Tarekegn
authors.forename: Neda
authors.initials: N
authors.lastname: Mulla
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Hopper
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Power
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D002302:Cardiac Output; D004195:Disease Models, Animal; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000188:drug therapy*; D007231:Infant, Newborn; D008706:Methemoglobin / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D010547:Persistent Fetal Circulation Syndrome / Q000188:drug therapy*; D012756:Sheep; D012977:Sodium Nitrite / Q000008:administration & dosage / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000336:Aerosols; D006454:Hemoglobins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C100003:deoxyhemoglobin; D008706:Methemoglobin; D012977:Sodium Nitrite; D010100:Oxygen