Hemoglobin-based red blood cell substitutes and nitric oxide

Abstract

Hemoglobin-based oxygen carriers (HBOCs) have been studied for decades as red blood cell substitutes. Profound vasoconstrictor effects have limited the clinical utility of HBOCs and are attributable to avid scavenging of nitric oxide (NO). Inhaling NO can charge the body's stores of NO metabolites without producing hypotension and can prevent systemic hypertension induced when HBOCs are subsequently infused. Concurrent breathing of low NO doses can prevent pulmonary vasoconstriction after HBOC infusion without augmenting plasma methemoglobinemia.

Figure 1

The optimal dimension of artificial oxygen carriers. The upper limit of 10 μm in particle diameter is to prevent capillary plugging and for the sterilization by membrane filters. Small particles (<10 nm in diameter) have high rates of renal excretion and vascular wall permeabilities with side effects such as hypertension and neurological disturbances. (Figure was modified from Sakai et al, 2007; reprinted with permission from Sakai H, et al. J Intern Med 2007;263:4-15)

Figure 2

(A) In WT mice, tail-cuff SBP (mmHg) was measured before and after i.v. infusion of whole blood (n=7), murine tetrameric Hb (n=5), or HBOC-201 (n=5). *P<0.001 differs versus whole blood infusion group. (B) In NOS3^−/− mice, SBP was measured before and after i.v. infusion of whole blood (n=5), murine tetrameric Hb (n=5), or HBOC-201 (n=5). There was no increase of SBP after infusion of murine tetrameric Hb or HBOC-201. (Reprinted with permission from Yu B, et al. Circulation 2008;117:1982-1990)

Figure 3

(A) Mean arterial pressure (MAP), (B) mean pulmonary arterial pressure (PAP), (C) systemic vascular resistance (SVR), (D) pulmonary vascular resistance (PVR), (E) Cardiac output, and (F) plasma methemoglobin concentration of awake lambs after infusion of autologous whole blood (n=6), intravenous HBOC-201 (n=5), or HBOC-201 after pretreatment by breathing 80 ppm NO for 1 h followed by continuously breathing 5 ppm NO for 2 h (high/low NO, n=6). *P<0.05 HBOC-201 differs from autologous whole blood and from HBOC-201 after high/low inhaled NO, †P<0.05 autologous whole blood differs from HBOC-201 with or without high/low inhaled NO, ‡P<0.05 HBOC-201 differs from autologous whole blood, §P<0.05 differs from autologous whole blood and HBOC-201. (Reprinted with permission from Yu B, et al. Anesthesiology 2009;110:113-122)