Nature Medicine
10, 1122 - 1127 (2004)
Published online: 12 September 2004; | doi:10.1038/nm1109
Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilatorChristian J Hunter1, 2, 3, 4, André Dejam3, Arlin B Blood4, Howard Shields5, Daniel B Kim-Shapiro5, Roberto F Machado1, 2, 3, Selamawit Tarekegn1, Neda Mulla6, Andrew O Hopper6, Alan N Schechter3, Gordon G Power4, 7
& Mark T Gladwin1, 2, 3, 71
Critical Care Medicine Department, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1662, USA. 2
Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1662, USA. 3
Laboratory of Chemical Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892-1662, USA. 4
Center for Perinatal Biology, Department of Physiology, Loma Linda University School of Medicine, 11234 Anderson Drive, Loma Linda, California 92350, USA. 5
Department of Physics, Wake Forest University, 1834 Gulley Drive, Winston-Salem, North Carolina 27109-7507, USA. 6
Department of Pediatrics, Loma Linda University School of Medicine, 11234 Anderson Drive, Loma Linda, California 92350, USA. 7
These two authors contributed equally to this work.
Correspondence should be addressed to Gordon G Power gpower@som.llu.edu or Mark T Gladwin mgladwin@nih.govThe 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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