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.

Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

“…has shown efficacy in reducing pulmonary pressures and preventing right ventricular hypertrophy (19)(20)(21). More recent work has demonstrated that acute IV administration of nitrite improves exercise capacity in patients with HFpEF, a group at high risk for secondary (Group 2) PH (22).…”

The Reaction between Nitrite and Oxyhemoglobin

“…The mechanism of nitrite-dependent oxidation of deoxyhemoglobin (deoxyHb) 2 under anaerobic conditions, and its physiological potential in hypoxic vasodilation has recently been established (3)(4)(5). However, the mechanism of reaction between oxyhemoglobin (oxyHb) and nitrite has not yet been fully elucidated.…”

Nitrate and Nitrite Electrocatalytic Reduction at Layer-by-Layer Films Composed of Dawson-type Heteropolyanions Mono-substituted with Transitional Metal Ions and Silver Nanoparticles

“…In particular, being the main source of the drinking water, ground waters are characterized worldwide as having increased nitrate concentration [6]. Being extensively used in industrial [7] and biomedical applications [8][9][10], nitrite is one of the most reactive substances in the nitrogen cycle and has a significant toxicity for humans, being the main cause of blue baby syndrome [11]. Consumed nitrate is also reduced to nitrite by enteric bacteria, which might subsequently lead to serious health risks [12,13].…”