Effect of Hemoglobin-Based Blood Substitutes on Nitric Oxide Transport: Mathematical Models

Abstract

Summary Nitric oxide is potent vasodilator acting through activation of soluble guanylate cyclase in the smooth muscle cells. Scavenging of free nitric oxide (NO) by hemoglobin-based oxygen carriers (HBOCs) is considered a major cause of vasoconstriction following transfusion with HBOC used as blood substitutes. However, direct measurements of NO concentration in the microvessels are limited and they are not available in the presence of HBOC. To gain a quantitative understanding of the effects of NO, we formulated several mathematical models to systematically investigate the transport of NO around microvessels in the presence of HBOC and its dependence on such factors as free-Hb concentration, HBOC reactivity with NO, shear-stress dependent rate of NO release by endothelium and free-Hb extravasation. The calculations predict a strong effect of HBOC extravasation and reactivity, but only a moderate effect of wall shear stress. The predicted NO concentration falls several-fold from its physiological level when HBOC is introduced. We analyzed the transport resistance in and around the red blood cell since it is a determining factor on the luminal NO consumption. Using similar approach, we also investigated NO transport characteristics of phospholipid vesicles encapsulating Hb introduced recently as the next generation of blood substitutes.