A mathematical model for the role of N 2 O 3 in enhancing nitric oxide bioavailability following nitrite infusion

Abstract

Nitrite infusion into the bloodstream has been shown to elicit vasodilation and protect against ischemia-reperfusion injury through nitric oxide (NO) release in hypoxic conditions. However, the mechanism by which nitrite-derived NO escapes scavenging by hemoglobin in the erythrocyte has not been fully elucidated, owing in part to the difficulty in measuring the reactions and transport on NO in vivo. We developed a mathematical model for an arteriole and surrounding tissue to examine the hypothesis that dinitrogen trioxide (N2O3) acts as a stable intermediate for preserving NO. Our simulations predict that with hypoxia and moderate nitrite concentrations, the N2O3 pathway can significantly preserve the NO produced by hemoglobin nitrite reductase in the erythrocyte and elevate NO reaching the smooth muscle cells. Nitrite retains its ability to increase NO bioavailability even at varying flow conditions, but there is minimal effect under normoxia or very low nitrite concentrations. Our model demonstrates a viable pathway for reconciling experimental findings of potentially beneficial effects of nitrite infusions despite previous models showing negligible NO elevation associated with hemoglobin nitrite reductase. Our results suggest that additional mechanisms may be needed to explain the efficacy of nitrite-induced vasodilation at low infusion concentrations.

Novel loci and a role for nitric oxide for seed dormancy and preharvest sprouting in barley

“…Release of NO was estimated via its main autoxidation product dinitrogen trioxide (N 2 O 3 ; Y. Liu, Buerk, Barbee, & Jaron, ; Planchet & Kaiser, ). This assay is suitable for quantitative assessment of this unstable, volatile compound in large samples such as whole seeds and for applications requiring differential quantification of many different samples.…”

A dynamic computational network model for the role of nitric oxide and the myogenic response in microvascular flow regulation

“…There are a number of other factors affecting the myogenic response and NO‐O 2 transport that are a potential area of future research and expansion of our model. RBC profiles, NO production from other NOS isoforms, and compensatory nitrite‐derived blood and tissue pathways under hypoxia have been studied previously and shown to have significant effect of elevating SMC NO under certain conditions. Exchange from neighboring vessels, such as an arteriole‐venule countercurrent pair, has also been shown to potentially elevate arteriole NO .…”

Nitric oxide release by deoxymyoglobin nitrite reduction during cardiac ischemia: A mathematical model

“…Coupled NO-O 2 transport models have been developed previously by us (Chen, 2006; Lamkin-Kennard et al, 2004; Liu et al, 2016) and others (Kavdia et al, 2002; Tsoukias, 2008) and our approach here is similar. Endothelial nitric oxide synthase (eNOS) in layer 3 was assumed to uniformly produce NO with a linear shear stress dependence and O 2 -dependent Michaelis-Menten kinetics (Eq.…”

“…Coupled nonlinear partial differential equations were written in cylindrical coordinates and solved for steady-state conditions by finite element numerical methods using the software COMSOL v5.1 (COMSOL, Inc., Burlington, MA), similar to our previous approach (Buerk et al, 2011; Liu et al, 2016). The model has concentric cylindrical layers: (i) red blood cell (RBC) core, (ii) a RBC-free plasma layer, (iii) endothelium, (iv) vascular wall, and (v) perivascular cardiac tissue (Fig.…”

“…The NO producing capabilities of cardiac Mb have previously been estimated using simple reaction kinetics calculations (Kim-Shapiro and Gladwin, 2014), without considering the effect of mass transport inside an arteriole environment. We have previously modeled (Liu et al, 2016) the effect of the deoxyhemoglobin nitrite reductase pathway on blood nitrite, but the deoxymyoglobin pathway is active on tissue nitrite and has different reaction kinetics. There is a need for mathematical models to analyze this scavenger and producer mechanism of myoglobin to explain the experimental effectiveness of cardiac tissue nitrite in releasing NO under ischemic conditions.…”