The Biological Chemistry of Nitric Oxide as It Pertains to the Extrapulmonary Effects of Inhaled Nitric Oxide

Abstract

The chemical properties of nitric oxide (NO) have been studied for over 200 years. However, it is only within the last 20 years that the biological implications of this chemistry have been considered. The classical model of NO action within the vasculature centers on production in the endothelium, diffusion to the smooth muscle, and subsequent activation of guanylate cyclase via binding to its heme iron. In the context of this model, it is difficult to conceptualize extrapulmonary effects of inhaled NO. However, NO possesses complex redox chemistry and is capable of forming a range of nitrogen oxide species and is therefore capable of interacting with a variety of biomolecules. Of particular interest is its reaction with reduced cysteine to form an S-nitrosothiol (SNO). SNOs are formed throughout NO biology and are a post-translational modification that has been shown to regulate many proteins under physiologic conditions. Hemoglobin, which was considered to be solely a consumer of NO, can form SNO in a conformationally dependent manner, which allows for the transport of inhaled NO beyond the realm of the lung. Higher oxides of nitrogen are capable of modifying proteins via nitration of tyrosines, which has been shown to occur under pathologic conditions. By virtue of its redox reactivity, one can appreciate that inhaled NO has a variety of routes by which it can act and that these routes may lead to extrapulmonary effects. Keywords: lung; nitric oxide; nitrotyrosine; S-nitrosothiol BIOCHEMICAL HISTORY OF NITRIC OXIDEThe history of chemical experimentation with nitrogen oxides traces back to Priestley's original experiments with the "gaseous oxide of azote" (1). Subsequently, Sir Humphry Davy performed the first biological experiments with NO, termed "nitrous air," while examining the effects of various gases on respiration and the circulatory system (2). Davy noticed that inhaling nitric oxide (NO)-containing gases caused animals "to die infinitely sooner than in common air or oxygen: but not nearly so short a time as in gases incapable of effecting positive changes in the venous blood." Davy noted that tissues from these animals were "purple red" in color, consistent with the formation of nitrosylheme within the periphery. It is fair to say that Humphry Davy, among his many other great achievements, was the first to discover an extrapulmonary effect of NO.Nearly 200 years later, the Nobel Prize in Physiology or Medicine was awarded for the discovery of the endothelium-derived relaxing factor and its identification as NO (3). The award recognized three seminal experiments: (1 ) the discovery that NO activated guanylate cyclase to induce smooth muscle cell relaxation (4), (2 ) the observation that the endothelium released a diffusible factor that was responsible for acetylcholine-mediated relaxation of blood vessels (5), and (3 ) the identification of the released factor as NO by spectroscopic examination of reaction products with hemoglobin (6). Along with the identification of NO synthase (NOS), these experime...

Transport rather than diffusion-dependent route for nitric oxide gas activity in alveolar epithelium

“…This was true for NO and ENO gases, as well as in vitro incubation with GSNO or spermine NONOate in the apical buffer. These findings add to the growing body of evidence that contradicts the idea that NO passively diffuses in biological systems in order to activate guanylyl cyclase [20] and to form other biologically relevant adducts like SNO [21]. Instead, our observations demonstrate that the major gateway for NO gas entry to alveolar epithelium sufficient to achieve biologically relevant signaling is via LAT rather than simple diffusion.…”

Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics

“…The negative association between BMI and exhaled NO does not necessarily imply that increasing BMI leads to less airway inflammation; it could imply however, that increasing BMI could lead to changes in baseline airway NO redox metabolism, through an increase in baseline airway oxidative stress. In the presence of increased reactive oxygen species, airway NO can be readily converted into reactive nitrogen species (RNS) [33]. Because the total measured exhaled NO is the end product of NO produced – NO consumed, an increase in the RNS/NO ratio would result in lower measured exhaled NO levels [34].…”

Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins

“…Heme is also an essential component of enzymes or allosteric proteins such as certain catalases, peroxidases, and cytochromes. A heme molecule contains a porphyrin ring and a single atom of iron that can combine with small gas molecules, including oxygen, nitric oxide (NO), and carbon monoxide [2,3]. In cases of destruction of erythrocytes (e.g., hemolysis) and enucleation of erythroblasts, which are accompanied by the release and metabolization of hemoglobin, heme is released into extracellular fluids.…”