Simulation of NO and O2 transport facilitated by polymerized hemoglobin solutions in an arteriole that takes into account wall shear stress-induced NO production

Abstract

A mathematical model was developed to study nitric oxide (NO) and oxygen (O2) transport in an arteriole and surrounding tissues exposed to a mixture of red blood cells (RBCs) and hemoglobin (Hb)-based O2 carriers (HBOCs). A unique feature of this model is the inclusion of blood vessel wall shear stress-induced production of endothelial-derived NO, which is very sensitive to the viscosity of the RBC and HBOC mixture traversing the blood vessel lumen. Therefore in this study, a series of polymerized bovine Hb (PolyHb) solutions with high viscosity, varying O2 affinity, NO dioxygenation rate constants and O2 dissociation rate constants that were previously synthesized and characterized by our group were evaluated via mathematical modeling, in order to investigate the effect of these biophysical properties on the transport of NO and O2 in an arteriole and its surrounding tissues subjected to anemia with the commercial HBOC Oxyglobin® and cell-free bovine Hb (bHb) serving as appropriate controls. The computer simulation results indicated that transfusion of high viscosity PolyHb solutions promoted blood vessel wall shear stress dependent generation of the vasodilator NO, especially in the blood vessel wall and should transport enough NO inside the smooth muscle layer to activate vasodilation compared to the commercial HBOC Oxyglobin® and cell-free bHb. However, NO scavenging in the arteriole lumen was unavoidable due to the intrinsic high NO dioxygenation rate constant of the HBOCs being studied. This study also observed that all PolyHbs could potentially improve tissue oxygenation under hypoxic conditions, while low O2 affinity PolyHbs were more effective in oxygenating tissues under normoxic conditions compared with high O2 affinity PolyHbs. In addition, all ultrahigh molecular weight PolyHbs displayed higher O2 transfer rates than the commercial HBOC Oxyglobin® and cell-free bHb. Therefore, these results suggest that ultrahigh molecular weight PolyHb solutions could be used as safe and efficacious O2 carriers for use in transfusion medicine. It also suggests that future generations of PolyHb solutions should possess lower NO dioxygenation reaction rate constants in order to reduce NO scavenging, while maintaining high solution viscosity to take advantage of wall shear stress-induced NO production. Taken together, we suggest that this mathematical model can be used to predict the vasoactivity of HBOCs and help guide the design and optimization of the next generation of HBOCs for use in transfusion medicine.

The quaternary state of polymerized human hemoglobin regulates oxygenation of breast cancer solid tumors: A theoretical and experimental study

“…However, the effect of wall shear stress changed at small blood vessel diameters. This likely is a result of variations in the RBC free plasma layer and velocity profile blunting that occurs within the simulated arteriole [ 47 , 48 ]. Previous studies have reported that shear stress is a modulator of angiogenesis [ 49 , 50 ].…”

Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood

“…However, O 2 delivered was mostly a function of blood flow and O 2 affinity for the acellular Hb. O 2 delivery to the tissues following a blood transfusion is significantly inferior to that of an HBOC transfusion, as acellular Hb enhances O 2 transport via facilitated O 2 diffusion of oxygenated-Hb (38, 39). The participation of an HBOC in O 2 delivery depends on the rate of diffusion of O 2 through the Hb solution, which is eightfold compared with plasma.…”

Polymerized Hemoglobin With Increased Molecular Size Reduces Toxicity in Healthy Guinea Pigs

“…NO scavenging occurs since oxyHb rapidly and irreversibly reacts with NO, producing oxidized Hb (metHb) and nitrate, a reaction that is normally buffered by the RBC membrane. O 2 oversupply occurs due to radial diffusion of HBOC molecules, as they are less restricted to the center of the vessel, which results in facilitated O 2 transport . Both NO scavenging and oversupply of O 2 cause vasoconstriction and hypertension, which are further exacerbated by the extravasation of acellular Hb into the perivascular space .…”

“…O 2 oversupply occurs due to radial diffusion of HBOC molecules, as they are less restricted to the center of the vessel, which results in facilitated O 2 transport. 9 Both NO scavenging and oversupply of O 2 cause vasoconstriction and hypertension, which are further exacerbated by the extravasation of acellular Hb into the perivascular space. 10 The vasoconstriction and hypertension observed with previous generations of HBOCs likely accounted for some of the injury observed in vital organs such as the kidney, liver, and spleen.…”