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

Abstract

Interactions between cardiac myoglobin (Mb), nitrite, and nitric oxide (NO) are vital in regulating O2 storage, transport, and NO homeostasis. Production of NO through the reduction of endogenous myocardial nitrite by deoxygenated myoglobin has been shown to significantly reduce myocardial infarction damage and ischemic injury. We developed a mathematical model for a cardiac arteriole and surrounding myocardium to examine the hypothesis that myoglobin switches functions from being a strong NO scavenger to an NO producer via the deoxymyoglobin nitrite reductase pathway. Our results predict that under ischemic conditions of flow, blood oxygen level, and tissue pH, deoxyMb nitrite reduction significantly elevates tissue and smooth muscle cell NO. The size of the effect is consistent at different flow rates, increases with decreasing blood oxygen and tissue pH and, in extreme pathophysiological conditions, NO can even be elevated above the normoxic levels. Our simulations suggest that cardiac deoxyMb nitrite reduction is a plausible mechanism for preserving or enhancing NO levels using endogenous nitrite despite the rate-limiting O2 levels for endothelial NO production. This NO could then be responsible for mitigating deleterious effects under ischemic conditions.

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 .…”

“…The pressure drop for upstream vessels was assumed to be 15 mm Hg (eg, a MAP of 100 mm Hg results in an entrance pressure of 85 mm Hg), and the downstream vessels were kept at a constant venule pressure of 5 mm Hg . Each vessel class (small artery, large arteriole, intermediate arteriole, and small arteriole) was then modeled at the vessel scale in cylindrical coordinates as simple concentric layers to predict NO‐O 2 interactions, similar to our previous approach . The myogenic response model was then adapted to predict how R NO affects SMC NO concentrations and vessel diameters.…”

“…5,16 Each vessel class (small artery, large arteriole, intermediate arteriole, and small arteriole) was then modeled at the vessel scale in cylindrical coordinates as simple concentric layers to predict NO-O 2 interactions, similar to our previous approach. 17 The myogenic response model was then adapted to predict how R NO affects SMC NO concentrations and vessel diameters. The vessel mass transport equations were then coupled to the myogenic response model under various conditions of MAP, O 2 , and R NO to predict the effect of pressure and flow perturbations on the dynamic response of individual blood vessels and the total network.…”

“…There is a need for mathematical simulations to quantify the effect of NO on vasoactivity and pressure-flow dynamics in microcirculatory networks. For this purpose, we have modified Carlson and Secomb's myogenic response model to incorporate NO-O 2 interactions that were developed for our previous mass transport models 9,13,14,17 to predict how vascular tone and vessel diameter depend on the rate of NO production and SMC NO bioavailability. This model allows us to simulate the effects of NO deficiencies, through both changing blood flow and blood PO 2 , on the vasodilatory capabilities of resistance vessels.…”

The Innate Immune Response to Ischemic Injury: a Multiscale Modeling Perspective

“…There is evidence that nitric oxide can mitigate the negative effects of reperfusion, which is explored through mathematical modeling in [50,51]. Other studies have focused on tissue-level phenomena such as hyperplasia formation or the effects of tissue oxygenation [52][53][54][55], or the mechanics of platelet deposition [56,57].…”