A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers.

Adriano R Tonelli,Batool Abuhalimeh,Mostafa K Ahmed,Raed A Dweik,Stephen C Rogers,David Timm,Allan Doctor,Benjamin Gaston,Kulwant S Aulak,Alfred Hausladen,Charlie J Casa,Joseph Alan Bauer

doi:10.1371/journal.pone.0221777

Abstract

RationaleInhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked.ObjectivesWe investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response.FindingsWe enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86–118) and 114 (87–129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104–170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3–5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively).ConclusionsBoth nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature.

Highlights

Over the past years the role of nitric oxide (NO) in biology has increased tremendously and is involved in diverse functions such as bacterial defense, neurotransmission and reproduction [1,2,3,4]
Volunteers were in excellent general health and underwent a detailed evaluation to rule out smoking or conditions that could affect the NO metabolism or cutaneous microcirculation
We observed a significant increase in nitrite (median (IQR) difference of 7 (-2 –+19) %, p = 0.048), total red blood cells (RBC) NO (29 (-12 –+111) %, p = 0.02) and selectively remove thiol bound NO (SNO)-Hb (median (IQR) difference of 59 (-15 - +282) %, p = 0.02) during NO inhalation compared to baseline

Summary

Introduction

Over the past years the role of NO in biology has increased tremendously and is involved in diverse functions such as bacterial defense, neurotransmission and reproduction [1,2,3,4]. NO is a highly diffusible gas synthesized by a group of nitric oxide synthases (NOS) [5]. It was identified in 1980s and initially referred as endothelium-dependent relaxation factor [6,7,8]. Three isoforms of NOS exist but the endothelial NOS (type 3 NOS) generates NO in the pulmonary vascular bed [9]. NO diffuses to adjacent cells [10]. NO can be rapidly oxidized to nitrate (NO3-) and nitrite (NO2-) [13], or taken by hemoglobin (Hb) to form nitrosyl-Hb (Hb:[Fe]NO) or S-nitrosothiol-Hb (SNO-Hb) [14]

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